Novel biotechnologies : intervening in the brain Ilya Klabukov
This document from the Nuffield Council on Bioethics examines the ethical issues related to novel neurotechnologies that can intervene in the human brain. It discusses technologies like deep brain stimulation, transcranial magnetic stimulation, brain-computer interfaces, and neural stem cell therapies. The report analyzes the ethical considerations regarding how these technologies are developed, tested, regulated, and applied both for medical purposes and non-medical uses.
Ontology based support for brain tumour study Subhashis Das
The document discusses building an ontology to support brain tumor study. It begins with background on brain tumors and issues with current information retrieval systems. The author then explains why ontology was chosen as a solution and the methodology used, which included identifying terminology, analyzing, synthesizing, and standardizing terms. The ontology structure with top-level branches for tumor types, symptoms, causes, and treatments is described. Potential uses for physicians and researchers are discussed.
A Call to Action: Improving brain & mental health via digital platforms,...SharpBrains
(Session held at the 2014 SharpBrains Virtual Summit; October 28-30th, 2014)
8:15–9:45am. A Call to Action: Improving brain & mental health via digital platforms, neuroplasticity research and the White House BRAIN initiative
- Dr. Thomas Insel, Director of the National Institute of Mental Health (NIMH)
- Dr. Adam Gazzaley, Director of UCSF Neuroscience Imaging Center and Co-founder of Akili Interactive Labs
- Dr. Daphne Bavelier, Head of the Brain & Learning Lab at the University of Geneva & U. of Rochester
- Jack Young, Head of Qualcomm Life Fund
- Chair: Alvaro Fernandez, CEO of SharpBrains
Learn more here:
http://sharpbrains.com/summit-2014/agenda/
This document discusses a Turing machine theory approach to developing a new therapeutic strategy for some spinal cord and brain conditions using depurative, toxicological, and pharmacological methods. It reviews literature on neurodegenerative diseases and toxic accumulation in the brain and spinal cord. The document suggests developing a conceptual map to translate needs into a practical hypothesis. It examines questions about the roles of the immune system and brain waste removal systems in neurodegeneration and toxic accumulation in different brain regions.
1) The document discusses the research of Dr. Adriana Bora into biomarkers for neurological disorders like HIV-associated neurological disorders (HAND) and autism spectrum disorder (ASD) using "omics" tools.
2) Her current research at Johns Hopkins has led to the discovery of novel protein biomarkers for early diagnosis of HAND. She is investigating molecular pathways affected by HIV in the brain using bioinformatics.
3) Working with Dr. Dejan Budimirovic, she is exploring the role of neuropeptides in ASD metabolism and developing assays to detect signature brain peptides in cerebral spinal fluid as potential ASD biomarkers.
Eukaryotic cells have their genetic material in the nucleus, in the other side, prokaryotes have it dispersed in the cytoplasm.
From this DNA will be synthesized RNA, which will act as an intermediary, carrying genetic information from the nucleus to the ribosomes located in the cytoplasm to carry out protein synthesis.
genetic code consists of 64 triplets (codons) of nucleotides, each codon encodes for one of the 20 amino-acids used in the synthesis of proteins.
The study of the genetic code, allow s us identify mutations in specific genes, to detect diseases or predispositions to some pathologies such as those proposed by the articles, and with tan information, implement a PREVENTIVE MEDICINE.
Knowing the sequence of genes that cause certain genetic diseases, is essential for GENE THERAPY branch. In brief it consist in introduce a correct copy of the defective gene that was visualized into the cells, by some vectors, previously studied.
With the knowledge of genetic information, can be provided counseling before and after pregnancy to future parents (Give information about the diseases to which it is susceptible and existing treatments), having always instilled an ethical principle: THE HUMAN LIFE RESPECT.
Promote investigation in medicine basic areas, such as cell biology, molecular biology, biochemistry and pharmacology, with the aim of implement humanity solutions .
This document discusses several key themes in neuroethics:
1) Neuroethics examines the social and ethical issues that arise from the intersection of neuroscience and society, such as how neuroscience may impact ideas of free will, personal responsibility, and human identity.
2) Rapid advances in neuroscience technologies like brain imaging raise issues regarding privacy, coercion, and the appropriate uses of such technologies.
3) A deeper scientific understanding of the biological basis of human cognition and behavior challenges traditional concepts of human nature, personality, and the relationship between mind, brain, and personal identity.
This document discusses a proposed theory using Turing machines to develop a new therapeutic strategy for treating some spinal cord and brain conditions using a depurative-toxicological-pharmacological approach. It reviews literature on neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS to understand common pathological mechanisms involving accumulation of toxic metabolic byproducts that the central nervous system lacks efficient means of removing. The theory aims to translate these insights into a practical hypothesis for reducing or delaying disease progression. The document also summarizes findings from studies showing cerebrospinal fluid from progressive multiple sclerosis patients causes mitochondrial dysfunction in neurons, identifying a potential biological mechanism and therapeutic target for progressive forms of the disease.
Cell Culture Techniques (Michael Aschner, Lucio Costa) (Z-Library).pdfsymbssglmr
This document provides prefaces and contributor information for the book "Cell Culture Techniques, Second Edition". The prefaces discuss the Neuromethods series focusing on tools and techniques for investigating the nervous system. The book aims to provide technical protocols as well as theoretical background to help readers understand the origins and potential developments of the techniques. The contributors section lists researchers who contributed chapters applying specific neuroscience methods and models.
1. Renick Lee took on a final year project with the Singapore Institute for Neurotechnology (SINAPSE) to study schizophrenia, the institute's first probe into this severe mental disorder.
2. His project used brain imaging techniques like structural MRI and diffusion tensor imaging to examine structural differences in brain networks between schizophrenia patients and healthy controls.
3. Preliminary findings revealed compromised brain networks in patients, which if validated could serve as a potential biomarker for further understanding the illness's progress and informing new therapies.
The document provides an overview of recent advances in bioinformatics research in the United States, highlighting developments in computational algorithms, machine learning, and multi-omics integration. It discusses new algorithms developed at Stanford University and Harvard University for protein structure prediction and single-cell RNA sequencing analysis. Advances in machine learning at UCSF, MIT, and UCSD for drug response prediction, biological graph generation, and signaling pathway mapping are also outlined. The integration of genomic, proteomic, and other omics data to improve understanding of biological systems is also mentioned.
Biotecnika Times newspaper Dated 1st Jan 2018shekhar suman
Researchers at the Scripps Research Institute have solved the structure of the Piezo1 protein, which is responsible for the sense of touch. Piezo1 converts physical stimuli like touch or blood flow into chemical signals. Understanding the structure of Piezo1 provides insight into how proteins sense mechanical force and which regions can be targeted with drugs. The findings shed light on the fundamental process of touch sensation and may help develop treatments for conditions caused by Piezo1 malfunctions.
Dr. Adriana Bora is submitting a research proposal to the Society for Neuroscience for the Peter and Patricia Gruber International Research Award, supported by the Gruber Foundation. Her proposal focuses on developing novel clinical assays using functional peptidomics/metabolomics to better understand and monitor the different stages of HIV-associated neurological disorders in patients, even those receiving antiretroviral therapy. She has previously identified important glycoproteins and biomakers in cerebral spinal fluid that are involved in various pathways impacted by HIV in the brain. Her future research aims to identify alternative pathways and routes used by HIV to alter brain metabolism and cause impairment, which could lead to more personalized treatment approaches for HAND patients.
Breakthrough Method for Mapping Brain Epigenomes | The Lifesciences MagazineThe Lifesciences Magazine
Researchers at the College of Engineering have made significant strides in brain research by developing a cost-effective method for spatially characterizing and mapping brain epigenomes.
This document discusses biomarkers for epileptogenesis and the challenges in developing clinically useful biomarkers to predict epilepsy risk, progression, and treatment response. It notes that while many potential biomarkers have been identified in preclinical studies, none have translated to clinical use. Some key challenges include the long timescales between injury and seizures, heterogeneity of epilepsy types and patients, and a focus on retrospective studies in refractory epilepsy patients rather than prospective validation. The document argues that combinatorial biomarkers analyzing multiple mechanisms may be more promising than single biomarkers, and that biomarkers should be validated as direct measures of patient outcomes rather than relying solely on seizure occurrence.
This document discusses harnessing the power of teams and networks to build better models of disease in real time. It notes that new technologies now allow the generation of massive amounts of human omics data and emerging network modeling approaches for diseases. Cloud computing infrastructure allows a generative open approach to biomedical problem solving. A nascent movement aims to give patients more control over their sensitive health information to facilitate sharing. Open social media also allows experts and citizens to collaborate to solve biomedical problems. The overall opportunity is to conduct more open, collaborative biomedical research involving diverse teams.
K Bobyk - %22A Primer on Personalized Medicine - The Imminent Systemic Shift%...Kostyantyn Bobyk
This newsletter discusses various topics related to science and healthcare. It provides information on free smartphone apps that can help with work, personalized medicine and the shift towards more tailored healthcare, the science and policy around marijuana, potential for an NIH equipment library, and a conference for NIDDK fellows. The conference will feature keynote speakers and discuss various research topics, with the goal of networking and career development for fellows.
In medical technologies, the potential of mRNA is thought to extend beyond the realm of vaccinations. Since mRNA can code for almost any protein, the same basic technique could theoretically pave the way for the creation of an enormous number of therapeutic interventions, each of which would work in much the same way as medicine.
Leroy Hood biomedical challenges at Skolkovoigorod
This document discusses biomedical challenges at Skolkovo and outlines several questions around the types of science and partnerships that will be involved. It discusses whether the initiatives will include both non-profit and for-profit organizations, and how to attract existing companies and enable new company creation. It also questions whether the funds will compete with other Russian science programs and if academic science in Russia will be reformed to align with the Skolkovo initiative. Overall, the document explores how to structure the biomedical programs and partnerships at Skolkovo across non-profit and for-profit organizations.
Stem cell research in Sweden has significant potential for healthcare advances and business opportunities. The country has a leading position in this field due to its scientific expertise, favorable regulatory environment, and resources to support commercialization. Major research institutions in Sweden are making breakthrough discoveries in areas such as neural stem cells that could lead to new treatments for conditions like Parkinson's disease.
Similar to ACROBioscience's Aneuro: An Overview of Neuroscience Research (20)
The document discusses SLAS (Society for Laboratory Automation and Screening), its role in connecting the life sciences sector, and the importance of collaboration. Key points include:
- SLAS is an international professional society with over 16,000 members that aims to advance life sciences research through education, content, and connecting its community.
- The COVID-19 pandemic accelerated the need for lab automation and highlighted the importance of innovating research methods. It also increased openness to collaboration between sectors.
- In-person scientific conferences are critical for SLAS as they foster important interactions and idea sharing that virtual formats cannot replace.
- Collaboration between academia, industry, and government is key to accelerating
Reach New Audiences, Generate Better Leads.
Learn how AZoNetwork Webinar production takes care of all the most stressful aspects of creating an effective virtual event, leaving you to do what you do best: talk about your product and how it helps your target audience.
This podcast episode discusses several topics including the importance of role models in engineering on International Women in Engineering Day, growing a marketing department from the ground up, building relationships with prospects on social media, answering questions about social media content creation in science and engineering industries, applying neuroscience techniques to marketing messages, how CEOs use social media to enhance leadership, tips for growing a personal network, Google's E-A-T algorithm and featured snippets, how relationship marketing can provide short and long term opportunities, and the importance of B2B branding and experiences with managing a company rebrand.
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
just download it to see!
Keys of Identification for Indian Wood: A Seminar ReportGurjant Singh
Identifying Indian wood involves recognizing key characteristics such as grain patterns, color, texture, hardness, and specific anatomical features. These identification keys include observing the wood's pores, growth rings, and resin canals, as well as its scent and weight. Understanding these features is essential for accurate wood identification, which is crucial for various applications in carpentry, furniture making, and conservation.
Additionally, the application of Convolutional Neural Networks (CNN) in wood identification has revolutionized this field. CNNs can analyze images of wood samples to identify species with high accuracy by learning and recognizing intricate patterns and features. This technological advancement not only enhances the precision of wood identification but also accelerates the process, making it more efficient for industry professionals and researchers alike.
This an presentation about electrostatic force. This topic is from class 8 Force and Pressure lesson from ncert . I think this might be helpful for you. In this presentation there are 4 content they are Introduction, types, examples and demonstration. The demonstration should be done by yourself
Testing the Son of God Hypothesis (Jesus Christ)Robert Luk
Instead of answering the God hypothesis, we investigate the Son of God hypothesis. We developed our own methodology to deal with existential statements instead of universal statements unlike science. We discuss the existence of the supernaturals and found that there are strong evidence for it. Given that supernatural exists, we report on miracles investigated in the past related to the Son of God. A Bayesian methodology is used to calculate the combined degree of belief of the Son of God Hypothesis. We also report the testing of occurrences of words/numbers in the Bible to suggest the likelihood of some special numbers occurring, supporting the Son of God Hypothesis. We also have a table showing the past occurrences of miracles in hundred year periods for about 1000 years. Miracles that we have looked at include Shroud of Turin, Eucharistic Miracles, Marian Apparitions, Incorruptible Corpses, etc.
El Nuevo Cohete Ariane de la Agencia Espacial Europea-6_Media-Kit_english.pdfChamps Elysee Roldan
Europe must have autonomous access to space to realise its ambitions on the world stage and
promote knowledge and prosperity.
Space is a natural extension of our home planet and forms an integral part of the infrastructure
that is vital to daily life on Earth. Europe must assert its rightful place in space to ensure its
citizens thrive.
As the world’s second-largest economy, Europe must ensure it has secure and autonomous access to
space, so it does not depend on the capabilities and priorities of other nations.
Europe’s longstanding expertise in launching spacecraft and satellites has been a driving force behind
its 60 years of successful space cooperation.
In a world where everyday life – from connectivity to navigation, climate and weather – relies on
space, the ability to launch independently is more important than ever before. With the launch of
Ariane 6, Europe is not just sending a rocket into the sky, we are asserting our place among the
world’s spacefaring nations.
ESA’s Ariane 6 rocket succeeds Ariane 5, the most dependable and competitive launcher for decades.
The first Ariane rocket was launched in 1979 from Europe’s Spaceport in French Guiana and Ariane 6 will continue the adventure.
Putting Europe at the forefront of space transportation for nearly 45 years, Ariane is a triumph of engineering and the prize of great European industrial and political
cooperation. Ariane 1 gave way to more powerful versions 2, 3 and 4. Ariane 5 served as one of the world’s premier heavy-lift rockets, putting single or multiple
payloads into orbit – the cargo and instruments being launched – and sent a series of iconic scientific missions to deep space.
The decision to start developing Ariane 6 was taken in 2014 to respond to the continued need to have independent access to space, while offering efficient
commercial launch services in a fast-changing market.
ESA, with its Member States and industrial partners led by ArianeGroup, is developing new technologies for new markets with Ariane 6. The versatility of Ariane 6
adds a whole new dimension to its very successful predecessors
A mature quasar at cosmic dawn revealed by JWST rest-frame infrared spectroscopySérgio Sacani
The rapid assembly of the first supermassive black holes is an enduring mystery. Until now, it was not known whether quasar ‘feeding’ structures (the ‘hot torus’) could assemble as fast as the smaller-scale quasar structures. We present JWST/MRS (rest-frame infrared) spectroscopic observations of the quasar J1120+0641 at z = 7.0848 (well within the epoch of reionization). The hot torus dust was clearly detected at λrest ≃ 1.3 μm, with a black-body temperature of
K, slightly elevated compared to similarly luminous quasars at lower redshifts. Importantly, the supermassive black hole mass of J1120+0641 based on the Hα line (accessible only with JWST), MBH = 1.52 ± 0.17 × 109 M⊙, is in good agreement with previous ground-based rest-frame ultraviolet Mg II measurements. Comparing the ratios of the Hα, Paα and Paβ emission lines to predictions from a simple one-phase Cloudy model, we find that they are consistent with originating from a common broad-line region with physical parameters that are consistent with lower-redshift quasars. Together, this implies that J1120+0641’s accretion structures must have assembled very quickly, as they appear fully ‘mature’ less than 760 Myr after the Big Bang.
The cryptoterrestrial hypothesis: A case for scientific openness to a conceal...Sérgio Sacani
Recent years have seen increasing public attention and indeed concern regarding Unidentified
Anomalous Phenomena (UAP). Hypotheses for such phenomena tend to fall into two classes: a
conventional terrestrial explanation (e.g., human-made technology), or an extraterrestrial explanation
(i.e., advanced civilizations from elsewhere in the cosmos). However, there is also a third minority
class of hypothesis: an unconventional terrestrial explanation, outside the prevailing consensus view of
the universe. This is the ultraterrestrial hypothesis, which includes as a subset the “cryptoterrestrial”
hypothesis, namely the notion that UAP may reflect activities of intelligent beings concealed in stealth
here on Earth (e.g., underground), and/or its near environs (e.g., the moon), and/or even “walking
among us” (e.g., passing as humans). Although this idea is likely to be regarded sceptically by most
scientists, such is the nature of some UAP that we argue this possibility should not be summarily
dismissed, and instead deserves genuine consideration in a spirit of epistemic humility and openness.
Ethical considerations play a crucial role in research, ensuring the protection of participants and the integrity of the study. Here are some subject-specific ethical issues that researchers need
Transmission Spectroscopy of the Habitable Zone Exoplanet LHS 1140 b with JWS...Sérgio Sacani
LHS 1140 b is the second-closest temperate transiting planet to the Earth with an equilibrium temperature low enough to support surface liquid water. At 1.730±0.025 R⊕, LHS 1140 b falls within
the radius valley separating H2-rich mini-Neptunes from rocky super-Earths. Recent mass and radius
revisions indicate a bulk density significantly lower than expected for an Earth-like rocky interior,
suggesting that LHS 1140 b could either be a mini-Neptune with a small envelope of hydrogen (∼0.1%
by mass) or a water world (9–19% water by mass). Atmospheric characterization through transmission
spectroscopy can readily discern between these two scenarios. Here, we present two JWST/NIRISS
transit observations of LHS 1140 b, one of which captures a serendipitous transit of LHS 1140 c. The
combined transmission spectrum of LHS 1140 b shows a telltale spectral signature of unocculted faculae (5.8 σ), covering ∼20% of the visible stellar surface. Besides faculae, our spectral retrieval analysis
reveals tentative evidence of residual spectral features, best-fit by Rayleigh scattering from an N2-
dominated atmosphere (2.3 σ), irrespective of the consideration of atmospheric hazes. We also show
through Global Climate Models (GCM) that H2-rich atmospheres of various compositions (100×, 300×,
1000×solar metallicity) are ruled out to >10 σ. The GCM calculations predict that water clouds form
below the transit photosphere, limiting their impact on transmission data. Our observations suggest
that LHS 1140 b is either airless or, more likely, surrounded by an atmosphere with a high mean molecular weight. Our tentative evidence of an N2-rich atmosphere provides strong motivation for future
transmission spectroscopy observations of LHS 1140 b.
Lunar Mobility Drivers and Needs - ArtemisSérgio Sacani
NASA’s new campaign of lunar exploration will see astronauts visiting sites of scientific or strategic
interest across the lunar surface, with a particular focus on the lunar South Pole region.[1] After landing
crew and cargo at these destinations, local mobility around landing sites will be key to movement of
cargo, logistics, science payloads, and more to maximize exploration returns.
NASA’s Moon to Mars Architecture Definition Document (ADD)[2] articulates the work needed to achieve
the agency’s human lunar exploration objectives by decomposing needs into use cases and functions.
Ongoing analysis of lunar exploration needs reveals demands that will drive future concepts and elements.
Recent analysis of integrated surface operations has shown that the transportation of cargo on the
surface from points of delivery to points of use will be particularly important. Exploration systems will
often need to support deployment of cargo in close proximity to other surface infrastructure. This cargo
can range from the crew logistics and consumables described in the 2023 “Lunar Logistics Drivers and
Needs” white paper,[3] to science and technology demonstrations, to large-scale infrastructure that
requires precision relocation.
ACROBioscience's Aneuro: An Overview of Neuroscience Research
2. 4 INSIGHTS FROM INDUSTRY
Unveiling Hidden Potential: Organoids
for Disease Modeling in Neuroscience
Research
13 WHITEPAPER
Using organoid culturing for
preclinical human disease models
18 WHITEPAPER
Discussing major hypotheses of
Alzheimer’s disease
25 WHITEPAPER
Combating Parkinson’s disease, the
second most common
neurodegenerative disease
33 WHITEPAPER
Pre-formed fibrils (PFFs) and the
modelling of neurodegenerative
diseases
42 WHITEPAPER
The pathology and epidemiology of
Amyotrophic Lateral Sclerosis (ALS)
49 WHITEPAPER
Multiple Sclerosis: Examining the
pathology, etiology, and potential
therapeutic drugs
T A B L E O F
C O N T E N T S
3. Aneuro offers a comprehensive panel
of high-quality proteins aiming to
provide researchers with the best tools
and valuable new ideas, facilitating
the acceleration of novel therapeutic
and diagnostic development.
Brain disorders are the leading cause of disability
and the second-highest source of mortality
worldwide.¹ Their impact on economic and social
outcomes surpasses that of cardiovascular disease
and cancer, with their global burden projected to
double by 2050.²
Due to their significant impact on global health,
the diagnosis and intervention of major brain-
related diseases are at the forefront of brain
research.³ This includes efforts to improve the
management of neurological conditions like
Parkinson’s disease and neuropsychiatric
conditions such as depression. ⁻ ⁴
The discovery of novel neuroscience biomarkers
and the mapping of entire neural networks has
inspired the innovation of new therapeutics.
However, the development of effective brain
therapies remains challenging.
The biological basis of brain disorders is not
understood completely, hindering the
development of effective therapies.⁴ Traditional
pharmacological treatments also prove
inadequate in addressing brain-related disorders.⁴
Finally, the scarcity of early diagnostic tools results
in clinically observable symptoms appearing only
in the advanced molecular stages of the disease.⁴
Aneuro offers products for various brain-related
disorders, including the following:
neurodegenerative diseases (Alzheimer's disease,
Parkinson’s disease, amyotrophic lateral sclerosis,
and Huntington’s disease), functional neurological
disorders (epilepsy, neuropathic pain),
neuropsychiatric disorders (depression, autism
spectrum disorder), neuroinflammatory diseases
(encephalitis, meningitis), neurovascular diseases
(stroke, subarachnoid hemorrhage), and structural
brain diseases (brain tumors and spinal muscular
atrophy).³
These tools are critical for cutting-edge
neuroscience research and global health.
To address this, ACROBiosystems, a leading
manufacturer of cutting-edge tools, reagents, and
equipment for biological drug development, have
developed Aneuro.³
Find Out More
1. World Federation of Neurology. (2023). Number of People Living With Brain
Disease Expected to Double by 2050. [Online] World Federation of Neurology.
Available at: https://wfneurology.org/activities/news-events/neurology-news/2023-
10-16-wcn (Accessed on 7 January 2020).
2. Davenport, L. (2023). Global Burden of Brain Disorders Surpasses CVD, Cancer.
[Online] Mescape. Available at: https://www.medscape.com/viewarticle/994287?
form=fpf (Accessed on 7 January 2020).
3. ACROBiosystems. (no date). Proteins for Neuroscience. [Online]
ACROBiosystems. Available at: https://acrobiosystems.com.cn/A1536-
Proteins-for-Neuroscience.html (Accessed on 7 January 2020).
4. Perez, AN,. Suarez, J., Le Bars, M., (2023). Sizing the Brain. [Online]
Deloitte Insights. Available at:
https://www2.deloitte.com/uk/en/insights/industry/health-care/global-
neuroscience-market-investment-report.html (Accessed on 7 January 2020).
³
³
4. Unveiling Hidden Potential: Organoids for
Disease Modeling in Neuroscience
Research
In our latest interview, News-Medical speaks with Rosanna Zhang from
ACROBiosystems about utilizing organoids for disease modeling in the field of
neuroscience research.
insights from industry
Rosanna Zhang
Head of Strategic Initiatives
ACROBiosystems
Please can you introduce yourself and tell us a
little about your background in neurology?
I’m Rosanna Zhang, and I currently serve as the head of Strategic Initiatives at
ACROBiosystems, leading its innovative endeavors across the globe starting
from Aneuro and transferring it into our global seed fund, focusing on
investment and licensing-in life science tools. I received my undergraduate
degree at MIT and conducted research at Harvard, MIT and Mass General
Hospital. My research was focused on uncovering the pathology of
neurodegenerative disease and finding a stem cell-based therapy for
amyotrophic lateral sclerosis.
Can you tell us about Aneuro? What does
Aneuro hope to achieve in the field of
neuroscience research?
Aneuro is our brand that encompasses all products and reagents for
neuroscience research. We started it in 2021 in hopes of providing more ready-
to-use tools to accelerate research for neuroscience-related diseases. With new,
potential biomarkers being consistently discovered alongside mapping the entire
brain neural network, up-to-date tools, and reagents such as recombinant
proteins, antibodies, cell lines, and organoids are all critical for performing
cutting-edge research. We aim to provide a comprehensive panel of products
for neuroscience research and help accelerate the development of novel
Insights from Industry
Read this article online 4
5. therapeutic and diagnostic options.
Image Credit: ACROBiosystems
How is Aneuro supporting therapeutic research
when it comes to neurodegenerative diseases?
As a scientist, having high-quality life science tools and solutions is essential
towards finding meaningful, reproducible data. Especially when combating a
disease that has been historically difficult to overcome such as Alzheimer’s,
ALS, and many other neurodegenerative diseases, it becomes even more critical
to have cutting-edge solutions to keep your research on track. Of course, this
applies not only to research but in industry, where emphasis focuses more on
more mature, scalable, and reproducible methods.
Aneuro supports both academic and industry applications by offering high-
quality solutions that are essential in studying the intricate cellular processes,
whether it includes higher-degree, complex disease modeling tools, or electrical
probes for in vivo research. These tools collectively aid in deciphering disease
mechanisms, identifying potential drug targets, and developing innovative
therapies, crucial for combating neurodegenerative disorders, ultimately striving
toward improved diagnostics and effective treatments for affected individuals.
What are organoids? How do organoids
contribute to advancing neuroscience
research, particularly in the context of disease
modeling?
Organoids are miniature three-dimensional organ-like structures grown from
stem cells that can emulate the complexity of human brain tissue in a lab
setting. These self-organizing structures mirror specific aspects of brain
Insights from Industry
Read this article online 5
6. Image Credit: nobeastsofierce/Shutterstock.com
development, offering an unprecedented platform to study neurological
disorders, synaptic connectivity, and neuronal behavior. Their resemblance to
actual brain tissue enables researchers to investigate disease mechanisms, test
drug responses, and explore personalized medicine approaches, fostering
deeper insights into conditions like Alzheimer's, autism, and other
neurodevelopmental disorders. Organoids represent a promising frontier,
bridging the gap between traditional cell cultures and human brains, propelling
advancements in understanding brain function and disease pathology.
Can you explain the key advantages of using
organoids over traditional cell culture models
when studying neurological diseases?
Key advantages of using
organoids really comes down
its ability to mimic the
cellular composition of the
human brain. It offers a
closer representation to the
complexity of the human
brain, which means that
when used for disease
modeling, results for
organoids are usually more
representative towards
human brains. This also
means the ability to study
limited brain functions outside of a living source and uncovering mysteries that
cannot be observed otherwise. Of course, this also unlocks the ability for
personalized medicine – by using patient-derived cell sources, disease models
specific for an individual can be developed. This means personalized treatment
plans and a better therapeutic action plan at the individual level rather than
population. Finally, organoids also address the ethical concerns regarding
animal testing, providing an alternative to the long-standing standard of mouse
and other animal testing.
Insights from Industry
Read this article online 6
7. What are the challenges associated with
creating and maintaining organoids for disease
modeling in neuroscience, and how are
researchers addressing these challenges?
As with any more recent advancements, the key challenge associated with
organoids is consistency. Reproducibility and standardization of organoid
generation has always been difficult due to the variability in cell culture
conditions and differentiation protocols available. Results have always been
heavily dependent on expertise, not to mention labor-intensive and time-
consuming. Generating these organoids at scale is a significant limiting factor
that prevents wider adoption in industry. As such, research and
commercialization efforts have been heavily dedicated towards improving
scalability and refining cell culture methods while addressing the varying ethical
concerns regarding developing brain tissue models.
In what ways do organoids accurately
recapitulate the complex cellular and
structural features of the human brain, making
them suitable for disease modeling?
Organoids emulate intricate cellular and structural aspects of the human brain,
enhancing their relevance in disease modeling. Their three-dimensional
architecture mirrors the organization of brain regions, allowing the development
of diverse cell types akin to those found in the brain. They exhibit neural
connectivity, synapse formation, and electrical activity resembling the human
brain, facilitating the study of neuronal interactions. So not only do organoids
have the same hallmark cellular composition of a brain, but they also mimic
that intracellular signaling between different cell types that conventional cell
lines lack. As such, certain organoids can exhibit limited physiological
functionalities under the right conditions, such as electrophysiological activities
(e.g. heartbeats) in cardiac organoids.
This limited functionality also means that disease-specific pathological
hallmarks can also be displayed, offering insight into disease progression.
Moreover, the incorporation of patient-derived cells allows personalized disease
modeling, capturing individual variations in disease presentation and drug
responses. While not an exact replica, these characteristics enable organoids to
Insights from Industry
Read this article online 7
8. simulate crucial features of the human brain, making them valuable tools for
understanding neurological disorders and advancing potential treatments.
Could you provide examples of specific
neurological disorders or conditions that have
been successfully modeled using organoids,
and discuss the insights gained from these
studies?
Organoids were first introduced in the early 2000s, with a wide array of
research and understanding derived from the use of organoid models.
Researchers have used organoids to observe how the Zika virus causes
microcephaly during embryo development, which in turn leads to stunted brain
development. At the cellular level, viral infection drives the premature
differentiation of neuron-producing cells, which is something that can be only
observed by utilizing in vitro models. Similarly, other researchers have used
organoids to connect disease pathology to a genetic-level insight – comparing
organoids derived from autistic patients to a control. Although a main genetic
abnormality involved in cell proliferation was identified, its role in autism
remains to be uncovered. Despite the lack of conclusion, these hints that are
unique to the use of organoids are what makes it so valuable as a tool in a
neuroscience researcher’s toolkit.
How do researchers ensure the reproducibility
and reliability of results obtained from
organoid-based disease models, considering
the variability in organoid cultures?
Ensuring reproducibility and reliability of organoids and its results really comes
down to experience and the materials that you use. Having consistent,
trustworthy reagents is the first step towards reproducible organoid culturing,
with your own experience and protocol driving the rest of your research. Having
a defined kit and protocol is always a great way to kickstart research in
organoids and saves a lot of time in troubleshooting and solving any potential
issues that might arise as one gets started in organoids.
Insights from Industry
Read this article online 8
9. Image Credit: Gorodenkoff/Shutterstock.com
Can you discuss the translational potential of
findings from organoid-based disease models
and how they might influence the development
of new therapeutic interventions?
The translational potential
of findings from organoid-
based disease models holds
significant promise in
shaping new therapeutic
interventions for various
neurological disorders. As
mentioned before, these
models provide a closer
representation of human
brain complexity, aiding in
the understanding of
disease mechanisms and potential treatment strategies. By using organoids
derived from patient-specific cells, researchers can replicate individual disease
characteristics, allowing for personalized medicine approaches. This
personalized modeling helps identify specific drug responses and potential
therapeutic targets, thus paving the way for precision medicine in treating
neurological conditions.
Additionally, organoid-based disease models enable more efficient drug
screening by offering a platform to test potential treatments in a system that
closely mimics human brain tissue. This facilitates the identification and
validation of novel drugs, potentially speeding up the drug development
process. Furthermore, insights gained from organoid studies regarding disease
progression and the underlying cellular and molecular mechanisms provide a
deeper understanding of neurological disorders. This knowledge can guide the
development of innovative therapeutic interventions, including gene therapies,
targeted drug delivery systems, and other precision-based treatments tailored
to the specific pathology of each disorder. While challenges exist, such as
scalability and standardization, the translational potential of organoid-based
disease models remains promising. They offer a bridge between bench research
and clinical applications, potentially revolutionizing the development of new
therapeutic interventions for neurological disorders.
Insights from Industry
Read this article online 9
10. As organoids continue to evolve as a tool for
neuroscience research, what are the most
pressing research questions or gaps in
knowledge that need to be addressed in the
field of organoid-based disease modeling? How
is Aneuro accelerating research to answer
these questions?
When it comes to neuroscience, the biggest research question is always ‘why.’
Understanding how our brains work and the influencing factors that might cause
diseases and abnormalities is always the first step in finding ways to combat
neurodegenerative disease and develop effective therapies. With Aneuro, we
seek to accelerate research by providing tools that scientists can trust and focus
more on contributing to the understanding of neurodegenerative diseases and
understanding our brains.
Finally, looking forward, what exciting
research developments are you optimistic
about, and what is next for Aneuro?
Although this isn’t that much of a research development, I am very optimistic
about the adoption and utilization of organoids into a more industry-related
context. The potential of organoids has been undeniable in research, and with
the increasing availability of consistent organoid kits, organoids, and other life-
science tools on the market, it seems likely that therapies combating
neurodegenerative diseases is right around the corner.
Where can readers find more information?
Visit the Aneuro Webpage
View the Aneuro Brochure
More from Aneuro on News Medical
About Rosanna Zhang
I currently serve as the Head of Strategic Initiatives at ACROBiosystems,
leading its innovative endeavors across the globe starting from Aneuro and
transferring it into our global seed fund, focusing on investment and licensing-in
Insights from Industry
Read this article online 10
11. Sponsored Content Policy: News-Medical.net publishes articles and related
content that may be derived from sources where we have existing commercial
relationships, provided such content adds value to the core editorial ethos of
News-Medical.Net which is to educate and inform site visitors interested in
medical research, science, medical devices and treatments.
life science tools. I received my undergraduate degree at
MIT and conducted research at Harvard, MIT, and Mass
General Hospital. My research was focused on attempting
to find a stem-cell therapy cure for ALS and uncover the
pathology of neurodegenerative diseases. Afterwards, I
gravitated towards entrepreneurship and research
commercialization, co-founding a healthcare IT start-up
company while investing in life-sciences and biotech
companies.
Coming to ACROBiosystems, I hope to provide
researchers with the best tools, reagents, and equipment required to tackle the
unsolved puzzles in life sciences, especially in neurodegenerative diseases. This
fight is somewhat personal to me, having an autistic family member. Thus, I
want to contribute as much as I can to helping develop therapies against
neurological diseases and significantly improve the lives of patients across the
world.
Insights from Industry
Read this article online 11
13. Using organoid culturing for preclinical
human disease models
Recent advancements in organoid structures have allowed scientists to
culture complex collections of cells that mimic the architecture and
functionality of a patient’s organs, imitating the environment of their
cellular tissue and organs.
These three-dimensional organoid structures contain populations of self-
renewing stem cells, which can separate into distinct cell types in the organ
tissues.
Organoids have richer compositions and improved physiological functions
compared to traditional two-dimensional models and thus have widespread use
in modeling disease, drug screening, biological function research, and the
development of artificial organs.
Figure 1. Organoid discovery of their corresponding organs through the years.
Image Credit: ACROBiosystems
Organoid sourcing and culturing: Stem cells
and growth factors
Organoids can be split into adult stem cells (ASCs) and pluripotent stem cells
(PSCs). PSCs further comprise embryonic stem cells and induced pluripotent
stem cells.
ASCs maintain stem cell potential in adult human organs, which can
1
Whitepaper
Read this article online 13
14. subsequently conserve homeostasis or damage the repair processes of organs.
They are organ-specific, and ASC organoids accurately represent adult tissues'
physical and practical characteristics.
PSCs alternatively must undergo various differentiation processes, simulating
the entire organ development process, and are, therefore, a vital tool for
studying organ development and gene function.
Both stem cell sources can mimic most major organs and tissues, but ASCs are
more widely used. However, there are exceptions where tissue is difficult to
obtain (for instance, brain tissue); in these circumstances, PSCs are
considerably superior.
Despite differences between stem cell sources, growth factors play crucial roles
in inducing and influencing the differentiation of cells. Organoid research
requires enhanced extracellular matrix compositions to guarantee good
physiological development; organoid culturing often contains several growth
factors and can vary significantly between types of organoids.
Figure 2. Confocal microscopy of mouse intestinal organoid growth with growth
factors: human EGF (Cat. EGF-H52H3), Noggin (Cat. NON-H5257), and R-
spondin1 (Cat. RS6-H4220). Image Credit: ACROBiosystems
Application of organoids in research
There are three key areas of research in which organoids have a vital position:
drug discovery, precision medicine, and regenerative medicine.
Organoids are perfect for high-throughput drug screening in precision medicine,
where cultured organoids from patient biopsies are exposed to xenobiotics to
screen for optimal effects, facilitating personalized medication and therapy.
Whitepaper
Read this article online 14
15. Organoids are exceptional for drug screening in a range of tumor types,
including colorectal, breast, non-small cell, and gastric cancer. Drug-response
prediction by organoids in some tumors has been demonstrated to be accurate
up to 80%, suggesting incredible potential in personalized diagnostic medicine.
Organoids represent a process which is, respectively, more accurate and cost-
effective than traditional cell lines and animal models. The complex tissue
structure, cell makeup, and physiological structure of organoids, alongside their
high repeatability and throughput of use in in vitro studies, make organoids
ideal for preclinical drug screening.
Gene editing can also be employed to build various models for diseases,
including cystic fibrosis, microcephaly, and colorectal cancer. Organoids can be
used to study the process of host–pathogen interactions in infections such as
COVID-19 and Heliobacter pylori; scientists have constructed various organ
models to study the infection process and how it influences changes in
physiological function in the former.
The 20 largest pharmaceutical companies in the world (e.g., Novartis, Pfiizer,
Johnson & Johnson) all use organoids to assess the safety and effectiveness of
new medications.
Figure 3. Various applications of organoids for disease research, drug
development, and personalized medicine. Image Credit: ACROBiosystems
2
Whitepaper
Read this article online 15
16. Organoids also test the potential of repairing damaged tissues in regenerative
medicine. For instance, researchers have assessed the possibility of
transplanting organoids to treat inflammatory bowel disease and short bowel
syndrome. Scientists have also initiated attempts to treat type I diabetes using
islet organoids, but these studies are in their first stages and are currently
limited to animal models.
Organoids have drawbacks in clinical applications, including the heterogeneity
of cultured organoids, the in vivo homing effect post-organoid transplantation
and the potential tumorigenicity of matrix gels in organoid cultures, but their
potential in regenerative medicine is undeniable.
The future of organoids
Academics are constantly advancing organoid cultivation and have recently
discovered which growth factors are necessary to direct cell differentiation;
organoids improve greatly on two-dimensional cell cultivation and have become
indispensable in developing and evaluating medication. They can mimic human
organs' physical and functional features and simulate the tumor
microenvironment.
Organoids are also set to become essential preclinical models for disease
prevention. Almost all human organs can be formed into organoids in vitro.
To support research on organoid cell culturing, ACROBiosystems has developed
a series of high-quality cytokines, including EGF, Noggin, R-Spondin 1, FGF10,
FGF2 and Activin A. These products are suitable as growth factors for organoid
culture that have been verified to promote organoid growth.
References and further reading
1. Han, Y., Chen, S., et al. (2022) Human Organoid Models to Study SARS-
CoV-2 Infection. Nature Methods, 19, pp.418-428.
2. Fatehullah, A., Barker, N., et al. (2016) Organoids as an In Vitro Model of
Human Development and Disease. Nature Cell Biology, 18(3), pp.246-254.
Whitepaper
Read this article online 16
18. Discussing major hypotheses of
Alzheimer’s disease
Alzheimer’s disease (AD) is a severe neurological condition. It was first
proposed by the German doctor Alois Alzheimer in 1911 and was officially called
Kraeplin. Memory loss, mental decline, and impaired motor balance are the
most common clinical signs of Alzheimer’s disease.
As an age-related condition, the rise in the older population also drives the
demand for Alzheimer’s treatment drugs. According to the World Alzheimer
Report, there will be 131 million Alzheimer’s individuals worldwide by 2050.
The pathological alterations in Alzheimer’s disease are complicated and varied.
Neuronal loss, synaptic problems (such as synaptic loss and protrusion plasticity
deficits), extracellular amyloid-beta (βA) deposition to form amyloid plaques,
and improperly phosphorylated Tau protein to produce intracellular
neurofibrillary tangles are all frequent in Alzheimer’s disease.
The reasons for various pathological changes cannot be explained at present,
and the pathogenesis is still unclear. There are three classic hypotheses on the
pathogenesis of AD.
Aβ cascade hypothesis
In the pathogenesis of Alzheimer’s disease, the Aβ cascade hypothesis is the
most popular theory. One of the key pathogenic features of AD is the
accumulation of Aβ to create amyloid plaque. Secretase degradation produces
Aβ from amyloid precursor protein (APP). The secretases α-secretase, β-
secretase (BACE), and γ-secretase are involved in two routes for APP
degradation.
In the amyloid pathway, BCAE cleaves APP to produce sAPPβ protein, which is
then cleaved by γ-secretase to produce Aβ polypeptides, such as Aβ1-42, Aβ1-
40, and released into the extracellular domain, where they eventually
aggregate to form amyloid plaques, leading to the development of AD.
Whitepaper
Read this article online 18
19. Hydrolysis pathway of APP in vivo. Image from reference
Binding to soluble, toxic aggregates of Aβ selectively to neutralize and eliminate
it is thought to help alleviate neurodegenerative processes in AD. Various drugs
have been developed based on this hypothesis. Aducanumab is a representative
drug targeting APP, a monoclonal antibody of Biogen, and was approved on
June 7 , 2021, for marketing by the FDA.
Schematic diagram of monoclonal antibodies targeting APP. Image from
reference
Furthermore, Lilly’s Donanemab and Roche’s Gantenerumab are now in clinical
phase III, while Eisai and Biogen’s Lecanemab is in the FDA’s rapid application
stage, based on the similar mechanism of action and target. Fierce Pharma
listed the most anticipated new medication releases for 2022 on February 7 ,
th
th
Whitepaper
Read this article online 19
20. 2022, with Donanemab and Ganteneruma coming in first and third place.
Abnormal phosphorylation of tau protein
Another prominent pathogenic characteristic of Alzheimer’s patients is
neurofibrillary tangles (NFTs). Excessive or abnormal phosphorylation of
intracellular Tau protein causes it to lose its biological activity of promoting
microtubule assembly, resulting in microtubule depolymerization and axonal
dysfunction, which leads to neuron degeneration and nerve cell apoptosis,
resulting in Alzheimer’s disease.
The abnormal phosphorylation of Tau protein is caused by the high expression
of various phosphorylated kinases, such as glycogen synthase kinase 3β (GSK-
3β), cyclin-dependent kinase 5 (CDK5), and tyrosine kinase, which are
considered potential drug targets for AD treatment.
Abnormal phosphorylation of Tau protein. Image from reference
Cholinergic hypothesis
The cholinergic theory was the first to describe the pathophysiology of
Alzheimer’s disease.
Whitepaper
Read this article online 20
21. In Alzheimer’s patients, Doucette et al. discovered a significant loss of basal
forebrain cholinergic neurons, which resulted in decreased acetylcholine
transferase (ChAT) operation for acetylcholine synthesis and serious depletion
of presynaptic cholinergic transmitters, resulting in cognitive function decline.
The cholinergic hypothesis proposes that the fall in cholinergic levels is due to
decreasing activity of Cholinesterase, which includes acetylcholinesterase
(AChE), butyrylcholinesterase (BChE), and ChAT.
The FDA has authorized many Cholinesterase inhibitors for the treatment of AD,
including donepezil hydrochloride and memantine hydrochloride/donepezil
hydrochloride. They are still used as first-line therapeutic drugs to treat mild to
moderate Alzheimer’s disease.
Even though these drugs play a significant role in postponing the onset of AD,
their limited effects prevent them from effectively treating the disease.
Summary
In addition to the three hypotheses of the Aβ cascade, other reasons for the
pathogenesis of AD include aberrant phosphorylation of Tau protein and
cholinergic, neuroinflammation, inappropriate excitation of the glutamate
system, mitochondrial dysfunction, and others. The pathophysiology of
Alzheimer’s disease is currently being researched by scientists.
Only aducanumab has been introduced to the market in nearly 20 years. More
drugs and therapies to improve the condition are urgently needed as the global
aging issue becomes more serious.
To aid with the development of AD treatment medications, ACROBiosystems has
created Tau protein (TAU-441), amyloid precursor protein (APP), and β-
secretase-1 (BACE1).
Whitepaper
Read this article online 21
22. Product list
Source: ACROBiosystems
Verification data
TAU-441 (Met 1 - Leu 441)
Human Tau-441 / 2N4R Protein, His Tag Human Tau-441, His Tag (Cat. No.
TAU-H51H3) on SDS-PAGE under reducing (R) condition. The gel was stained
overnight with Coomassie Blue. The purity of the protein is greater than 90%.
Image Credit: ACROBiosystems
Whitepaper
Read this article online 22
23. TAU-441 (Gly 273 - Glu 380)
The purity of Human Tau-441 (273-380), His Tag (Cat. No. TAU-H51H5) is
greater than 95% verified by SDS-PAGE and more than 90% verified by SEC-
MALS. Image Credit: ACROBiosystems
TAU-441 (Ser 241 - Glu 380)
The purity of Human Tau-441 (241-380), His Tag (Cat. No. TAU-H51H4) is
greater than 95% verified by SDS-PAGE and more than 90% verified by SEC-
MALS. Image Credit: ACROBiosystems
Whitepaper
Read this article online 23
24. SAPP
The purity of Human SAPPbeta, His Tag (Cat. No. APP-H52H5) is greater than
95% verified by SDS-PAGE and more than 90% verified by SEC-MALS. Image
Credit: ACROBiosystems
BACE1
The purity of Human BACE-1, His Tag (Cat. No. BA1-H5220) is greater than
95% verified by SDS-PAGE and more than 95% verified by SEC-MALS. Image
Credit: ACROBiosystems
References
1. Ju Y, Tam KY. Pathological mechanisms and therapeutic strategies for
Alzheimer’s disease. Neural Regen Res. 2022 Mar;17(3):543-549. doi:
10.4103/1673-5374.320970.
2. Zhang X, Song W. The role of APP and BACE1 trafficking in APP processing
and amyloid-β generation. Alzheimer’s Res Ther. 2013 Oct 8;5(5):46. doi:
10.1186/alzrt211.
3. Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function
and dysfunction. J Cell Sci. 2004 Nov 15;117(Pt 24):5721-9. doi:
10.1242/jcs.01558.
Whitepaper
Read this article online 24
25. Combating Parkinson’s disease, the second
most common neurodegenerative disease
What is Parkinson’s Disease?
Parkinson’s disease (PD) is the second most prevalent neurological disease that
affects middle-aged and elderly people. Resting tremors, stiffness,
bradykinesia, impaired gait, and posture are the most common clinical signs.
Parkinson’s disease is more common as people become older; the typical
starting age is around 60 years old, and only around 4% of PD patients are
diagnosed just before age of 50. Men are also 1.5 times more likely than
women to develop Parkinson’s disease. According to published studies,
Parkinson’s disease affects about 1.7% of China’s population over the age of 65.
Furthermore, the bulk of Parkinson’s cases arises at random, with just around
10% having a genetic link.
According to Frost & Sullivan statistics, the number of individuals over 65 in
China with Parkinson’s disease continues to rise, reaching 2,831,000 in 2018. In
2023, this number is expected to rise to 3,459,000. According to the most
recent research, the number of PD cases in the United States is predicted to
rise to over 1 million by 2030. As a result, there is a significant need for a
unique and effective therapy for Parkinson’s disease sufferers all over the world.
Etiology and pathological hallmarks of PD
The etiology of Parkinson’s disease is unknown; the risk of getting the disease
is dependent on the interaction of genetic and environmental risk factors.
Deterioration of dopaminergic neurons in the substantia nigra pars compacta
(SNc) and aberrant aggregation of alpha-synuclein (SNCA), the primary
component of Lewy bodies, are two pathological hallmarks of Parkinson's
disease.
SNCA
SNCA is a presynaptic protein of 140 amino acids that plays a role in neural
plasticity, membrane vesicle preparation, and neurotransmitter release. An N-
terminal lipid-binding domain, a core non-beta-amyloid component, and also an
Whitepaper
Read this article online 25
26. acidic C-terminal domain make up SNCA.
Multiple neurological dysfunctions and degeneration pathways have been linked
to abnormal SNCA, including inflammation, decreased mitochondrial function,
changed protein degradation systems, and oxidative stress.
Normal SNCA is found in the form of unfolded monomers. In Parkinson’s
disease, SNCA experiences inappropriate post-translational changes, such as
phosphorylation at the Ser129 site, causing it to fold into dimers, trimers, and
oligomers, however, it is unclear which polymerization form causes
neurotoxicity. These polymers then clump together to form protofibrils and
amyloid fibrils, which build up inside neurons, limiting function and eventually
leading to neuron death.
In both sporadic and familial PD, SNCA has emerged as a significant target for
creating novel PD treatments.
Multiple pathways that influence the onset of PD. Image from reference
Whitepaper
Read this article online 26
27. Advances in the development of drugs
targeting SNCA
Currently, therapies aimed at reducing SNCA levels directly or indirectly, as well
as modulating the inflammatory process, are being developed. Immunotherapy
for SNCA can take the form of passive or active vaccination.
Immunotherapy targeting SNCA. Image from reference
Active immunization is a traditional vaccination approach in which SNCA
antigens are used as immunological stimulants to promote a long-lasting
humoral response and specific antibody formation.
Product List. Source: ACROBiosystems
Drug Name Status Indications Company
ACI-7104 Phase I Parkinson's Disease Ac Immune
UB-312 Phase I
Parkinson's Disease;
Parkinsonism
United Neuroscience
Affitope-PD01 Phase I
Multiple Sclerosis;
Parkinson's Disease;
Neurodegenerative
disease
Affiris
PV-1950 PreclinicalParkinson's Disease
Institute For Molecular
Medicine;
Nuravax
Whitepaper
Read this article online 27
28. Affitope-PD03
(AFFiRiS)
No
advance
Multiple Sclerosis;
Parkinson's Disease;
Neurodegenerative
disease
Affiris
Several anti-SNCA antibody drugs are currently undergoing clinical trials in
Phase II, Phase I, and preclinical phases in passive immunotherapy.
Cinpanemab/BIIB054 was shown to be safe and tolerated in the Phase I clinical
study; however, the Phase II clinical trial was stopped owing to safety concerns
that did not satisfy the primary and secondary objectives.
Due to the different binding sites of SNCA, and as Cinpanemab binds to the N
terminus of SNCA and Prasinezumab attaches to the C terminus, Prasinezumab
appears to provide beneficial effects.
Product List. Source: ACROBiosystems
Drug Name Target
Drug/Therapy
Type
StatusIndications Company
PrasinezumabSNCA
Humanized
monoclonal
antibody
Phase
II
Parkinson's
Disease
Prothena
Lu AF-82422
(Lundbeck
A/S)
SNCA
Monoclonal
antibody
Phase
II
Multiple Sclerosis;
Parkinson's
Disease
Lundbeck;
Genmab
UCB-7853 SNCA
Monoclonal
antibody
Phase
I
Parkinson's
Disease
Ucb Biopharma
Srl
MEDI-1341 SNCA Antibody
Phase
I
Parkinson's
Disease
AstraZeneca
plc;
Takeda
Pharmaceutical
Co Ltd
Anti-a-syn
antibody
SNCA Antibody
Pre-
clinical
Parkinson's
Disease
Ac Immune
ATV:aSyn SNCA Antibody
Pre-
clinical
Parkinson's
Disease
Denali
Therapeutics
Inc
ABL-301
IGF1R;
SNCA
Bispecific
antibody
Pre-
clinical
Parkinson's
Disease
Abl Bio
Whitepaper
Read this article online 28
29. PR-004
GlcCer;
SNCA
Genetic therapy
Pre-
clinical
Neurodegenerative
disease
Eli Lilly
Existing research continues to fall short of meeting the clinical demands of
Parkinson’s disease treatment. The underlying neuropharmacology of symptoms
is minimally understood in comparison to motor symptoms. Furthermore, the
predictive usefulness and effective application of preclinical models have not
been adequately investigated, and clinical studies frequently lack novel
evaluable drugs.
Scientific research and technology innovation is intended to improve
symptomatic and disease-modifying treatment for Parkinson’s disease patients.
To aid with the study and development of Parkinson’s disease therapeutic
medications, ACROBiosystems has SNCA/Alpha-Synuclein protein (Met 1 - Ala
140).
Product List. Source: ACROBiosystems
Cat. No. SpeciesProduct Description
ALN-H52H8Human Human Alpha-Synuclein Protein, His Tag
ALN-H82H8Human Biotinylated Human Alpha-Synuclein Protein, His, Avitag™
High-purity SNCA/Alpha-Synuclein proteins are verified using SDS-PAGE.
Whitepaper
Read this article online 29
30. Purity>90%(Cat. No. ALN-H52H8). Image Credit: ACROBiosystems
Purity>95%(Cat. No. ALN-H82H8). Image Credit: ACROBiosystems
Other strategies for PD treatment
LRRK2
The most important genetic risk factor for PD is the leucine-rich repeat kinase 2
(LRRK2) gene, which generates the most prevalent monogenic variants of the
disease. LRRK2 is a kinase that controls the activity of other proteins by
phosphorylating them. LRRK2 kinase enzymatic activity is increased by
pathogenic mutations.
The RAB GTPase subgroup, which regulates cellular processes, such as vesicular
transport, cellular breakdown pathways, and immunological and microglial cell
responses, is one of LRRK2’s regulatory targets. Small molecule LRRK2 kinase
inhibitors are neuroprotective in preclinical PD models, making LRRK2 one of
the most relevant targets for PD therapy development.
Targeting dopamine-related pathways: DRD1, DRD2, DRD3, MAO-B,
DDC
Motor symptoms in Parkinson’s disease are caused by the death of
dopaminergic neurons in the substantia nigra. When these neurons die, the
Whitepaper
Read this article online 30
31. basal neuromotor circuit becomes dysregulated, affecting motor integration,
execution and process control.
When the function of the substantia nigra is damaged, it is unable to provide
proper reciprocal inhibition of the active and antagonistic muscles, resulting in
uncoordinated irregularities in the active and antagonistic muscles and the
onset of Parkinson’s symptoms.
Changes in the basal ganglia-thalamocortical motor circuit in parkinsonism.
Image from reference. Image Credit: Frontiers in Neuroanatomy
A key technique for treating Parkinson’s disease is to target a dopamine-related
pathway. Overall, enhanced dopamine binding to receptors and dopamine
pathway activity may be useful in reducing Parkinson’s symptoms.
In clinical applications, levodopa drugs are the most often used drugs for
PD therapy. These drugs can pass across the blood-brain barrier and
convert to dopamine in the brain. Dopamine receptor agonists, which
imitate dopamine’s activity and bind to the DRD1, DRD2 and DRD3
dopamine receptors, can also be used for therapy.
DOPA decarboxylase (DDC) is a catalytic enzyme that catalyzes the
decarboxylation of dopa to generate dopamine (i.e., hydroxytyramine).
Although levodopa may penetrate the blood-brain barrier, only 1-5% of
dopaminergic neurons enter the brain, and most of the levodopa is
Whitepaper
Read this article online 31
32. digested by peripheral DDC before reaching the brain; hence, DDC
inhibitors are frequently given together with it. DDC inhibitors that do not
penetrate the blood-brain barrier are frequently used with levodopa to
raise levodopa levels in the central nervous system.
Monoamine oxidase B (MAO-B) is a key enzyme in the breakdown of
neurotransmitters including dopamine. The MAO inhibitor (MAOI) family of
drugs works by blocking the action of MAO-B.
Product List. Source: ACROBiosystems
MoleculeCat. No. SpeciesProduct Description
DDC
DDC-
H55H6
Human Human DDC/Dopa Decarboxylase Protein, His Tag
MAOA
MAA-
M5547 Human Human MAOA Protein, His Tag (active enzyme)
MAOA
MAA-
M5548
Mouse Mouse MAOA Protein, His Tag
MAOB
MAB-
H5547
Human
Human MAOB / Monoamine Oxidase B Protein, His
Tag (active enzyme)
References
1. S.H. Fox, J.M. Brotchie. Special Issue on new therapeutic approaches to
Parkinson disease. Neuropharmacology(2022). https://doi.org/10.1
016/j.neuropharm.2022.108998
2. Fleming, S.M., Davis, A., Simons, E. Targeting alpha-synuclein via the
immune system in Parkinson’s disease; current Vaccine therapies
Neuropharmacology(2022). https://doi.org/10.1016/j.neuropharm.202
1.108870
3. Simon, D. K., Tanner, C. M., & Brundin, P. Parkinson Disease Epidemiology,
Pathology, Genetics, and Pathophysiology. Clinics in geriatric medicine
(2020). https://doi.org/10.1016/j.cger.2019.08.002
4. Galvan, A., Devergnas, A., & Wichmann, T. Alterations in neuronal activity
in basal ganglia-thalamocortical circuits in the parkinsonian state (2015).
https://doi.org/10.3389/fnana.2015.00005
Whitepaper
Read this article online 32
33. Pre-formed fibrils (PFFs) and the
modelling of neurodegenerative diseases
Neurogenerative diseases are a significant burden on the global health
system at the personal, public health, and societal levels. Degenerative,
progressive neurological disorders are increasing in prevalence. They
include Parkinson’s Disease (PD) and Alzheimer’s Disease (AD.)
Currently incurable, over 130 million people globally are afflicted with either AD
or PD. The prevalence of these diseases increases dramatically with age. The
aging world population is causing increased burdens on the global health
system due to the increasing prevalence of neurogenerative disorders.
As life spans continue to increase, the number of patients afflicted with these
disorders is predicted to increase in the near future. While this is a growing
public health emergency, neurological disease research is hindered by
inadequate understanding or incomplete perspectives on disease pathology.
This has translated to a woefully poor track record in developing efficacious
treatments for neurodegenerative disease and discovering new therapeutic
avenues.
Using in vivo and in vitro models has been key in elucidating disease pathology.
Both these models are invaluable tools that provide new insights into cellular
mechanisms, disease progression, and several other vital factors that influence
the development and severity of numerous medical conditions.
In regard to neurodegenerative disease, limited comprehension is partly due to
the use of premature experimental models. Transgenic mouse models are
typically used in existing models, employing over-expressed or knock-out
proteins and pathogenic genes.
These types of models have some key drawbacks, however, as they do not
accurately and completely reproduce natural disease progression. Therefore,
they provide an incomplete imitation of neurodegeneration in human patients.
Pre-formed fibrils (PFFs) are a recently developed novel tool. They can model
PD and AD, and are increasingly being employed in related studies in
neurodegenerative disease research.
1
Whitepaper
Read this article online 33
34. PFFs are generated in vitro and can effectively imitate endogenous protein
aggregation in cellular and animal models. More accurate models which closely
align with neurogenerative disease traits, including transmission and seeding of
pathogenic proteins, can be enabled using pre-formed fibrils.
In this article, the current limitations of conventional disease models are
discussed, along with an in-depth discussion about PFFs and their current
applications in neurogenerative disease research.
Current neurodegenerative disease models
Protein misfolding and aggregation is a key characteristic of neurogenerative
diseases. This results in cellular dysfunction, synaptic connection loss, and,
ultimately, damage to the brain.
While the proteins involved differ between different diseases, clinical indications
and disease progression are similar.
Most of the current experimental approaches used to study neurodegenerative
disease are based on animal models, with transgenic rodents widely used in
research that express human genes, especially for AD research
Other models involve physically and chemically induced animals as these
models can capture disease symptoms that transgenic animal models struggle
with, such as PD.
Whitepaper
Read this article online 34
35. Figure 1. Amyloid aggregation associated with neurodegenerative diseases.
Reproduced from Stroo et al. Image Credit: ACROBiosystems
Transgenic mouse models typically employed in AD research only exhibit
amyloid accumulation, a key characteristic that defines AD. However, they lack
neurofibrillary tangle (NFT) development. These insoluble, twisted fibers in the
brain are a secondary characteristic of AD.
A misfolded tau protein (a constituent of microtubule structures) leads to the
formation of NFTs. Microtubules transport nutrients and other molecules
between nerve cells in the brain. When NFTs form, these microtubule structures
collapse.
In transgenic mouse models, only 4R tau isoforms are expressed due to
endogenous mouse tau inhibiting human tau aggregation. 3R and 4R isoforms
are present in Alzheimer’s Disease.
Transgenic mice can be modified using a P301S or P301L mutation to express
4R human tau, overcoming the issue of NFT non-formation. However, this
reduces model accuracy due to these mutations not being associated with AD.
Furthermore, this can influence toxicity or cause interaction with amyloid
plaques.
Overexpression of mutated tau proteins in transgenic mouse models can result
in motor deficits typically not associated with Alzheimer’s Disease. Furthermore,
the accuracy of cognitive testing can be impacted by this strategy.
The classical, widely used approaches for modeling PD are toxin-induced mouse
models. These include MPTP and 6-OHDA. Neurotoxins are introduced into
animals used in these models, inducing dopaminergic neuron degeneration in
PD-related regions. This is a rapid degeneration.
Using this approach produces a robust and accurately characterized motor
deficit. However, only the clinical symptoms are stimulated in these models. The
molecular pathology of PD cannot be accurately replicated in this approach.
Types of PD-associated molecular pathology include Lewes bodies and α-syn
accumulation.
Transgenic mice with specific mutations in DJ-1, PINK1, Parkin, SNCA, and
LRRK2 are also used in PD research. Linked to inherited PD forms, these
2
3
Whitepaper
Read this article online 35
36. mutations express PD-implicated proteins. However, these models often lack
dopamine neuron loss. They lack the consistent, reproducible deficits that toxin-
induced models display.
Pre-formed fibrils and formation
Pre-formed fibrils are more cost-effective for neurodegenerative disease
research than transgenic and toxin-induced models and provide a different
perspective PFFS overcome the reported issues with conventional transgenic
and toxin-induced mouse models.
Employing PFFs in studies is more direct, with pre-formed pathogenic fibrils
being injected. Protein aggregates are formed, inducing rapid
neurodegeneration. The scientific burden and length of mouse maturation time
are reduced, and molecular pathology is induced more rapidly than in
transgenic mouse models.
In addition, PFFs can be used at the in vitro level. This innovative approach
enables a direct method with improved reproducibility. Thus, enhanced
identification and measurement of disease pathology and a model for testing
new drug candidates are promoted by employing pre-formed fibrils.
Figure 2. Immunohistochemical GFAP staining of the substantia nigra pars
compacta region in a mouse brain. Optical density analysis of GFAP-positive
cells reveals an increased amount of astrogliosis in PFF α-syn treated mice in
comparison to monomer α-syn, revealing neuroinflammation associated with α-
syn accumulation. Reproduced from Earls 2019. Image Credit:
ACROBiosystems
PFFs are formed in a simple process at room temperature from protein
monomers. Monomers are incubated and shaken either with or without heparin.
4
Whitepaper
Read this article online 36
37. The ability of the monomer of choice to aggregate influences the selection
protocol. Different PFFs require different concentrations and incubation periods.
For instance, tau-441 PFFs require an initial monomer concentration of 2 mg
ML in the presence of heparin and a seven-day incubation and shaking period.
Alpha-synuclein PFFS, in contrast, requires an initial monomer concentration of
5 mg mL and does not require heparin.
Other monomers and pathogenic fragments with increased aggregation
tendencies require a shorter incubation period (typically 4-5 days.)
Before their use as disease models, PFF verification is a key consideration.
Visual and chemical verification should be employed to verify the presence of
fibrillary structures. ThT assays can be employed for chemical verification, as
they are useful for analyzing high molecular weight species.
ThT assays are also effective at determining the presence of adequately formed
cross-beta structures in prepared pre-formed fibrils. TEM or AFM should be
employed to confirm aggregate size and morphology. Moreover, PFFs should be
sonicated before use in seeds under 50 nm due to the importance of fibril
length in pathogenicity.
Figure 3. Transmission Electron Microscopy of Human Tau-441/2N4R pre-
formed fibrils(ACROBiosystems, Cat. No. #TAU-H5115). Protein aggregates
with distinct fibrous structures are visible with accurate morphology. Image
Credit: ACROBiosystems
Current applications of pre-formed fibrils
Research has developed several well-established tau PFF models for use in
neurons, astrocytes, microglia, and other neurological cellular systems. These
-1
-1
Whitepaper
Read this article online 37
38. have been employed successfully in studying neurodegenerative diseases, such
as AD, and drug discovery and development.
Studies on PFFs have demonstrated that tau PFFs undergo internalization by
cells in the brain by endocytosis. They can act as a seed for endogenous tau
and induce misfolding. After internalization, the mouse’s endogenous tau
undergoes intracellular fibrilization.
Tau aggregates are externalized after recruitment via mechanisms such as
degenerating axions. Unknown mechanisms may be involved in this process.
Interconnected and surrounding neurons then adopt these externalized tau
aggregates.
Animal-based tau pre-formed fibril models have been more challenging to
establish than cell-based models. Injection of some types of tau PFFs appears
to have limited seeding capacity.
One study used in vitro approaches to introduce truncated tau PFFs into
transgenic mice through the frontal or hippocampal cortex. Tau fibrilization and
the spread of pathology to the interconnected region of the brain were observed
through a combination of PFF models and transgenic mice.
The results of this study demonstrated hippocampal neuronal loss. The study’s
observations led to a new in vitro model for neurodegeneration and pathological
spread.
5,6
Whitepaper
Read this article online 38
39. Figure 4. Nissl staining of the hippocampus of P301L mice injected with buffer
or truncated tau PFFs. AT8 (green, identifier of tau-presence) was apparent in
mice treated with PFFs and shown to preceed neuronal loss found in the 3
month post-injection mice. Reproduced from Peeraer 2015. Image Credit:
ACROBiosystems
α-syn PFF models have widespread use in PD research. These models are used
to model two major disease processes in PD progression: selective midbrain
dopamine neuron degeneration and intraneuronal Lewy body/neurite
accumulation.
Tau PFFs cannot properly induce protein aggregates in vivo, but α-syn PFF
models have been extensively established in both in vivo and in vitro. In-vitro
models have been used to target organ-on-a-chip , human-iPSC-derived
dopaminergic neurons , and primary neurons in research.
These methods are highly suitable tools for high-throughput drug screening and
testing. Other studies have demonstrated the effectiveness of α-syn PFF seed
aggregation and fibrilization in wild-type mice.
One study injected α-syn PFFs which targeted the dorsal striatum in mice. This
approach successfully identified hyperphosphorylated α-syn deposits. 30 days
post-injection, Lewy-body-like accumulations were observed in the inter-neural
connectivity. This suggested cell-to-cell transmission methods.
The study also observed PD-related clinical symptoms. Injecting a single
misfolded α-syn PFF initiated the PD-associated neurodegenerative cascade.
Figure 5. α-Syn immunostaining of substantia nigra pars compacta of mice
following intrastriatal PFF injection. Lewy-body like inclusions (black arrows)
7
10
9 8
11
Whitepaper
Read this article online 39
40. were observed in ipsilateral sections but were not observed in contralateral
sections; this supports the theory of a cell-to-cell transmission method for
Lewy-bodies comprised of misfolded α-syn. Reproduced from Luk 2012.
Image Credit: ACROBiosystems
Conclusion
Novel tools that can model more “natural” neurodegenerative disease
pathophysiology, pre-formed fibrils have demonstrated efficaciousness in
disease progression modeling and drug discovery and development. They have
been used to study both PD and AD, in both in-vivo and in-vitro studies.
PFFs can accurately mimic pathogenic protein seeding and transmission activity.
They are more suitable than toxic-induced and transgenic mouse models,
providing enhanced neurodegenerative disease hallmark replication with
reduced scientific burdens.
While they have proven effective in academic studies, clinical research using
PFFs is still limited. Reproducible protocols and quantifiable, stable phenotypes
are needed to widen the large-scale drug screening and testing applications of
pre-formed fibrils.
While key challenges persist in research, many researchers and companies are
focusing on developing PFF models by analyzing their activity mechanisms and
structural features. A deeper understanding will enhance the development of
high-quality PFFs for neurological disease research.
If these challenges are addressed properly in future research, PFFs could
represent a revolutionary breakthrough in providing clinical researchers with an
advanced neurogenerative disease therapeutic modeling platform.
References and Further Reading
1. Gitler AD, et al. (2017) Neurodegenerative disease: models, mechanisms,
and a new hope. Dis Model Mech. 10(5):499-502.
2. Stroo E, et al. (2017). Cellular Regulation of Amyloid Formation in Aging
and Disease. Front Neurosci. 14;11:64.
3. Drummond E & Wisniewski T. (2017) Alzheimer's disease: experimental
models and reality. Acta Neuropathol. 133(2):155-175.
11
Whitepaper
Read this article online 40
41. 4. Earls, R.H., et al. (2019) Intrastriatal injection of preformed alpha-
synuclein fibrils alters central and peripheral immune cell profiles in non-
transgenic mice. J Neuroinflammation. 16, 250.
5. Frost B, et al. (2009) Propagation of tau misfolding from the outside to the
inside of a cell. J. Biol. Chem. 284:12845–12852.
6. Guo JL & Lee VM. (2011) Seeding of normal Tau by pathological Tau
conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem.
286:15317–15331.
7. Peeraer E, et al. (2015) Intracerebral injection of preformed synthetic tau
fibrils initiates widespread tauopathy and neuronal loss in the brains of tau
transgenic mice. Neurobiol Dis. 73:83-95.
8. Volpicelli-Daley LA, et al. (2011) Exogenous α-synuclein fibrils induce Lewy
body pathology leading to synaptic dysfunction and neuron death. Neuron.
72(1):57-71.
9. Tanudjojo, B., et al. (2021) Phenotypic manifestation of α-synuclein strains
derived from Parkinson’s disease and multiple system atrophy in human
dopaminergic neurons. Nat Commun. 12, 3817.
10. Pediaditakis I, et al. (2021) Modeling alpha-synuclein pathology in a
human brain-chip to assess blood-brain barrier disruption. Nat Commun.
12(1):5907.
11. Luk KC, et al. (2012) Pathological α-synuclein transmission initiates
Parkinson-like neurodegeneration in nontransgenic mice. Science.
338(6109):949-53.
Whitepaper
Read this article online 41
42. e pathology and epidemiology of
Amyotrophic Lateral Sclerosis (ALS)
Pathological symptoms of ALS
Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative
disorder with a two- to three-year median survival after the appearance of
symptoms.
ALS mainly affects upper and lower motor neurons, but neurons in the frontal
cortex and other neuroanatomical areas may also be disrupted. Muscle
weakness, atrophy, spasms, and fasciculation result in the degradation of lower
motor neurons from the spinal cord to the muscles. Spasms, sloppiness,
impaired reflexes, and limited mobility result from the loss of upper motor
neurons in the brain.
Some patients also experience extra-motor symptoms, like cognitive and
behavioral issues. The most typical medical manifestation is muscle weakness
and atrophy in the hands, as though the body were progressively freezing.
Pathophysiological mechanism of ALS. Image from reference
Whitepaper
Read this article online 42
43. Epidemiology of ALS
Clinical results indicate that individuals with a history of the disease have a
considerably higher incidence of the disease, and a combination of
environmental and genetic aspects raises the chances of sporadic ALS.
The US National ALS Registry Act has significantly increased the overall
understanding of the epidemiology of ALS, and it estimated the ALS incidence
rate in the United States in 2013 to be five cases per 100,000 population.
Roughly, 10% of ALS cases are familial and induced by a genetic mutation that
is typically acquired in a mendelian autosomal dominant manner.
The most widely recognized genetic cause of ALS is a hexanucleotide G4C2
repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72),
which accounts for 30-40% of familial ALS and provokes frontotemporal
dementia (FTD).
Mutations in genes encoding copper-zinc superoxide dismutase (SOD1),
transactive response DNA-binding protein 43 (TDP-43), and fused in sarcoma
(FUS) contribute to more than 50% of familial ALS cases along with the C9orf72
repeat expansion, and another 30 or so genes have been recognized as
potentially causing ALS.
The pathogenesis of ALS
The pathogenesis of ALS is still unknown, but pathological features and gene
mutations associated with ALS have offered essential insights into the etiology
of ALS. The inclusion of pathological proteins in the cells that make up the
nervous system is a standard occurrence of many neurodegenerative disorders,
resulting in cell impairment and even fatality.
TDP-43 ectopic aggregation in the brain is found in 97% of ALS patients
(transmission from the nucleus to the cytoplasm and creation of protein
aggregation), and cellular and animal studies have revealed the neurotoxicity of
this pathological TDP-43. As a result, researching the mechanism of
pathological TDP-43 has become an essential step toward curing ALS.
A study published in Nature Structural & Molecular Biology in 2021 proposed a
Whitepaper
Read this article online 43
44. feed-forward loop model involving oxidative stress. According to the findings of
this study, TDP-43 nucleates gather in the cytoplasm.
On the one side, obtaining microRNA reduced the inhibitory effect of
downstream target mRNAs while increasing the expression of some
mitochondrial genes. Specialized mitochondrial proteins, on the other hand,
were stimulated to co-agglomerate, culminating in their functional impairment.
This causes an imbalance in mitochondrial structure and function, which
contributes to greater ROS and improved TDP-43 truncation and aggregation.
This favorable feed cycle demonstrates that the interaction between oxidative
stress and specific gene mutations may be an effective element for the onset
and progression of ALS.
Model of feed-forward loop mitochondrial imbalance caused by TDP-43
aggregation. Image from reference
Triggering receptor expressed on myeloid cells 2, (TREM2) is only found in
central nervous system microglia. TREM2 mutations are linked to Alzheimer’s
disease, Parkinson’s disease (PD), and several other neurodegenerative
disorders.
Whitepaper
Read this article online 44
45. TREM2 mutations have also been linked to an increased risk of ALS in clinical
studies. A 2021 study published in Nature Neuroscience was the first to show
that microglia TREM2 plays a defensive function in TDP-43-related
neurodegenerative diseases (not just ALS) and the first to identify TDP-43 as a
ligand of microglia TREM2.
Depending on this, a slight improvement in microglia TREM2 expression and
activity at specific disease phases may aid in the relief of ALS-related disorder.
In an animal model of Alzheimer’s disease, a single dose of anti-TREM2 mAb
promoted microglial metabolic activation and proliferation, boosting amyloid-
beta phagocytosis (Aβ).
Therapeutic drugs for ALS
The FDA chose riluzole, a glutamate receptor antagonist, for the treatment of
ALS in 1995. In 2017, the FDA approved edaravone, a powerful antioxidant and
free radical scavenger initially used to cure acute ischemic stroke. As well as
Ezogabine and Rasagiline, scientists are also dynamically exploring small
molecule drugs, genetic pathogenesis, biological drugs, and cell therapy as
potential treatments for ALS.
Aneuro focuses on neuroscience and provides SOD1 and TREM2
proteins for therapeutic drug development for ALS.
Product list
Source: ACROBiosystems
MoleculeCat. No. Species Product Description
SOD1
SO1-
H5148
Human Human SOD1 / Cu-Zn SOD Protein, His Tag
TREM2
TR2-
H5254
Human Human TREM2 Protein, Fc Tag
TR2-
H5256
Human Human TREM2 Protein, Mouse IgG2a Fc Tag
TR2-
H82E7
Human
Biotinylated Human TREM2 Protein, His,
Avitag™
TR2-
H52H5
Human Human TREM2 Protein, His Tag
Whitepaper
Read this article online 45
46. TR2-
M52H3
Mouse Mouse TREM2 Protein, His Tag
TR2-
M5254
Mouse Mouse TREM2 Protein, Fc Tag
TR2-
C52H3
CynomolgusCynomolgus TREM2 Protein, His Tag
Verification data
High purity veri ed by SDS-PAGE
Human SOD1, His Tag (Cat. No. SO1-H5148) on SDS-PAGE under reducing (R)
condition. The gel was stained overnight with Coomassie Blue. The purity of the
protein is greater than 97%. Image Credit: ACROBiosystems
Human TREM2, Fc Tag (Cat. No. TR2-H5254) on SDS-PAGE under reducing (R)
condition. The gel was stained overnight with Coomassie Blue. The purity of the
protein is greater than 95%. Image Credit: ACROBiosystems
Whitepaper
Read this article online 46
47. High bioactivity veri ed by ELISA and BLI
Immobilized Human TREM2, Fc Tag (Cat. No. TR2-H5254) at 1 μg/mL (100
μL/well) can bind Anti-TREM2 Antibody, Human IgG1 with a linear range of 1-
20 ng/mL (QC tested). Image Credit: ACROBiosystems
Loaded Human TREM2, Fc Tag (Cat. No. TR2-H5254) on Protein A Biosensor,
can bind Human Apolipoprotein E, His Tag (Cat. No. APE-H5246) with an affinity
constant of 106 nM as determined in BLI assay (ForteBio Octet Red96e). Image
Credit: ACROBiosystems
Whitepaper
Read this article online 47
48. References
1. Kiernan MC, Vucic S, Talbot K, McDermott CJ, Hardiman O, Shefner JM, Al-
Chalabi A, Huynh W, Cudkowicz M, Talman P, Van den Berg LH,
Dharmadasa T, Wicks P, Reilly C, Turner MR. Improving clinical trial
outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. 2021 Feb;
17(2):104-118.
2. Oskarsson B, Gendron TF, Staff NP. Amyotrophic Lateral Sclerosis: An
Update for 2018. Mayo Clin Proc. 2018 Nov; 93(11):1617-1628.
3. Zuo X, Zhou J, Li Y, Wu K, Chen Z, Luo Z, Zhang X, Liang Y, Esteban MA,
Zhou Y, Fu XD. TDP-43 aggregation induced by oxidative stress causes a
global mitochondrial imbalance in ALS. Nat Struct Mol Biol. 2021 Feb;
28(2):132-142.
4. Xie M, Zhao S, Bosco DB, Nguyen A, Wu LJ. Microglial TREM2 in
amyotrophic lateral sclerosis. Dev Neurobiol. 2022 Jan; 82(1):125-137.
5. Xie M, Liu YU, Zhao S, Zhang L, Bosco DB, Pang YP, Zhong J, Sheth U,
Martens YA, Zhao N, Liu CC, Zhuang Y, Wang L, Dickson DW, Mattson MP,
Bu G, Wu LJ. TREM2 interacts with TDP-43 and mediates microglial
neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci.
2022 Jan; 25(1):26-38.
Whitepaper
Read this article online 48
49. Multiple Sclerosis: Examining the
pathology, etiology, and potential
therapeutic drugs
Multiple sclerosis (MS) is a central nervous system immune-mediated
inflammatory demyelinating disease. A relapsing-remitting course, a
progressive disease course, or a combination of the two may define the clinical
course of MS.
There are about 2 million MS patients globally, and it is the most prevalent
cause of permanent disability in young adults, aside from traumatic brain injury,
resulting in a significant socioeconomic burden. In the United States alone,
there are approximately 1 million individuals with MS, with associated costs
exceeding $24 billion.
Prevalence of MS in different age groups. Image from reference
Pathology and etiology of MS
The pathological damage in MS consists of gliosis, inflammatory demyelination,
and sclerotic plaque formation. In the past few years, it has been displayed that
MS can also result in primary axonal damage and neuronal degeneration. This
exhibits damage to the gray matter of the brain, practically the cerebral deep
gray matter.
MS has a complex etiology and pathogenesis, and various clinical and
experimental studies have already shown that it is caused by a combination of
genetic and environmental factors:
Whitepaper
Read this article online 49
50. Genetic factors encompassing both ethnicity and separate susceptibility
Environmental factors include environmental pollution, viral infections,
frequent immunizations, genetically altered foods and several surgical
traumas, amongst several others
Pathogenesis of MS: Molecular mimicry
Experimental virological and immunological studies have disclosed that when a
virus attacks the body, mononuclear macrophages in the body phagocytose and
digest the virus and send the viral antigen signal, sharing antigenicity with
myelin basic protein, to helper T cells.
This helps trigger the CNS, then activate effector T cells, discharge a large
number of cytokines, and activate complement and B cells. This results in
oligodendrocyte degeneration and myelin damage—eventually resulting in MS
pathogenesis.
Various researches on animal models of experimental autoimmune
encephalomyelitis (EAE) have confirmed this hypothesis, which is now widely
recognized as molecular mimicry.
T-cell migration in the central nervous system during experimental autoimmune
encephalomyelitis (EAE). Image Credit: Fletcher et al., 2020
Whitepaper
Read this article online 50
51. Drugs for MS
Small chemical molecules, monoclonal antibodies, and interferons are among
the more than 20 drugs approved for the treatment of MS around the world.
Glucocorticoids were majorly employed for the early treatment of MS, but they
were proven useless in reducing several relapses and the rate of disease
progression; in the 1990s, interferon was utilized in the clinical treatment of the
disease.
In 1996, the bulky product glatiramer acetate was marketed; since then,
various oral small-molecule chemical drugs and monoclonal antibodies have
been initiated, thereby offering numerous avenues for the treatment of MS.
MS-related therapeutic targets
The integrin alpha-4 (ITGA4) gene is considered to be one of the genetic factors
that impact MS pathogenesis. Also, the encoding of ITGA4 helps in the
migration of leukocytes throughout the blood–brain barrier in MS.
Thus, ITGA4 is known to be a potent therapeutic target for MS. Natalizumab,
developed for this target, was accepted by the US FDA in 2004 to treat MS and
Crohn’s disease. Natalizumab efficiently treats symptoms of both diseases,
thereby increasing remission rates and, avoiding relapses, cognitive decline,
and vision loss, and considerably enhancing the quality of life in MS patients.
Whitepaper
Read this article online 51
52. Mechanism of action of natalizumab in the treatment of MS. Image from
reference
The interferon-alpha/beta receptor alpha chain (IFNAR1) gene encodes a type I
membrane protein that adds up one of the two chains of interferon α and β
receptors. The receptor for type I interferon includes two subunits, IFNAR1 and
IFNAR2.
Binding of type I IFN by IFNAR1 activates the JAK-STAT signaling pathway,
which is essential for regulating growth, survival, differentiation, pathogen
resistance, and antiviral immunity, triggering many protein IFN/IFNAR1
activation of immune mechanisms is also an important target for MS therapy.
Signal pathway of IFN/IFNAR1. Image from reference
Sphingosine-1-phosphate receptor 5 (S1PR5) has been expressed
predominantly in CNS white matter bundles and considerably expressed by
oligodendrocytes and is involved in and controls natural killer cell trafficking.
Modulators that target S1PR are a comparatively new class of therapies, being
the first oral therapy for MS, the first approved for pediatric MS, and also the
first to prove efficient in secondary progressive MS (SPMS).
Its main mechanism of action is via binding to S1PR isoforms on lymphocytes,
thereby resulting in receptor internalization and loss of responsiveness to the
S1P gradient that propels lymphocyte drainage from lymph nodes.
Whitepaper
Read this article online 52
53. The decrease in circulating lymphocytes might restrict the migration of
inflammatory cells to the CNS. Four S1PR modulators (fingolimod, Siponimod,
ponesimod, ozanimod) have been approved to treat MS.
S1PR5 expression in the CNS system. Image from reference
Ocrelizumab, a monoclonal antibody targeting CD20, was approved for
marketing in March 2017 as the first drug for main progressive MS. New clinical
studies have displayed that the use of Rituximab in patients with relapsing–
remitting MS led to a quick reduction of B cells, as well as myelin lesions and
clinical relapses, with impacts lasting around 3 to 12 months.
In a phase II study of Rituximab in patients suffering from relapsing–remitting
MS, a considerable decrease in MRI and clinical markers of disease activity were
displayed. Around 104 patients with RRMS were assigned randomly to 2 × 1000
mg of intravenous Rituximab or placebo and tracked for around 48 weeks.
The Rituximab group displayed a considerable decrease in various contrast-
enhanced MRI lesions (p < 0.001) and T2 lesion volume (p = 0.04) at weeks 24
and 36, respectively, compared to the placebo group. Furthermore, the
Rituximab group decreased the annualized MS recurrence rate, statistically
significant at week 24 but not at week 48.
CD52 is a cell surface antigen that is present on all monocytes and
lymphocytes. Alemtuzumab, a humanized monoclonal antibody targeting CD52,
was approved for marketing by the FDA in May 2001 for leukemia treatment
and was given MS orphan drug status by Mexico in 2014.
Two-phase III clinical studies verified the effectiveness of alemtuzumab, with a
Whitepaper
Read this article online 53
54. 55% lower annual relapse rate and similar disability progression rates than
interferon. But because alemtuzumab has serious adverse impacts, especially
secondary autoimmune disease, in 2019, the European Medicines Agency
suggested that alemtuzumab must be restricted for use in adults with MS.
Summary
MS is a central nervous system immune-mediated disorder that can lead to
severe disability and a reduction in quality of life. Monoclonal antibodies
targeting a variety of immune pathways have made significant advances in MS
treatment outcomes following a better understanding of the disease’s
pathogenesis and disease process.
Relapsing disease and focal brain inflammation are now nearly completely
under control thanks to the advancement of extremely effective therapies.
However, the efficacy of disease-progressing therapeutics remains insufficient,
as treatment options only provide partial protection against MS-related
neurodegenerative lesions.
An evidence-based, personalized approach to MS treatment and management
that promotes early treatment is the need of the hour. Ultimately, new
techniques are being developed to identify and evaluate the remyelination
ability and neuroprotective capacity of drugs, which will help to promote
ongoing MS therapeutic advances.
Aneuro concentrates on brain science research and the development of MS
drugs and therapeutics, and it can offer additional integrin alpha-4 (ITGA4),
interferon-alpha/beta receptor alpha chain (IFNAR1), CD20, CD52, and other
target proteins, as well as more MS diagnosis and treatment-related proteins
(including S1PR5).
References
1. Tian DC, Zhang C, Yuan M, Yang X, Gu H, Li Z, Wang Y, Shi FD. Incidence
of multiple sclerosis in China: A nationwide hospital-based study. The
Lancet Regional Health. 2020 Aug 6;1:100010. doi.org/10.1016/j.la
nwpc.2020.100010
2. Cavallo S. Immune-mediated genesis of multiple sclerosis. Journal of
Whitepaper
Read this article online 54
55. Translational Autoimmunity. Jan 28;3:100039. doi.org/10.1016/j.jt
auto.2020.100039
3. Constantinescu CS, Farooqi N, O'Brien K, Gran B. Experimental
autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis
(MS). British Journal of Pharmacology. 2011 Oct;164(4):1079-106. doi:
10.1111/j.1476-5381.2011.01302.x.
4. Bates, David W. “Natalizumab (Tysabri ) – Redefining Efficacy in Multiple
Sclerosis – Data from Clinical Trials to Postmarketing Experience.” (2010)
5. Gonzalez-Cao M, Karachaliou N, Santarpia M, Viteri S, Meyerhans A, Rosell
R. Activation of viral defense signaling in cancer. Therapeutic Advances in
Medical Oncology. 2018 Aug 29;10:1758835918793105.
doi.org/10.1177/1758835918793105.
6. Mark B. Skeen, MD. Sphingosine-1-Phosphate Modulators for Multiple
Sclerosis. https://practicalneurology.com/articles/2020-feb/sphingosine-1-
phosphate-modulators-for-multiple-sclerosis
®
Whitepaper
Read this article online 55
56. ACROBiosystems is a cornerstone enterprise of
the pharmaceutical and biotechnology industries.
Our mission is to help overcome challenges with
innovative tools and solutions from discovery to
the clinic. We supply life science tools designed
to be used in discovery research and scalable to
the clinical phase and beyond. By consistently
adapting to new regulatory challenges and
guidelines, we deliver solutions, whether it comes
through recombinant proteins, antibodies, assay
kits, GMP-grade reagents, or custom services.
We empower scientists and engineers dedicated
towards innovation to simplify and accelerate the
development of new, better, and more
affordable medicine.
Our way of addressing challenges in biologics
development is to offer a comprehensive array of
tools and solutions designed for each
development phase. Starting from discovery and
development and moving beyond
commercialization, we strive to deliver high
quality solutions that support each step of the
development process. This means bringing
together innovation and technology through
product development and collaborations to help
our customers achieve results that are
translatable into the clinic and beyond.
Find Out More