Focus Feature: Neuroscience
Urchins and AI and antibodies...oh my!
A roundup of some cutting-edge R&D news in neuroscience
By Jeffrey Bouley
Discoveries in the life-sciences related to human health come from a wide range of sources, some of them a bit unexpected. Here we present to you three interesting approaches to understanding and treating neurological conditions in humans, with insights from sea urchins to machine learning advances to putting antibodies to work in treating neurodegeneration.
Urchins provide insight on preserving nervous system
Dr. Andrea Bodnar of the Gloucester Marine Genomics Institute (GMGI) began research more than a decade ago at The Bermuda Institute of Ocean Sciences into sea urchins and their long-lived nature—as well as how that relates to their nervous systems. That research is being built on today to see how it might apply to preserving the nervous systems in humans as we age.
As it happens, the red sea urchin lives for centuries without showing signs of aging. In a new study titled “Unique age-related transcriptional signature in the nervous system of the long-lived red sea urchin Mesocentrotus franciscanus,” scientists at GMGI revealed features of the red sea urchin nervous system that help explain this extraordinary lifespan.
“Sea urchins and humans actually share a close genetic relationship and these genetic similarities have made sea urchins a valuable animal model for scientific research into questions ranging from early embryonic development to tissue regeneration and aging. Many of the genes analyzed in this study are conserved in both humans and sea urchins,” said Bodnar, who is GMGI’s Donald G. Comb Science Director. “Ultimately, our hope is that what we learn from sea urchins will translate into preventative or therapeutic strategies for age-related degenerative diseases in humans.”
Continuing Bodnar’s research over more than 10 years now, GMGI scientists investigated age-related patterns of gene expression—the extent to which various genes are turned on and off—in tissues of the red sea urchin. The results revealed a unique pattern of gene expression in nerve tissue that is distinctly different to that seen in the aging nervous system of humans.
This includes increased expression of genes involved in nerve function, neuroprotection and autophagy, a process that prevents the accumulation of damaged cellular components and protein aggregates, which are characteristic of neurodegenerative diseases such as Alzheimer’s disease in humans.
The research revealed how sea urchins are uniquely able to maintain nervous system integrity with age. Future functional studies will determine if the observed changes in gene expression act to preserve tissue function and mitigate aging in these long-lived animals.
Georgia State scientists work to transform neuroimaging research
Researchers at Georgia State University, with colleagues at the Massachusetts Institute of Technology (MIT) and the Massachusetts General Hospital (MGH), have received a $2.5 million grant from the National Institutes of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative for research aimed at revolutionizing scientists’ understanding of the human brain.
The team will develop Nobrainer, an open-source deep-learning framework for 3D image processing, to integrate machine learning into neuroimaging research and clinical applications.
“Advances in artificial intelligence and deep learning can help researchers extract greater insight from brain scans while cutting down on the time it takes to process this data,” said Dr. Sergey Plis, an associate professor of computer science at Georgia State and institutional lead on the grant proposal. “For example, we could learn more about the specifics of how mental disorders or aging affect the structure of the brain.”
Models that can elucidate these kinds of complex patterns are data-hungry, and assembling huge sets of brain data is challenging, particularly for small research groups.
“When Google wants to create a chatbot, they can train it using data from every internet search,” said Plis, who is also director of machine learning core at the Center for Translational Research in Neuroimaging and Data Science. “For brain imagers, though, the barriers can be too high. Gathering thousands of brain scans as well as the hardware needed for training is expensive and you have to anonymize the data in order to get around the privacy issues.”
The team is led by Satrajit Ghosh of MIT, Bruce Fischl of MGH and Plis. They plan to create deep neural networks that have been pretrained on brain scans from more than 65,000 individuals. They will disseminate the technology as a set of widely available tools and ready-to-use models for neuroscientists. The tools and the resulting models will be standardized, ensuring scientists can get comparable results and share them more easily, without patient confidentiality concerns.
The team is developing a unique feature in which the models can critique what they know, quantifying the degree of uncertainty in their own analyses and reporting where they’re likely to be wrong. This could help scientists decide when to trust the model and when more data need to be collected. As more researchers use the models, posing new questions or tuning the models to new datasets, the tools will continue to learn, becoming more accurate.
Another major benefit is the tools’ ability to process data much faster than available models. The research team trained Nobrainer to make some of the same predictions as Freesurfer, a best-in-class MRI analysis tool developed by MGH. Preliminary studies show the technology outperforms Freesurfer, making some of the same calculations in minutes versus hours. The team plans to work on automating and speeding up other parts of the Freesurfer platform and other types of neuroimaging analysis using their tools. Reducing the time needed to perform complex analytics may quicken scientific and clinical discoveries about the brain.
Antibodies against neurodegeneration
AC Immune SA, a Swiss-based, clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, recently announced the initiation of Investigational New Drug-enabling studies for the company’s first-in-class therapeutic antibody targeting TDP-43 (TAR DNA-binding protein 43). The anti-TDP-43 antibody reportedly is the first therapeutic candidate shown to mitigate TDP-43 neuropathology in vivo, and the company plans to develop the antibody for the treatment of neuro-orphan indications.
Advancing the anti-TDP-43 antibody towards clinical development is the latest in a series of important milestones already achieved this year in the company’s therapeutic and diagnostic programs targeting TDP-43, which it says are among the most comprehensive in the field.
TDP-43 pathology is strongly associated with cognitive decline and episodic memory loss in neurodegenerative diseases. Effectively slowing or stopping the spread of TDP-43 pathology throughout the brain could provide the first TDP-43 targeted therapeutic approach for treating conditions such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), where almost half of all FTLD cases exhibit TDP-43 pathology—offering significant market potential for AC Immune’s TDP-43 antibody. Other indications include limbic-predominant age-related TDP-43 encephalopathy and sub-populations of argyrophilic grain disease and Lewy body dementia.
Additionally, pathological aggregation of TDP-43 has emerged as an important co-pathology in Alzheimer’s disease linked to disease severity and occurring in roughly half of patients.
“This milestone reinforces AC Immune’s position as a leader in developing novel therapies against neurodegenerative diseases, with our anti-TDP-43 antibody on track to become the first in the world to reach clinical development,” said Prof. Andrea Pfeifer, CEO of AC Immune SA. “Aggregation of pathological forms of TDP-43 is an increasingly validated therapeutic target and a well-established hallmark of neurodegeneration.
“The company’s success is driven in part by our proprietary SupraAntigen platform, which has already produced therapeutic monoclonal antibody candidates targeting Abeta and Tau that were successfully out-licensed to leading pharmaceutical companies and are currently advancing in multiple Phase 2 clinical studies. Advancement of the anti-TDP-43 antibody further validates the continuing productivity of this platform, which, together with our Morphomer platform for small-molecule development, are responsible for discovery and development of our maturing pipeline of first-in-class or best-in-class therapeutic and diagnostic candidates.”
TDP-43 is an RNA/DNA-binding protein that functions primarily in the nucleus as a regulator of gene transcription and RNA metabolism. TDP-43 pathology has been shown to start from a focal point in the brain and spread to other brain regions with disease progression. Antibody-mediated clearance of pathological TDP-43 therefore represents an attractive strategy for therapeutic intervention.
Check out DDN’s first eBook
We have entered the world of eBooks now, with our first such offering giving you a look at some of the best coverage in this magazine of neuroscience R&D in pharma, biotech and life-sciences institutions.
Best of Neuroscience features notable articles and guest commentaries, mostly from between 2018 and 2020, that still have relevance to work in the field today. Within it, you can review highlights of major breakthroughs in understanding neurology and useful advice for researching therapeutic and diagnostic approaches to neurological diseases, including:
- A look at how we need neurobehavioral animal models to translate better to humans
- Ways in which researchers are reframing approaches to depression
- Insights into new strategies in the fight against Parkinson’s disease
- An examination of the growing role of Cannabis in neuroscience research
- Insights into the role of the tau protein in Alzheimer’s disease
To get the free eBook, visit https://go.drugdiscoverynews.com/drug-discovery-news-best-of-neuroscience
Fast-tracking Alzheimer’s drug development research
WEST LAFAYETTE, Ind.—A $2-million grant from the National Institute on Aging at the National Institutes of Health to Neurodon, a Purdue University-affiliated startup, will help fast-track molecules that could improve memory and reduce Alzheimer’s disease neurodegeneration.
The Neurodon team is working with scientists at Purdue and Northwestern University on targeted neuroprotective molecules. The molecules have been shown in lab studies to improve memory and cognition in preclinical models of Alzheimer’s disease by preserving calcium ion balance in neurons and offering a new therapeutic strategy for neurodegeneration drug development.
“We are on a mission to find a cure for Alzheimer’s and do not plan to stop until we succeed,” said Russell Dahl, chief executive officer of Neurodon. “This grant will help us move forward and much closer to human trials.”
The Phase II grant comes after team members successfully completed the Phase I work, where they narrowed down the molecules to select a few of the most promising candidates to help Alzheimer’s patients.
Wendy Koss, an experienced researcher at Purdue, and Gary Schiltz, a research professor at Northwestern, will help direct the studies. Colleen Mauger, a Purdue alumna and registered nurse who has clinical experience treating patients with various chronic diseases, including Alzheimer’s disease, is also on the Neurodon team.
Dahl will work closely with the Purdue Institute for Integrative Neuroscience.
Neurodon, a biotech startup located in the Purdue Research Park of Northwest Indiana, is working toward discovering neuroprotective drugs. Dahl and his team research treatments to different cell death illnesses, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.
Biogen and Denali collaborate on LRRK2 program for Parkinson’s and more
CAMBRIDGE, Mass. & SOUTH SAN FRANCISCO, Calif.—Biogen Inc. and Denali Therapeutics Inc. have signed a binding agreement to co-develop and co-commercialize Denali’s small-molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) for Parkinson’s disease. Biogen will also receive rights to opt into two programs and a right of first negotiation for two additional programs, in each case for neurodegenerative diseases leveraging Denali’s Transport Vehicle technology platform to cross the blood-brain barrier (BBB).
“Our collaboration with Denali represents an opportunity to advance the development of a potential first-in-class oral therapy that may slow the progression of Parkinson’s disease,” said Michel Vounatsos, CEO of Biogen. “Denali’s LRRK2 program is highly complementary to our existing Parkinson’s disease pipeline and its successful development would enhance Biogen’s portfolio of medicines for treating serious neurological and neurodegenerative diseases.”
Added Dr. Ryan Watts, Denali’s CEO: “This collaboration will allow us to accelerate the development of our LRRK2 program and gives us the resources to build a fully integrated company with the goal of bringing transformative medicines to patients suffering from neurodegenerative diseases.”
Mutations in the LRRK2 gene can cause Parkinson’s disease. LRRK2 is a regulator of lysosomal function, which is impaired in Parkinson’s disease and may contribute to neurodegeneration. Inhibition of LRRK2 activity may slow the progression of Parkinson’s disease in patients with and without known genetic risks based on restoration of lysosomal function.
DNL151 is a small-molecule inhibitor of LRRK2 invented at Denali which has completed dosing of 162 healthy volunteers in an ongoing Phase 1 clinical study and completed dosing in 25 Parkinson’s patients in a Phase 1b clinical study. Denali is currently completing further dose escalation cohorts in an expanded Phase 1 and an additional cohort in the Phase 1b study to define the full therapeutic window of the molecule. Based on the clinical data to date that has been generated in Europe, DNL151 appears to have an acceptable safety and tolerability profile and has met desired target engagement goals. An Investigational New Drug application for DNL151 was cleared by the U.S. Food and Drug Administration in July 2020 and enables expansion of Denali clinical trials for DNL151 globally.
Mapping the brain’s sensory gatekeeper
CAMBRIDGE, Mass.—Many people with autism experience sensory hypersensitivity, attention deficits, and sleep disruption. One brain region that has been implicated in these symptoms is the thalamic reticular nucleus (TRN), which is believed to act as a gatekeeper for sensory information flowing to the cortex.
A team of researchers from the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard has now mapped the TRN in unprecedented detail, revealing that the region contains two distinct subnetworks of neurons with different functions. The findings could offer researchers more specific targets for designing drugs that could alleviate some of the sensory, sleep, and attention symptoms of autism, says Dr. Guoping Feng, one of the leaders of the research team.
“The idea is that you could very specifically target one group of neurons, without affecting the whole brain and other cognitive functions,” explained Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT and a member of MIT’s McGovern Institute for Brain Research.
When sensory input from the eyes, ears, or other sensory organs arrives in our brains, it goes first to the thalamus, which then relays it to the cortex for higher-level processing. Impairments of these thalamo-cortical circuits can lead to attention deficits, hypersensitivity to noise and other stimuli, and sleep problems.
One of the major pathways that controls information flow between the thalamus and the cortex is the TRN, which is responsible for blocking out distracting sensory input. In 2016, Feng and MIT Assistant Professor Michael Halassa, discovered that loss of a gene called Ptchd1 significantly affects TRN function. In boys, loss of this gene, which is carried on the X chromosome, can lead to attention deficits, hyperactivity, aggression, intellectual disability, and autism spectrum disorders.
In that study, the researchers found that when the Ptchd1 gene was knocked out in mice, the animals showed many of the same behavioral defects seen in human patients. When it was knocked out only in the TRN, the mice showed only hyperactivity, attention deficits, and sleep disruption, suggesting that the TRN is responsible for those symptoms.
In the new study, the researchers wanted to try to learn more about the specific types of neurons found in the TRN, in hopes of finding new ways to treat hyperactivity and attention deficits. Currently, those symptoms are most often treated with stimulant drugs such as Ritalin, which have widespread effects throughout the brain.
“Our goal was to find some specific ways to modulate the function of thalamo-cortical output and relate it to neurodevelopmental disorders,” Feng said. “We decided to try using single-cell technology to dissect out what cell types are there, and what genes are expressed. Are there specific genes that are druggable as a target?”
To explore that possibility, the researchers sequenced the messenger RNA molecules found in neurons of the TRN, which reveals genes that are being expressed in those cells. This allowed them to identify hundreds of genes that could be used to differentiate the cells into two subpopulations, based on how strongly they express those particular genes.
They found that one of these cell populations is located in the core of the TRN, while the other forms a very thin layer surrounding the core. These two populations also form connections to different parts of the thalamus, the researchers found. Based on those connections, the researchers hypothesize that cells in the core are involved in relaying sensory information to the brain’s cortex, while cells in the outer layer appear to help coordinate information that comes in through different senses, such as vision and hearing.
The researchers now plan to study the varying roles that these two populations of neurons may have in a variety of neurological symptoms, including attention deficits, hypersensitivity, and sleep disruption. Using genetic and optogenetic techniques, they hope to determine the effects of activating or inhibiting different TRN cell types, or genes expressed in those cells.
Adapted from an article written by Anne Trafton for the MIT News Office
Autism researchers map brain circuitry of social preference
JUPITER, Fla.—For individuals with conditions such as autism, unfamiliar social interactions can produce negative emotions such as fear and anxiety. A new study from Scripps Research reveals how two key neural circuits dictate the choice between social approach and avoidance.
To better understand and treat this, brain mapping efforts have implicated multiple areas, including the emotional center of the brain and the region responsible for coordinating thoughts and actions. Assigning cause and effect to changes in these regions to the symptoms of autism, however, has been challenging.
A recent study from the lab of neuroscientist Dr. Damon Page uses a variety of innovative techniques to address this challenge, finding two specific circuits capable of independently controlling social preference in mice. Both link the areas of higher-level thought and decision-making in the prefrontal cortex to the emotional regulation center of the brain, the amygdala.
“To understand something properly, you need to know where to look. It’s a needle-in-the-haystack problem,” Page says. “Understanding how this circuit works normally enables us to now ask the questions, ‘How is this wiring changed in a condition like autism? How do therapeutic interventions impact the function of this circuit?’”
The group found that one neural circuit connecting the mouse infralimbic cortex to the basolateral amygdala impairs social behavior if its activity is dialed down. The other key circuit connects the prelimbic cortex to the basolateral amygdala. Dialing up activity of that circuit produced similarly impaired social behavior, says Aya Zucca, the study’s co-first author.
Zucca notes that both mice and humans use corresponding brain regions to process social information, so the mouse model is a good one for studying these issues.
“Using a technique called optogenetics in mice, we controlled the neurons that were active during negative experiences at the precise time of social engagement. This manipulation of the circuit resulted in them avoiding social interaction. It’s a bit like when you see a friendly face, but then have a flashback of a negative experience that’s strong enough to make you decide to walk the other way.”
With this social preference circuitry now identified, other questions can be addressed, such as, how this circuitry is wired during development, and whether genetic or environmental risk factors for autism cause mis-wiring of this circuitry, Page says.
Alzheimer’s gene triggers early breakdowns in BBB, predicting cognitive decline
LOS ANGELES--New research out of the University of Southern California (USC) reveals how APOE4, a genetic culprit for Alzheimer’s disease, triggers leaks in the blood-brain barrier (BBB) part of the brain, allowing toxic substances to seep into areas that are responsible for memory encoding and other cognitive functions.
The damage is linked to future problems in learning and memory, even when the disease’s signature sticky plaques have not appeared. The findings suggest that the smallest blood vessels in the brain, which form the BBB, might be a potential target for early treatment.
“This study sheds light on a new way of looking at this disease and possibly treatment in people with the APOE4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline,” said senior author Dr. Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC. “Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers. APOE4 seems to speed up breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury.”
Scientists have long known that the APOE4 gene—which occurs in up to 14 percent of the population—increases the probability of developing Alzheimer’s disease. Until now, it’s been unclear how different pathologies determine the course of the disease in its early stages, or what underlying mechanisms lead to cognitive decline in APOE4 carriers.
Zlokovic’s previous research shows that people who develop early memory problems also experience the most leakage in their brain’s blood vessels, independent of amyloid plaque or tau, which are two common contributors to Alzheimer’s. The leakage starts when cells called pericytes, which line the walls of blood vessels in the brain and maintain blood-brain barrier integrity, are damaged. These injured pericytes can be detected with a unique biomarker, developed by Zlokovic’s lab in 2015, which shows up in cerebrospinal fluid.
For this study, scientists used standard memory tests to check the participants’ cognitive abilities and their neuropsychological performance. They also used advanced neuroimaging and employed the biomarker that indicates damage to the brain’s blood vessels.
In participants who had the APOE4 gene, researchers found damaged capillaries in the brain’s memory center, the hippocampus and medial temporal lobe. The damage correlated with increased levels of a protein that causes inflammation, cyclophilin A—an early sign of the disease in people already at higher risk of developing Alzheimer’s.
AxoProtego goes after chemotherapy-induced peripheral neuropathy
GLEN BURNIE, Md.—AxoProtego Therapeutics has announced that it has licensed a novel investigational therapy for patients with chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is a large unmet medical need for this life-altering condition as 30 to 80 percent of cancer patients develop chemotherapy-induced peripheral neuropathy whether from traditional chemotherapy, biologics or cell-based therapies. Currently, no cure exists.
AxoProtego has licensed the rights for the worldwide development and commercialization of Ethoxyquin and its derivatives (including EQ-6, the company’s lead compound) from Johns Hopkins University. AxoProtego is focused on developing this potent small molecule and subsequent derivatives for the prevention of CIPN, a common and dose-limiting complication of many chemotherapy drugs affecting several million patients in the United States alone. EQ-6 is a patented approach for cytoprotection of the peripheral nerves against chemotherapy-induced toxicities and may limit chemotherapy-induced peripheral neuropathy.
EQ-6 reportedly has exhibited in-vivo neuroprotective effects while not interfering with the chemotherapeutic activity of paclitaxel and cisplatin. Preliminary data indicate that EQ-6 halts the initiation of neurodegeneration and the neurons are protected from the chemotherapy toxins. EQ-6 is water soluble and bioavailable both orally and intravenously, with demonstrated rapid accumulation in the peripheral nerves.