Focus Feature on Neuroscience: Preclinical progress on neurodegeneration

Making the rounds of brain-related therapeutic and diagnostic R&D, with a focus on neurodegenerative disease and dementia

March 26, 2021
Jeffrey Bouley
Focus Feature on Neuroscience: Preclinical progress on neurodegeneration

Focus Feature: Neuroscience 

Preclinical progress on neurodegeneration

A brief tour of recent R&D, from AI design to animal models and Parkinson’s disease to Friedreich’s ataxia


In drug development, the clinic is where, as the saying goes, “the rubber meets the road.” Trials are when pharma and biotech companies finally determine whether their promising candidates do any good in actual people. Often, the results fall short—or fall flat entirely—hence the high cost involved in discovery and development.

But as nebulous as human safety and efficacy might be the early stages of development, the preclinical arena is where the ideas are born, and even when those early-stage efforts don’t pan out over the long run, they can often set the stage for work on other compounds down the road.

So, with neuroscience on the mind for this Focus Feature and neurodegeneration one of the biggest areas of concern in neurological drug discovery and development, let’s see what some of the recent progress is for Parkinson’s disease, Friedreich’s ataxia, and Huntington’s disease—after all, we can’t let Alzheimer’s disease dominate all of the spotlight.

Using artificial intelligence in drug design

Canadian drug discovery and research commercialization center IRICoR, Université de Montréal (UdeM), the Institute for Research in Immunology and Cancer (IRIC) of UdeM, and AI-enabled drug design company Valence Discovery recently announced a collaboration focused on the discovery of novel drug candidates for the treatment of levodopa-induced dyskinesia in Parkinson’s disease (PD) patients.

Around five million people worldwide—most over the age of 60—suffer from this progressive neurodegenerative disease, and almost all of them in treatment for the condition  receive levodopa (L-dopa), a dopamine precursor that can enable patients to reinitiate normal movement.

Although this line of therapy does offer relief from the major motor symptoms of PD for most patient, there is a serious side effect. In a majority of patients, prolonged L-dopa use leads to abnormal involuntary movements called levodopa-induced dyskinesia, which can be highly debilitating.

Levodopa-induced dyskinesia occurs with an average latency of around six years and affects 95 percent of all patients within 15 years of starting chronic L-dopa treatment. Current treatments for this condition are not universally effective, have only transient efficacy, and are associated with side effects including fainting, dizziness, and hallucinations.

That’s where the Canadian collaborators we mentioned a few paragraphs ago come in.

The researchers involved in this team effort are building on research from the team of Dr. Daniel Levesque, a professor and associate dean for research and graduate studies of the Faculty of Pharmacy at UdeM.

“We are extremely pleased to have Valence’s support on this important drug discovery program, and are confident that our joint efforts will significantly accelerate our path to identifying novel compounds that can treat levodopa-induced dyskinesia,” Levesque said.

“We’re thrilled to be working with Dr. Levesque and the world-class team at IRIC, who have an extensive track record of collaborating with leading industry partners including BMS, Ipsen, and Merck,” added Daniel Cohen, CEO of Valence Discovery. “This collaboration is an important example of how we’re bringing modern machine learning methods, custom-built for drug discovery, to innovative R&D organizations of all shapes and sizes.”

The work will focus on the design of highly selective modulators of the Nur77/RXR nuclear receptor complex, which the collaborators say is a promising new pharmacological target for movement disorders. Scientists in the Drug Discovery Unit at IRIC are looking to rapidly advance selected hits through lead optimization, leveraging Valence’s machine learning platform for few-shot learning, generative chemistry, and multiparameter optimization—all of which are meant to address critical challenges in lead optimization.

“This collaboration is a testament to IRICoR’s commitment to investing in high-potential projects for indications with high unmet medical need, while staying at the cutting edge of drug discovery by combining an impressive array of homegrown technologies at the intersection of machine learning, chemistry, and biology,” said Dr. Steven Klein, vice president of business development at IRICoR. “We are extremely excited about what we’ve seen from the team at Valence and look forward to exploring future partnerships across IRICoR’s broader portfolio of discovery programs.”

A novel target in Parkinson’s

Boston-based biopharmaceutical company Yumanity Therapeutics has reported that its lead program, YTX-7739, demonstrated pharmacological, physiological, and behavioral preclinical proof of concept in a mouse model of PD. This work was conducted in collaboration with the laboratories of Drs. Silke Nuber and Dennis Selkoe at Brigham & Women’s Hospital.

YTX-7739 is a proprietary small-molecule investigational therapy designed to penetrate the blood-brain barrier and inhibit the activity of a novel target, stearoyl-CoA desaturase (SCD). According to Yumanity Therapeutics, by inhibiting SCD, YTX-7739 modulates an upstream process in the alpha-synuclein pathological cascade and has been shown to rescue or prevent toxicity in preclinical models.

The enzyme SCD catalyzes fatty acid desaturation, and it also plays a significant role in modulating neurotoxicity related to the alpha-synuclein protein, which is a driver of PD and other neurodegenerative disorders. SCD expression is regulated by the transcription factor SREBF1, which is a risk factor for Parkinson’s. Preclinical work has shown that SCD inhibition may normalize how pathological alpha-synuclein interacts with membranes, thereby improving neuronal function, reducing toxicity, and improving neuronal survival.

“Evidence suggests that α-synuclein pathology is a strong risk factor for Parkinson’s disease,” said Dr. Dan Tardiff, interim head of research and scientific co-founder at Yumanity Therapeutics. “Our proprietary discovery platform led us to the target stearoyl-CoA desaturase (SCD), which when inhibited decreases the toxicity associated with pathogenic α-synuclein. Inhibition of SCD, an enzyme involved in lipid metabolism, has been shown to prevent α-synuclein pathology in multiple models, including patient-derived neurons, in vitro. The results from the current study demonstrate that YTX-7739 has a similar effect in a mouse model of Parkinson’s disease-related pathology. These results lend additional evidence to support our ongoing clinical program in Parkinson’s disease patients.”

This work assessed YTX-7739 vs. control in a mouse model of PD, looking at the effect of the inhibitor on motor function, lipid metabolism, neuronal survival, and associated biochemical features. The study showed that YTX-7739 prevented motor function deficits in mouse models after four months of oral dosing compared to placebo-treated mice, and YTX-7739 brain concentrations reached levels that inhibited SCD activity consistent with in-vitro studies. SCD inhibition was also found to decrease monounsaturated fatty acids—which may contribute to alpha-synuclein pathology—in both plasma and the brain. Several biochemical measures of alpha-synuclein pathology were significantly improved in the YTX-7739-treated mice compared to controls, including levels of pathological alpha-synuclein. In addition, YTX-7739-treated mice showed enhanced survival of dopaminergic neurons.

The company presented the data from this study at the 15th Annual International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) 2021 Virtual Conference, held March 9 to 14.

This follows on the heels of a February update of Yumanity's progress with its YTX-7739 program in humans. In a Phase 1, single-ascending dose study in healthy volunteers, no safety concerns were identified and YTX-7739 was found to be well tolerated. As noted in the press release, “The half-life of YTX-7739 combined with a favorable dose-proportional pharmacokinetic profile, in the fed state, supports that low daily doses administered with food will sustain the target range of exposure. Drug plasma concentrations in the study exceeded levels of exposure estimated to be sufficient for target engagement based on pharmacodynamic modeling. Consistent with preclinical data, YTX-7739 also demonstrated clinically relevant drug concentrations in the cerebral spinal fluid.”

In moving from single-ascending dose studies to multiple-ascending doses studies, the company reported that it had completed enrollment in its Phase 1 multiple-ascending dose study to evaluate the safety, tolerability, and pharmacokinetics of once-daily oral administration of two doses of YTX-7739 (15 mg and 25 mg) for 14 to 28 days in 16 healthy male and female volunteers. Yumanity also began dosing in a Phase 1b study of YTX-7739 in PD patients to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic parameters, including potential biomarkers of SCD activity and target engagement in cerebral spinal fluid, plasma, and other fluids or tissues.

Pitting leriglitazone against Friedreich’s ataxia

Late last year, Spanish clinical-stage biotech Minoryx Therapeutics—a Phase 3 clinical stage company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders with high unmet need—announced the publication in the journal Neurobiology of Disease of preclinical data on its lead compound, leriglitazone. Specifically, the compound showed potential therapeutic action and protection against neurodegeneration, in particular against Friedreich’s ataxia (FRDA).

According to the company, the preclinical data supported ongoing clinical development for the approach with FRDA, with results showing that leriglitazone improves impairments that are derived from frataxin loss—the genetic deficiency that causes FRDA.
Key highlights of the results in FRDA models with leriglitazone included:

  • Increased frataxin levels and mitochondrial markers
  • Protected animals from neurodegeneration by improving mitochondrial function
  • Prevented formation of lipid droplets in frataxin-deficient cardiomyocytes
  • Rescued the motor function deficit in transgenic mice

“At Minoryx, we’re committed to making new therapies available for patients suffering from severe, orphan diseases. Leriglitazone is currently in clinical development for the treatment of a range of orphan central nervous system disorders and is currently completing a pivotal Phase 2/3 clinical trial in adrenomyeloneuropathy and a Phase 2 proof-of-concept trial in Friedreich’s ataxia,” said Dr. Marc Martinell, co-founder and CEO of Minoryx. “This preclinical data provides further evidence of the potential for therapeutic action and protection against neurodegeneration in Friedreich’s ataxia.”

FRDA is an orphan genetic disease characterized by frataxin deficiency, leading to mitochondrial dysfunction  and resulting in a loss of coordination and muscle strength because of degeneration of nerves—symptoms can include the inability to coordinate movements, imbalance, muscle weakness, and tremors. Within 10 to 15 years after disease onset, patients lose their ability to stand, sit, and walk, and FRDA is typically fatal, mainly due to cardiac failure. There is currently no curative therapy available; existing treatments solely address symptoms.

Leriglitazone (currently designated as MIN-102) is a novel bioavailable and selective PPAR-γ agonist with a potential best-in-class profile indicated for CNS diseases.

Thus far, according to Minoryx, it has demonstrated sufficient brain penetration and a favorable safety profile, and it has shown “robust preclinical proof-of-concept in animal models of multiple diseases by modulating pathways leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, demyelination, and axonal degeneration.”

An S1R agonist vs. Huntington’s disease

Pridopidine is a first-in-class small molecule in development for the treatment of Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS)—said to be the most selective, high-affinity sigma-1-receptor (S1R) agonist in clinical development. Activation of the S1R by pridopidine exerts neuroprotective effects in preclinical models of HD and other in neurodegenerative diseases.

HD is a fatal, inherited, neurodegenerative disorder. Every offspring of an HD patient has a 50 percent chance of inheriting the gene. Usually starting at around 40 years of age, HD patients suffer from movement disorder, progressive functional and cognitive decline, psychiatric disturbances, and behavioral symptoms. Functional, motor, and cognitive functions decline steadily after diagnosis, ultimately leading to immobility, dementia, and premature death.

According to Prilenia Therapeutics B.V., which has orphan drug designations for pridopidine for the treatment of HD in both the United States and Europe, there is extensive preclinical evidence that supports pridopidine’s potential for treating HD, noting that the “therapeutic effect has been shown to be mediated exquisitely by the sigma-1 receptor using multiple deletion and antagonist models.”

In recent months, the company has been able to see results of that preclinical work translate over into clinical setting as well, accounting the publication of articles in The Journal of Huntington’s Disease highlighting positive efficacy and safety data for pridopidine, as demonstrated by new analyses of the Phase 2 PRIDE-HD and Open-HART trials.

“Pridopidine has demonstrated an excellent long-term safety profile and suggestion of improvement in clinical trials, as well as in exploratory analyses, where early HD populations appear to particularly benefit. In view of these promising data, the newly initiated Phase 3 study in HD will be of great interest to the entire HD community,” said Dr. Andrew McGarry, lead author of the PRIDE-HD and Open-HART publications.

Added Dr. Michael R. Hayden, CEO of Prilenia: “Pridopidine is showing strong scientific and clinical data in support of its use for Huntington’s disease and other neurodegenerative diseases, such as ALS. By understanding the mechanism of action clearly, we are now delighted about the reported positive data in terms of efficacy and safety.”

Targeting pathological alpha-synuclein and TDP-43

Swiss company AC Immune SA recently outlined preclinical data presented for at the AD/PD 2021 virtual conference that focused on the company’s wholly owned, first-in-class therapeutic and diagnostic programs targeting pathological forms of alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). Together, the presentations further illustrated the synergy between AC Immune’s SupraAntigen and Morphomer technology platforms to deliver a precision medicine approach to treating neurodegenerative diseases, according to the company.

Alpha-synuclein and TDP-43 are hallmarks of major neurodegenerative diseases, such as Parkinson’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE), respectively—they are also recognized as co-pathologies in Alzheimer’s disease that are linked to accelerated cognitive decline.

AC Immune targets pathological forms of these proteins with highly specific antibody and small-molecule therapeutics, as well as first-in-class positron emission tomography (PET) diagnostic candidates.

“We continue to expand our position as a global leader in precision medicine for neurodegenerative diseases by leveraging our Morphomer and SupraAntigen platforms to discover and advance first-in-class therapeutics in parallel with companion diagnostics,” said Prof. Andrea Pfeifer, CEO of AC Immune. “Our approach informs and enables targeting the right proteinopathies, in the right patient, at the right time—and provides a pathway toward tailored combination therapies in the future. In addition to our pipeline targeting amyloid-beta and tau pathologies, the alpha-synuclein and TDP-43 programs highlighted in our AD/PD presentations are crucial components of such an approach, as these proteins have recently emerged as key targets across a multitude of neurodegenerative diseases.”

According to Pfeifer, in-vivo characterization of the company’s next-generation alpha-synuclein PET tracer candidate further illustrated its “strong diagnostic profile,” and AC Immune expects to report initial clinical results from the program in the third quarter of this year.

“Success in this exciting program could greatly accelerate the advancement of therapeutics for Parkinson’s disease and other alpha-synucleinopathies, including our first-in-class alpha-synuclein aggregation inhibitors, by enabling accurate diagnosis, patient selection, and longitudinal drug efficacy measurement based on changes in alpha-synuclein pathology in the brain,” added Pfeifer. “This precision medicine approach is mirrored by our TDP-43 antibody and PET tracer programs, for which we’ve also demonstrated highly encouraging therapeutic and diagnostic potential.”




Researchers identify three molecular subtypes of Alzheimer’s disease

A team of researchers at the Icahn School of Medicine at Mount Sinai have identified and characterized three major molecular subtypes of Alzheimer’s disease (AD) using data from RNA sequencing—advancing the understanding of the mechanisms of AD and paving the way for developing novel, personalized therapeutics.

The work was funded by the National Institute on Aging, part of the National Institutes of Health (NIH), and published in Science Advances on Jan. 6, 2021.

AD is the most common form of dementia, but it is quite diverse in its biological and pathological manifestations, the researchers note, and there is growing evidence that disease progression and responses to interventions differ significantly among Alzheimer’s patients. Some patients have slow cognitive decline while others decline rapidly, some have significant memory loss and an inability to remember new information while others do not, and some patients experience psychosis and/or depression associated with AD while others do not.

“Such differences strongly suggest there are subtypes of AD with different biological and molecular factors driving disease progression,” said Dr. Bin Zhang, the lead author of the study and director of the Center for Transformative Disease Modeling at the Icahn School of Medicine, as well as a professor of genetics and genomic sciences there.

To identify the molecular subtypes of AD, the researchers used a computational biology approach to illuminate the relationships among different types of RNA, clinical and pathological traits, and other biological factors that potentially drive the disease’s progress. The research team analyzed RNA sequencing data from more than 1,500 samples across five brain regions from hundreds of deceased patients with AD and normal controls, and identified three major molecular subtypes of AD. These AD subtypes were independent of age and disease stage, and were replicated across multiple brain regions in two cohort studies.

These subtypes correspond to different combinations of multiple dysregulated biological pathways leading to brain degeneration. Tau neurofibrillary tangle and amyloid-beta plaque, two neuropathological hallmarks of AD, are significantly increased only in certain subtypes.

Many recent studies have shown that an elevated immune response may help cause AD. However, more than half of AD brains don’t show increased immune response compared to normal healthy brains. The analysis further revealed subtype-specific molecular drivers in AD progression in these samples.

The research also identified the correspondence between these molecular subtypes and the existing AD animal models used for mechanistic studies and for testing candidate therapeutics, which may partially explain why a vast majority of drugs that succeeded in certain mouse models failed in human AD trials, which likely had participants belonging to different molecular subtypes.

Although the subtyping described by the researchers was performed post mortem using the patients’ brain tissue, the researchers said that if the findings were validated by future studies, they could lead to the identification in living patients of biomarkers and clinical features associated with these molecular subtypes and earlier diagnosis and intervention.

“Our systematic identification and characterization of the robust molecular subtypes of AD reveal many new signaling pathways dysregulated in AD and pinpoint new targets,” said Zhang, “These findings lay down a foundation for determining more effective biomarkers for early prediction of AD, studying causal mechanisms of AD, developing next-generation therapeutics for AD, and designing more effective and targeted clinical trials, ultimately leading to precision medicine for AD. The remaining challenges for future research include replication of the findings in larger cohorts, validation of subtype specific targets and mechanisms, identification of peripheral biomarkers and clinical features associated with these molecular subtypes.”

The AD subtyping study is supported by the National Institute on Aging (NIA) and is part of the NIA-led Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) Target Discovery and Preclinical Validation program. This public-private partnership aims to shorten the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s disease treatment and prevention.



Partnership investigates STARs in treating Gaucher disease and Parkinson’s disease

Gain Therapeutics Inc. late last year announced a research collaboration with the University of Maryland School of Medicine (UMSOM) to investigate Gain’s structurally targeted allosteric regulators (STARs) in cellular models of neuronopathic Gaucher disease (nGD) and Parkinson’s disease (PD), and if everything remains on track, initial data should be available by the middle of this year.

STARs are proprietary small molecules targeting novel allosteric binding sites on enzymes. These small-molecule drug candidates are designed to cross the blood-brain barrier and penetrate other hard-to-treat organs such as bone and cartilage, stabilize the effective enzyme to restore function, and reduce toxic substrate.

The research is being led by Dr. Ricardo A. Feldman, an associate professor of microbiology and immunology at UMSOM.

Under the terms of the collaboration, UMSOM is investigating Gain’s STAR candidates in macrophage and neuronal models of nGD and GBA-associated PD. These diseases are characterized by mutations in the GBA gene, where misfolding of the enzyme encoded by GBA [beta-glucocerebrosidase (GCase)] interferes with its normal transport to the lysosome. The research program will aim to further elucidate the mechanism of action of Gain’s STAR candidates by studying their effect on GCase, including GCase’s enzyme activity and transport to the lysosome. Additionally, other effects such as prevention of alpha-synuclein aggregation in PD dopaminergic neurons will be evaluated.

“We are exceedingly proud to be advancing our work in nGD and Parkinson’s in close collaboration with the University of Maryland School of Medicine,” said Eric Richman, CEO of Gain. “The expertise and experience of UMSOM and Dr. Feldman will be instrumental as we work to further validate the exciting potential of Gain’s STAR candidate for these devastating diseases. I am confident these foundational studies will bring us closer to a potential new treatment option for those with these disorders.”

Added Feldman: “Our laboratory has used human induced pluripotent stem cell models of GD and GBA-associated PD to uncover the molecular mechanisms leading to these diseases. We have also developed very sensitive assays to evaluate the therapeutic efficacy of small molecules in reversing the phenotypic abnormalities caused by mutant GBA in the cell types affected by these diseases, including macrophages and neuronal cells.

“I have been impressed by Gain’s initial results evaluating the potential of STARs in correcting enzyme misfolding and restoring function, and look forward to working with Gain’s team to further advance its program to treat these diseases.”
This February, Gain also highlighted three e-poster presentations at the 17th annual WORLDSymposium, a research conference dedicated to lysosomal diseases.

Just a few of the key findings included:

  • GCase STARs identified via Gain’s proprietary See-Tx platform effectively bind GCase, as measured by direct binding studies performed by surface plasmon resonance
  • GCase STARs stabilize GCase in a dose-dependent manner, as evaluated by a thermal shift assay with GCase in the presence and absence of STARs
  • GCase STARs do not inhibit GCase activity when administered to wildtype fibroblasts
  • Treatment with GCase STARs leads to an increase in lysosomal GCase
  • STARs enhance GCase activity in wildtype and a panel of Gaucher patient-derived fibroblasts bearing prevalent mutations
  • GCase STARs enhance GCase activity across both wildtype and a series of Gaucher patient-derived fibroblasts
  • Treatment with GCase STARs is associated in a significant reduction of toxic GCase substrate accumulated in neuropathic L444P fibroblasts
  • STARs enhance GCase activity in a dopaminergic-like neuronal cell model
  • STARs are brain penetrant and orally bioavailable

“We continue to see evidence that structurally targeted allosteric regulators have the ability to increase enzymatic activity in proteins whose deficiency can lead to devastating diseases such as Gaucher disease and GLB1-related disorders,” said Dr. Manolo Bellotto, general manager and president at Gain.



Funding diverse pipelines to thwart dementia

In recent months, the Alzheimer’s Drug Discovery Foundation (ADDF) announced seven new investments totaling more than $5.8 million, with the goal of advancing promising approaches to diagnosing, treating, and preventing Alzheimer’s disease and related dementias.

This funding supports three clinical trials, including one that explores the use of gene therapy to lower the risk of Alzheimer’s disease, and another that is testing a repurposed drug originally developed to treat sickle cell anemia as potential treatment for early and mild stages of Alzheimer’s. Funding also includes support of a prevention program investigating the potential use of intranasal insulin to prevent or treat postoperative delirium or cognitive dysfunction.

Additionally, four investments, as part of the ADDF’s Diagnostics Accelerator, focus on accelerating the discovery of innovative biomarkers and diagnostic technologies that will aid in Alzheimer’s diagnosis and clinical trial design.

Clinical funding

Nearly $2 million was earmarked for a Phase 1 clinical trial for an AAV-mediated gene therapy treatment of APOE4 homozygous Alzheimer’s disease lead by Dr. Ronald Crystal of LEXEO Therapeutics. ADDF began funding Crystal and his gene therapy project at Weill Cornell Medical College in 2004. Crystal’s group has generated what ADDF considers impressive preclinical data in animals delivering APOE2 to the brain using an injection method.

In his current Phase 1 clinical trial, Crystal is testing the safety and preliminary efficacy of the APOE2 gene therapy in people with two copies of the APOE4 gene who have mild cognitive decline or early dementia. With his new company, LEXEO Therapeutics, Crystal and his team seek to expand the work and move the program into Phase 2 trials.

Dr. John Olichney of the University of California, Davis (UC Davis) received a $600,000 award for a Phase 2 repurposing trial of senicapoc—originally developed for sickle cell anemia—for prodromal and mild Alzheimer’s disease. An interdisciplinary team of researchers at UC Davis identified a potassium activated calcium channel that modulates microglial activity as a novel anti-inflammatory target for Alzheimer’s disease, and senicapoc blocks this ion channel. The ADDF previously provided funding to manufacture the drug for this clinical trial, and is now providing add-on funding that will enable the team to expand the trial with additional patients. It will also add a brain imaging sub-study to help gain more insight into the drug’s effectiveness.

Preventive funding

Brain function may decline after surgery and older patients undergoing open heart surgery are especially at risk. Surgeries can trigger inflammation, which in turn can contribute to impaired insulin signaling in the brain, leading to cognitive dysfunction. Currently, there are no medications available that prevent or treat postoperative delirium or postoperative cognitive dysfunction.

With the help of just over $336,000 in ADDF funds, Dr. Dimitrios Kapogiannis of the National Institute on Aging will carry out the biomarker arm of a clinical trial supported by the ADDF which is testing whether intranasal insulin preserves cognitive function and decreases risk of postoperative delirium and postoperative cognitive dysfunction.

The intranasal route has the benefit of delivering insulin directly into the brain to decrease brain insulin resistance and brain inflammation. Intranasal delivery of insulin does not affect insulin levels in the blood, and therefore does not cause hypoglycemia. Kapogiannis and his team will isolate vesicles of neuronal origin from the patients’ blood to evaluate the treatment’s effect on insulin resistance in the brain.

Biomarker funding

ADmit Therapeutics has developed a way to measure the dysfunction inside cells by examining modifications to mitochondrial DNA, which can be associated with various disorders including neurodegenerative diseases, and will be aided by nearly $500,000 in funding from ADDF.

Researchers at the company have found that specific modifications of this DNA are predictive of progression to Alzheimer’s disease and may represent an early indicator of the disease. Development of a blood test to evaluate these DNA modifications could potentially enable better selection of patients for clinical trials and further understanding of the disease.

Meanwhile, Biological Dynamics Inc. has developed the Verita system, which enables the automated capture and analysis of proteins on the surface of exosomes, which can contain many types of biomarkers, including those that reflect pathological changes in the brain which indicate Alzheimer’s disease.

Detecting several exosome-based biomarkers has the potential to improve detection and diagnosis of Alzheimer’s, as well as enhancing drug discovery applications, and ADDF has pledged just over $1.8 million toward this work.

NeoNeuro, for its part, has developed a potentially revolutionary approach to diagnostics using aptamers, for which ADDF is providing a $363,000 award. Aptamers are small synthetic DNA sequences that bind to targets in blood that could be diagnostic of various stages of Alzheimer’s disease.

These aptamers can be rapidly and cost-effectively used on individual blood samples with the polymerase chain reaction platforms already available in testing laboratories. The blood test could potentially identify individuals with high levels of amyloid and aid in pre-screening of potential enrollees for clinical trials.

Finally, a team at the Sheba Medical Center, under the leadership of Dr. Ramit Ravona-Springer, is developing a novel virtual reality tool intended to objectively measure apathy. Apathy impacts many patients with Alzheimer’s disease and is often misdiagnosed as depression, leading to unnecessary and incorrect therapeutic intervention as well as increased caregiver burden. ADDF has assigned almost $250,000 toward this project.

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