In the first two months of 2017, the Alzheimer’s Drug Discovery Foundation (ADDF) awarded eight new grants totaling over $4 million to advance treatments for Alzheimer’s and related dementias. Several of the awards support new approaches to treating these diseases.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “This significant investment demonstrates the ADDF’s bold approach. We are able to accelerate so many first-in-class drugs because we are willing to take risks on great ideas. Just because an approach is untested doesn’t mean it’s unsound. When a strong scientific rationale for a target is there, so is ADDF funding.”
Leen Kawas, PhD, M3 Biotechnology, Inc.
Phase I Clinical Trials of a Novel Small-Molecule Neurotrophic Activator
As Alzheimer’s disease progresses, our neurons degenerate and die. Neurotrophic growth factors can help neurons survive, which may slow Alzheimer’s disease and restore cognitive function. Dr. Leen Kawas is developing a small-molecule drug to activate one type, called hepatocyte growth factor (HGF), which has shown great potential for treating Alzheimer’s and other neurodegenerative disorders. In preclinical studies, Dr. Kawas’s drug, NDX-1017, restored brain functions. With this funding, she will conduct a first-in-humans Phase 1a clinical trial of NDX-1017 to evaluate its safety and determine optimal dosing range.
Kevin Hodgetts, PhD, Lab for Drug Discovery in Neurodegeneration (LDDN) at Brigham and Women’s Hospital and Harvard Medical School
Chiral Switching and Drug Repurposing: Evaluation of (R)-Ricobendazole
Tau is an integral component of our neurons’ transport system. In Alzheimer’s disease and several other disorders, however, tau loses its normal function and begins to accumulate into toxic tangles. Some drugs in development aim to prevent this tau aggregation, but a more effective approach may be to enhance tau clearance. Albendazole, an FDA-approved anti-parasitic drug, was recently shown to reduce levels of Alzheimer’s-related tau in cells. Dr. Hodgetts will conduct preclinical studies with a form of Albendazole that more easily crosses into the brain to determine whether it reduces tau in the brain and cerebrospinal fluid (CSF). These studies will provide a “proof-of-concept” for further development of the drug as a repurposed therapy for Alzheimer’s disease.
Michael Peel, PhD, Cypralis Ltd.
Selective Cyclophilin D Inhibitors for Neurodegeneration
The degeneration and death of neurons leads to the progression of Alzheimer’s disease. Mitochondria, the energy powerhouse inside neurons and other cells, can experience dysfunction that leads to cellular death. Previous studies indicate that Cyclophilin D, located within the mitochondria, is involved in the first steps of cell death, and inhibiting it could help delay or prevent the death of neurons. Dr. Peel and his colleagues at Cypralis have discovered new inhibitors of Cyclophilin D. With this funding, Cypralis will improve these Cyclophilin D-inhibiting compounds with the goal of developing them into an entirely new class of drugs for Alzheimer’s.
Yukari Perrella, MBA, Yuma Therapeutics Corporation
IND-enabling program for Yuma Therapeutics' novel and proprietary lead Hsp90 inhibitor, YT-83, for the treatment of Alzheimer's disease
The folding of proteins into their proper three dimensional configurations is essential for health. Molecular chaperones aid in proper protein folding and maintain protein stabilization. One of these molecular chaperones, Hsp90, becomes overactive in neurons of Alzheimer’s patients. As a result, tau proteins misfold into toxic forms, which lead to the formation of tau tangles. With previous ADDF funding, researchers at Yuma Therapeutics developed a novel small molecule Hsp90 inhibitor that significantly reduced toxic tau proteins in preclinical studies. Now, Yuma researchers will complete the initial phase of studies needed for the FDA’s investigational new drug (IND) application, which is required before human trials can begin. If the IND application is approved, Yuma’s drug will become the first Hsp90 inhibitor to enter clinical trials for Alzheimer’s disease.
Xinglong Wang, PhD, Case Western Reserve University School of Medicine
Mitochondrial TDP-43 as a Novel Therapeutic Target for Frontotemporal Dementia
A protein called TDP-43 accumulates into clumps in the brains of patients with frontotemporal dementia (FTD). FTD is the second most common form of dementia after Alzheimer’s disease in those under age 65. Dr. Wang recently published groundbreaking research findings demonstrating that TDP-43 accumulates in neurons’ mitochondria, which are the “energy powerhouse” of the cell, likely leading to the death of the neuron. In this study, Dr. Wang will test whether the suppression of TDP-43 mitochondrial accumulation could be a promising novel therapeutic approach for FTD patients.
Yan Jessie Zhang, PhD, University of Texas, Austin
Fragment-Based Inhibitor Design of Human Scps for Neuron Regeneration
Unlike other cells in the body, adult neurons cannot repair themselves after being damaged by diseases such as Alzheimer’s. While Alzheimer’s patients progressively lose brain cells, their neuronal stem cells (immature cells that regenerate neurons) remain dormant. Dr. Zhang has identified a multi-protein complex called REST, which represses the expression of genes that help convert stem cells into neurons. With previous ADDF funding, Dr. Zhang developed chemical compounds that modulate REST and reactivate neuronal stem cells. In the current project, Dr. Zhang will search for chemical compounds with similar capabilities but higher likelihood of advancing to human trials. If successful, this approach could stimulate the generation of new neurons and reverse cognitive impairment in Alzheimer’s patients.
Shijun Zhang, PhD, Virginia Commonwealth University
Target identification and mode of action studies for novel NLRP3 inflammasome inhibitors
Inflammation in the brain is a major underlying factor in the development of Alzheimer’s disease. Recent studies have linked Alzheimer’s progression with elevated activity of the NLRP3 inflammasome, which regulates immune response. Dr. Zhang and colleagues have been developing novel inhibitors of the NLRP3 inflammasome that reduced Alzheimer’s pathology in preclinical studies. With this funding, Dr. Zhang will build on data generated over the last year of ADDF funding to refine and improve the binding of the NLRP3 inflammasome inhibitors. His goal is to make create a more potent drug that can reverse harmful inflammation in Alzheimer’s disease.
Sharon Inouye, MD, MPH, Hebrew SeniorLife
Exploring the Role of Inflammation in Long-Term Cognitive Decline Following Surgery and Delirium
A major cause of cognitive decline in older adults is surgery, with as many as 10 million patients suffering from postoperative delirium each year. These patients have a 6-fold higher risk of developing dementia, by conservative estimates, suggesting that surgery accelerates the onset of dementia in high-risk patients. Anti-inflammatory drugs may be effective treatments to prevent cognitive decline following surgery, but to test them we need to be able to identify patients at high risk for post-operative decline and biomarkers to reliably track inflammation. With this funding, Dr. Inouye will use an existing data set of patients who underwent surgery to develop a predictive model. And, using a new sample of patients undergoing major surgery, she will identify plasma, cerebrospinal fluid (CSF), and neuroimaging biomarkers of inflammation.