The Alzheimer’s Drug Discovery Foundation (ADDF) announces 10 new grants totaling over $2.6 million. These awards are driving promising new approaches to treating and diagnosing Alzheimer’s and related dementias.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “We ensure that promising new ideas to treat Alzheimer’s have the seed funding they need to advance. The pipeline of drugs in development is diverse because of investments like these, and the ADDF will continue to accelerate the progress of these programs and others like them as they move toward the clinic.”
Steven Finkbeiner, MD, PhD, The J. David Gladstone Institutes/UCSF
Utility of Potent Small Molecule Inducers of Autophagy as Potential Agents to Lower Levels of Tau
The abnormal buildup of tau proteins—resulting in toxic tangles—is a hallmark of Alzheimer's disease. One of our brain’s major defenses against accumulating toxic proteins such as tau is a cellular recycling system called autophagy. Treatments that enhance autophagy may help clear excess tau and slow the progression of Alzheimer’s. Dr. Finkbeiner has developed novel small molecules that enhance autophagy in brain cells and may be effective for treating other neurodegenerative diseases such as ALS and Huntington's. With this funding, Dr. Finkbeiner and his colleagues will conduct preclinical tests of the small molecules to further evaluate their potential effectiveness using innovative robotic microscopy developed in the Finkbeiner lab. If successful, he plans to develop the most promising of these small molecules into drugs for later clinical testing.
Thomas Franke, MD, PhD, New York University School of Medicine
Targeting Calcium Dysregulation in Alzheimer’s Disease
Calcium-dependent signaling in brain cells is critical for normal brain function and cognition; the failure of calcium signaling can lead to the cell death seen in Alzheimer’s disease. Researchers have identified a “hub” for calcium signaling—CaMKK2—that is involved in the formation of tau tangles in Alzheimer’s disease. With this grant, Dr. Franke and his team will develop and test potential CaMKK2-inhibiting drugs, using a computer-aided drug design approach. Dr. Franke’s group will eventually use these compounds to test whether inhibiting CaMKK2 reduces cognitive deficits in Alzheimer’s. If successful, this would validate a new target and a new set of compounds as potential treatments for Alzheimer’s disease.
Masashi Kitazawa, PhD, University of California, Irvine
A Potent Lipoxin Analogue as a Potential Treatment for Alzheimer's Disease
Normally, inflammation protects the body from harm and then turns off. But as we age, inflammation is more likely to last longer than needed. Chronic inflammation in the brain plays a pivotal role in the onset and progression of Alzheimer’s disease, because it damages brain cells. Researchers have discovered chemical signals called pro-resolving molecules, which can turn off the immune response. With this funding, Dr. Kitazawa will test a novel compound that mimics one of these pro-resolving molecules, called lipoxin, to reduce chronic brain inflammation, related Alzheimer’s pathology, and cognitive dysfunction. If successful, this study will provide important preclinical data to support future transition into the clinic.
Chien-liang Lin, PhD, The Ohio State University
Development of Small Molecule Activators of Glutamate Transporter EAAT2 Translation for Alzheimer's Disease
Glutamate, an amino acid, is an important chemical messenger in the brain. While glutamate is critical for normal brain function, excessive levels can be toxic to brain cells. Normally, glutamate levels are maintained by the EAAT2 protein, which removes excess amounts and prevents glutamate-induced damage in the brain. Loss of the EAAT2 protein is commonly found in Alzheimer's disease patients. Dr. Lin has identified compounds that increase the production of EAAT2. Preliminary studies with one of these compounds restored memory, improved brain cell connections, and reduced levels of beta-amyloid plaques. Over the last two years of ADDF funding, Dr. Lin has made extensive progress in developing compounds with improved drug-like properties. With this funding, he will continue optimizing these compounds and identify the best candidate for human clinical trials. Dr. Lin was previously selected as an ADDF-Harrington Scholar through a partnership with the Harrington Discovery Institute.
Christopher Norris, PhD, University of Kentucky College of Medicine
Preclinical Assessment of the Therapeutic Utility of Small Molecule Inhibitors of the Calcineurin/NFAT System in Alzheimer’s Disease
Gene expression is regulated by a complex system, involving many factors. One such factor is NFAT, which works with another factor called calcineurin and is involved in the brain’s immune response and the function of synapses. Overactivation of the NFAT-calcineurin system can lead to neuroinflammation and brain cell death, and it is associated with early stages of Alzheimer’s disease. Current FDA-approved drugs that inhibit calcineurin hold promise as Alzheimer’s treatments, but can cause many adverse side effects. In this project, Dr. Norris will test a novel compound that inhibits NFAT activity, but not calcineurin (the cause of the adverse effects. If preclinical testing shows it to be safer than current drugs, Dr. Norris plans to further develop this compound as a treatment for Alzheimer’s disease.
Evgeny Rogaev, PhD, University of Massachusetts Medical School
Targeting APOE4 in Alzheimer's Disease by Novel RNA-based Therapeutic Compounds
APOE is the most common gene associated with late-onset Alzheimer’s disease. It comes in three different forms—e2, e3, and e4—and those carrying the e4 version are at higher risk of developing Alzheimer’s. Preclinical studies have shown that reducing expression of the APOE4 gene reduces Alzheimer’s pathology. Dr. Rogaev along with Dr. Anastasia Khvorova and their team have developed a new class of gene therapies that can interfere with the expression of genes with unprecedented efficiency, safety, and wide distribution throughout the brain. With this grant, they plan to use this new gene therapy technology to design several molecules to specifically target and reduce APOE4. Dr. Rogaev and Dr. Khvorova will then test these molecules to determine which is the most efficient at lowering APOE4 gene expression and therefore appropriate for further development.
Sharon Rosenzweig-Lipson, PhD, AgeneBio Inc
GABA-A alpha-5 Positive Allosteric Modulators for the Treatment of MCI Due to Alzheimer's Disease
Mild cognitive impairment (MCI) is an intermediate stage between normal cognition and Alzheimer's disease in which memory and cognitive abilities are worse than expected for a person’s age. Approximately 80% of patients with MCI progress to Alzheimer's disease within 7 to 10 years. AgeneBio’s goal is to develop therapies for MCI to prevent the onset of Alzheimer’s disease. It already has a repurposed drug, AGB 101, advancing into a Phase 3 clinical trial in MCI patients. With this funding, Dr. Rosensweig-Gibson and her colleagues will develop novel drugs to target brain hyperactivity, which prior research suggests is a major contributor to cognitive decline and MCI. These novel drugs are designed to enhance the activity of the GABA-A alpha-5 receptor, which improves memory function in preclinical testing.
Tamara Maes, PhD, Oryzon Genomics S.A.
Clinical Development of a Companion Biomarker for the Dual LSD1/MAO-B Inhibitor ORY-2001
Epigenetic mechanisms determine how much a gene is expressed by increasing or decreasing its expression levels, without affecting the underlying genetic code. Prior research has shown that some epigenetic changes—caused by lifestyle factors including stress—have significant effects on genes that control learning and memory and can lead to Alzheimer’s disease. With prior funding from the ADDF, Dr. Maes and her team at Oryzon developed the epigenetic drug ORY-2001, which is now preparing for Phase 2 clinical trials in Alzheimer’s patients. With this funding, Dr. Maes plans to develop a companion biomarker to assess epigenetic changes in human brains. If successful, the effect of ORY-2001 in humans can be monitored by measuring these changes in future clinical trials. This will help identify patients that could benefit most from treatment with ORY-2001 and improve the design and potential success of future clinical trials.
Dominic M. Walsh, PhD, Brigham & Women's Hospital
Neurally Derived Exosomes for the Diagnosis and Staging of Sporadic Alzheimer's Disease
Recent clinical trials in Alzheimer’s disease have highlighted the need for biomarkers to better diagnose study participants and monitor their response to therapy. Two proteins are strongly linked to Alzheimer’s—tau and beta-amyloid. Current tools—brain imaging and measuring proteins levels in cerebrospinal fluid—can diagnose early symptomatic stages of Alzheimer’s disease but are very expensive and/or painful. Thus, there is an urgent need for less costly and intrusive tests. Recently, researchers discovered that brain cells release small packages called extracellular vesicles, which have contents similar to brain cells. These extracellular vesicles can pass from the brain into the blood and therefore provide a unique opportunity to detect changes occurring in the brain. With this funding, Dr. Walsh will isolate extracellular vesicles from blood and analyze their tau and beta-amyloid levels. The ultimate goal of this work is to develop a simple, inexpensive blood test to diagnose individuals with early stage Alzheimer’s and identify those at risk of developing the disease.
Richard Mohs, PhD, Global Alzheimer's Platform Foundation
A Pilot Project to Enhance Recruitment into Clinical Trials Supported by ADDF
The Global Alzheimer's Platform (GAP) initiative aims to speed up clinical trials of potential Alzheimer’s treatments by improving patient recruitment. Recruitment for Alzheimer’s trials is often slow, leading Phase 2 and 3 trials to take up to 8 years to complete. Recruitment challenges are even greater for trials seeking patients at risk of Alzheimer’s because many don’t know they are at risk. The GAP initiative is working to increase the number of potential study participants developing a comprehensive network around trial sites. Its methods include: volunteer registries; collaborations between health insurers, accountable care organizations, government agencies, and clinical trial sites; and national trial recruitment call centers to screen potential participants. This funding supports the network of GAP clinical sites (GAP-Net) in setting up and using these recruitment resources.