A New Approach to Treating Alzheimer's Disease

Stephen Martin, PhD
University of Texas at Austin (Austin, TX)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to August 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$185,020
Grant Reference ID:
A2016443S
Award Type:
Standard
Award Region:
US Southern

This grant is made possible in part by a bequest from the Trust of Francis C. Dykeman and in honor of Marie E. Dykeman.

A New Approach to Treating Alzheimer's Disease

Summary

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting the elderly, but all approved medications for AD only temporarily address the symptoms, not the progression, of AD.  Because there is an urgent, unmet need for drugs to treat both the symptoms and the disease, the proposed program will explore a novel strategy to treat AD by targeting a biological pathway different from those of all existing drugs and all but one known clinical candidate. If successful, a compound will be identified that holds promise for those suffering from AD, thus representing a new way to treat this devastating disease.

Details

The overall goal of this project is to identify a new drug lead that may be further developed to treat Alzheimer's disease (AD) through a mode of action that is different from currently available therapies.

Our first specific aim is to improve the drug-like properties of our current lead. We will use contemporary medicinal chemistry strategies to design and prepare new analogs that bind better and more selectively to a receptor (sigma receptor 2/progesterone receptor membrane component 1, or Sig2R/PGRMC1) that has only recently been associated with AD. The main thrust of this phase of our study is to identify a potential clinical candidate that can be orally dosed. We will first evaluate all new compounds in assays to determine their relative potencies and selectivities, and then we will assess the drug-like properties of the more promising candidates in a range of tests to assess their relative oral bioavailability.

Our second specific aim is to elucidate how compounds that bind to Sig2R/PGRMC1 affect neuron health and function. This important goal will be achieved using a series of electrophysiology and imaging techniques to study hippocampal neurons in vitro. These experiments will enable us to assess and understand how neuron firing, synapse plasticity, intracellular calcium ion levels, and morphology vary upon exposure to our compounds.

Our third specific aim is to assess how an optimized, orally-bioavailable drug candidate affects behavior and cognition in animal models. We will first perform a series of studies to determine oral bioavailability, brain exposure, and tolerance of several new compounds. We will then evaluate how the most promising clinical candidate affects performance of healthy and transgenic AD mice in a series of learning and memory tests. Plasma and tissue will then be analyzed for evidence of toxicity, and brain tissue will be studied for signs of reduced inflammation and neuroprotection.

The positive impacts arising from completion of our research are significant. We expect to identify an orally bioavailable lead to treat AD that can be advanced in studies that will enable filing of an Investigative New Drug Application with the FDA. Importantly, this new therapeutic approach has the potential to not only treat disease symptoms, but to slow disease progression. We anticipate that our neurophysiology studies will provide a better understanding of how Sig2R/PGRMC1 is involved in the health and function of neurons, and how modulating this receptor affects synapse integrity and communication between neurons. This knowledge will generally lead to a greater understanding of neurodegenerative processes and how these aberrant pathways might be suppressed. 

About the Researcher

A native of New Mexico, Stephen Martin received his Bachelor of Science degree in chemistry from the University of New Mexico, whereupon he went to Princeton University, where he received his PhD degree. After postdoctoral years at the University of Munich and Massachusetts Institute of Technology, he joined the faculty at the University of Texas at Austin in 1974, where he currently holds the M. June and J. Virgil Waggoner Regents Chair in Chemistry. His research interests lie broadly in organic and bioorganic chemistry and chemical biology. He is especially renowned for his work in the synthesis of biologically-active heterocyclic natural products and for studies of energetics and structure in protein-ligand interactions. He has recently collaborated on the design and synthesis of small molecules that may be used as molecular probes to study biological function and as potential leads to treat cancer and neurodegenerative and neurological disorders. He has received numerous awards, including the NIH Career Development Award; an American Cyanamid Academic Award; the Alexander von Humboldt Prize; an Arthur C. Cope Scholar Award; a Japanese Society for the Promotion of Science Award; a Wyeth Research Award; and, most recently, the International Society of Heterocyclic Chemistry Senior Award. He is a fellow of the American Association for the Advancement of Science, and he serves as an editor of Tetrahedron and as chairman of the Executive Board of Editors for Tetrahedron Publications. He has published over 310 scientific papers in primary journals, reviews, and articles, and he has authored a number of patent applications. He is co-author of the popular undergraduate laboratory book, Experimental Organic Chemistry: A Miniscale and Microscale Approach. On the all too rare occasions he is not engaged in professional activities, he enjoys music, travel, fly fishing, photography, and being with his wife and daughter.

James Sahn will be collaborating on the project. Dr. Sahn received his PhD from North Carolina State University, whereupon he joined Stephen Martin’s group at the University of Texas at Austin as a postdoctoral fellow. He is currently a research scientist in the Department of Chemistry. His research interests include organic synthesis, medicinal chemistry, neurodegenerative disease biology, and brain health. He currently directs a variety of collaborative projects focused on understanding the role of the membrane protein Sig2R/PGRMC1 in disorders of the central nervous system. His team has developed small molecule chemical tools for studying Sig2R/PGRMC1 and elucidating its involvement in neuron function. They have thus recently discovered drug leads for neurodegenerative diseases and traumatic brain injury. He is listed as a co-inventor on six patent applications. He is passionate about cooking, yoga, and spending time with his wife and boys.

Personal Story

This promising research program, which is targeted toward developing new approaches to treat Alzheimer’s disease (AD), emanates from our keen interest in creating new molecules that have potential applications in medicine. These investigations led to the serendipitous discovery that some novel compounds we designed are potent and selective binders of a receptor found in the brain that has not been well-studied in the context of neurodegenerative disease. After preliminary studies by our team established critical links between this receptor and neuron health and cognition in animal models, we will now focus upon evaluating whether compounds that modulate this receptor might be developed into a new approach to treat the symptoms and slow the progression of AD--an outcome that represents the 'Holy Grail' of AD research. Because we have personally witnessed the devastation that AD wreaks upon family members, we are especially grateful to the donors of BrightFocus for supporting this exploratory program that seeks to shine new light on AD.

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