Grant: Project Grant

Cognitive deficits, including impaired attention, learning, memory and problem solving, occur in the majority of depressed patients and are a hallmark of normal aging. They greatly reduce the quality of life for affected individuals and their family, and significantly impact the health care system and society's productivity. Notably, cognitive deficits are not treated, and in some cases are negatively affected by current drugs, and persist in periods of remission. In normal aging and depression, we previously reported biological changes affecting a subtype of brain cells that provide chemical inhibition, namely somatostatin (SST)-positive GABA neurons. Preclinical rodent models confirm the alterations in SST-neurons and support a causal role in cognitive deficits. SST-neurons signal through a5-GABA-A receptors (a5-GABAA-R), suggesting that augmenting brain inhibition through a5-GABAA-R may have pro-cognitive effects. Over the last 10+ years we and colleagues have developed and optimized a series of compounds that activate a5-GABAA-Rs and that display drug-like properties and therapeutic efficacy in mouse models of cognitive deficits in depression and during aging. A patent application was submitted and conversations are on-going with biotech companies. Here we will select the best candidate among our optimized leads, based on drug-like profile and therapeutic efficacy (Aim 1). We will then complete studies under regulatory guidelines to submit a new drug application to health care regulatory institutions (Aim 2). Finally, we will develop in parallel a non-invasive neurophysiological tool to measure brain inhibition in human subjects (Aim 3). This tool will be used to stratify patients based on pathological severity, and to facilitate subsequent clinical trials. Industry partnership will be sought throughout the project. At completion, this project will deliver the first potential cognitive enhancer drug and a companion diagnostic tool to test it in humans.