# Structurally Diverse GABA-A a5 Positive Allosteric Modulators for Treatment of MCI due to AD

> **NIH NIH R44** · AGENEBIO, INC. · 2021 · $625,713

## Abstract

The overall objective of this SBIR application is to develop a potent, selective and orally active
GABA-A α5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive Impairment
due to Alzheimer’s Disease (MCI due to AD). There are currently no approved therapeutics for
this indication making this an area of extremely high unmet need. There is strong support from
preclinical AD models and human patients, particularly in this early stage of AD, that neuronal
circuits in the hippocampus become excessively active contributing to neuronal pathology and
brain dysfunction. AgeneBio’s GABA-A α5 PAM program represents a novel approach to
addressing the excess hippocampal activity in this patient population at high risk for dementia.
The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported
by recent preclinical and clinical studies using the atypical antiepileptic levetiracetam. Ranging
from research on age-associated memory impairment in rodents to clinical studies in patients
with amnestic MCI, beneficial effects on key circuits in the medial temporal lobe/hippocampus
and on memory performance have been demonstrated by treatment at low doses of
levetiracetam that reduce hippocampal overactivity. The strong hippocampal localization of
GABA-A α5 receptors coupled with its role to control tonic inhibition make GABA-A α5 PAMs
well suited to reduce the excess hippocampal activity in MCI due to AD.
Preclinical studies in rats with age-associated memory loss which show hippocampal
overactivity demonstrate that selective GABA-A α5 receptor PAMs are effective therapeutic
agents to improve memory. The screening tree is well defined, all assays are in place, and
compounds have advanced through the screening tree.
The program lead series (funded by the Blueprint Neurotherapeutics Network) has potent and
selective GABA-A α5 PAM compounds with good in vivo efficacy in an age-impaired rat.
However, should the lead series falter at any point for reasons independent of mechanism of
action, it is critical that a second series be identified that could rapidly be evaluated to mitigate
the overall program risk. The purpose of this SBIR grant is to expand the structurally distinct,
non-BZD second series scaffold to identify potent and selective GABA-A α5 compounds for the
treatment of MCI due to AD.

## Key facts

- **NIH application ID:** 10248568
- **Project number:** 5R44AG063607-03
- **Recipient organization:** AGENEBIO, INC.
- **Principal Investigator:** Sharon Rosenzweig-Lipson
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $625,713
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248568

## Citation

> US National Institutes of Health, RePORTER application 10248568, Structurally Diverse GABA-A a5 Positive Allosteric Modulators for Treatment of MCI due to AD (5R44AG063607-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248568. Licensed CC0.

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