# Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.

> **NIH NIH UG3** · BROAD INSTITUTE, INC. · 2020 · $2,240,361

## Abstract

PROJECT SUMMARY
In this proposal we aim to identify gene regulatory elements that permit the targeting and manipulation of brain
circuit models of human brain function. Gaining genetic access to specific neuron populations in nontransgenic
animals and humans would enable targeted circuit modulation for hypothesis testing and provide a means to
evaluate the safety and efficacy of circuit modulation for the treatment of epilepsy and psychiatric disorders. Our
approach capitalizes on our combined expertise in the development and maturation of brain cell-types and
circuits (Gord Fishell), identification of CIS-regulatory elements that function across species (Jordane
Dimidschstein) and AAV engineering combined with large-scale screening methods (Ben Deverman). Our efforts
will benefit from an ongoing collaboration with John Reynolds at the Salk Institute on observation and
manipulation of cortical circuits during complex visual perception tasks. This project will build upon success that
we and others have had in identifying gene regulatory elements that enable cell type-restricted gene expression
when used within recombinant adeno-associated virus (AAV) vectors. Identifying additional enhancer sequences
that function in the context of the limited carrying capacity of AAV has been slow due to the limited success rate
and low throughput nature of these efforts. Here we aim to apply a novel high-throughput screening approach
for the rapid identification of a suite of enhancers that enable the study and manipulation of genetically defined
cell types and circuits across species. Our preliminary data demonstrates that our enhancer identification
strategy can yield novel and highly specific enhancers that restrict expression to target populations. In addition,
we have demonstrated that it is possible to use the engineered AAV-PHP.eB capsid to screen enhancers across
the brain with a single noninvasive injection. These successes have highlighted the need for more rapid and
comprehensive assessment of putative enhancers. In the UH3 portion of this proposal we will examine the
tolerance to neuronal activity manipulation within the target neuronal populations in several species. We will also
apply the AAV-enhancer viruses for querying disease-related circuits using Rabies tracing in conjunction with
optogenetics. This proposal will be transformative in devising methods to target and manipulate the brain activity
of specific neuronal cell populations across species, including human cell-derived organoids.

## Key facts

- **NIH application ID:** 10001022
- **Project number:** 5UG3MH120096-02
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Benjamin E Deverman
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,240,361
- **Award type:** 5
- **Project period:** 2019-08-22 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001022

## Citation

> US National Institutes of Health, RePORTER application 10001022, Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species. (5UG3MH120096-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001022. Licensed CC0.

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