# Novel AAVs engineered for efficient and noninvasive cross-species gene editing throughout the central nervous system

> **NIH NIH UG3** · BROAD INSTITUTE, INC. · 2020 · $819,283

## Abstract

Project Summary:
Many genetic diseases that affect the central nervous system (CNS) remain untreatable due to a lack effective
small molecule drugs or biologics. Targeting the genetic underpinnings of these diseases with somatic cell gene
editing would therefore be particularly impactful, but its successful implementation will require methods to safely
and efficiently deliver genes and gene editing machinery throughout the CNS. AAVs are the state-of-the-art
vehicles for in vivo gene transfer because they can provide safe and long lasting in vivo gene expression. AAVs
are the only gene therapy vectors that have been approved for direct administration to humans by regulatory
agencies in both the US and Europe. Moreover, in 2017, AAVs became the first vehicle used as part of an early
phase clinical trial to evaluate the safety of in vivo gene editing. Despite their impressive preclinical and clinical
safety record, naturally occurring AAVs tested to date lack the efficiency required for gene delivery across most
organ systems, including the CNS. To address the need for better vehicles for CNS gene delivery, we recently
used directed evolution and a new cell type-specific in vivo selection method to engineer several novel AAVs,
most notably AAV-PHP.B and AAV-PHP.eB, that have, for the first time, made it possible to noninvasively
transfer genes to the majority of neurons and astrocytes throughout the adult mouse CNS. Here, we aim to build
upon the success of this selection approach by engineering AAVs that enable efficient gene transfer throughout
the CNS of multiple species, including nonhuman primates. The AAVs we develop will be evaluated in several
species for their ability to provide CNS-wide transgene expression and targeted genome editing in neurons, and
improved AAV variants will be shared with the scientific community. Successful completion of this project, which
involves pairing the new AAVs with next-generation gene editing technologies, will provide support for evaluating
the safety of CNS gene editing in human trials.

## Key facts

- **NIH application ID:** 10001044
- **Project number:** 5UG3NS111689-03
- **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:** $819,283
- **Award type:** 5
- **Project period:** 2018-09-30 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001044

## Citation

> US National Institutes of Health, RePORTER application 10001044, Novel AAVs engineered for efficient and noninvasive cross-species gene editing throughout the central nervous system (5UG3NS111689-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001044. Licensed CC0.

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