# Unlocking microglia targeting for neurotherapeutics

> **NIH NIH DP5** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $445,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Microglia are the long-lived resident macrophages of the brain and spinal cord, which constantly
survey the microenvironment to respond rapidly to injury and infection. Unlike neurons or other
glia, microglia are transplantable, making them ideal candidates for targeted therapies to treat
neurological diseases. A major barrier to creating and refining such treatments is an inability to
genetically engineer microglia with lentiviruses. This proposal aims to identify and overcome
microglia restriction factors to enable gene editing with lentiviruses and gain insights into
microglia-mediated antiviral immunity. Aim 1 will test the hypothesis that cGAS/STING, a
known anti-viral pathway, underlies microglial viral restriction using inhibitors and transgenic
mouse microglia in vitro, with in vivo validation using a new microglia-specific Cre mouse. In Aim
2, I will perform an unbiased microglia-focused CRISPR knockout screen using newly created
AAVs with microglia tropism to discover new anti-viral pathways that prevent lentiviral infection.
Aim 2 demonstrates the first CRISPR screen in primary microglia. This Early Independence
application offers a vision for my independent research program. It is based on a platform of
microglia-based discovery tools I created over the last decade, and driven by my work as a
pediatric neurologist who cares for children with neuroimmunological conditions including
leukodystrophies and interferonopathies. It will provide new approaches to genetic targeting of
microglia for neurotherapeutics, direct testing of microglia antiviral immunity, and will influence
future directions related to the neurological sequelae of HIV latency and the pathogenesis of
neuroimmunological disease.

## Key facts

- **NIH application ID:** 10932153
- **Project number:** 5DP5OD036159-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Mariko L. Bennett
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,000
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932153

## Citation

> US National Institutes of Health, RePORTER application 10932153, Unlocking microglia targeting for neurotherapeutics (5DP5OD036159-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932153. Licensed CC0.

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