# Genetic Correction of Mutant Huntingtin in Vivo

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $424,375

## Abstract

The proposed research is intended to determine if a monogenetic disease such as Huntington's disease (HD)
can be treated by using homologous recombination (HR) to genetically correct the disease containing allele in
vivo. The approach will utilize a genome engineering system, CRISPR (Clustered Regulatory Interspaced
Short Palindromic Repeats) delivered in vivo. In recent work in HD-iPSCs (induced pluripotent stem cells), we
utilized homologous recombination to genetically correct the disease containing cells and found this completely
reverses HD disease phenotypes. We have adapted the CRISPR technology to carry out genetic
correction/expansion and have found very high levels of homologous recombination in human cells
(Preliminary Results). The overall goal is to use this technology in vivo and carry out genetic correction of
disease-containing mutations such as the CAG expansion in huntingtin (HTT). This work will serve as a proof
of concept to demonstrate utility not only for monogenic neurodegenerative diseases but also for other types of
genetic diseases. To achieve our goals we will carry out the following aims: Specific Aim 1. To demonstrate
robust CRISPR-mediated recombination of the mutant HTT in human HD patient-derived neural cells using
lentivirus; Specific Aim 2. To demonstrate robust CRISPR-mediated recombination in mouse models of HD
expressing the human HTT protein using viral delivery; Specific Aim 3. To develop a protein-mediated delivery
system using the nickase Cas9 D10A protein, gRNA and DNA to mediate homologous recombination in
human-patient HD neural stem cells and HD mouse models. These studies will advance our understanding of
how to perform genetic correction in cells derived from the brain. The successful demonstration of in vivo
genetic correction of the disease allele in the brain would be a major leap forward in neuroscience.

## Key facts

- **NIH application ID:** 10011868
- **Project number:** 5R01NS094422-05
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Lisa M Ellerby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,375
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011868

## Citation

> US National Institutes of Health, RePORTER application 10011868, Genetic Correction of Mutant Huntingtin in Vivo (5R01NS094422-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10011868. Licensed CC0.

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