# Research Project I: AAV-CRISPR to Treat Huntington's Disease

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $1,396,185

## Abstract

PROJECT SUMMARY / ABSTRACT
Background: Huntington's disease (HD) is a fatal, dominant neurogenetic disorder caused by
polyglutamine repeat expansion in exon 1 of the HD gene encoding huntingtin (HTT). It is
estimated that 1−3 in every 10,000 persons (nearly 30,000 in the USA) have HD. Patients suffer
from progressive neurodegeneration in the basal ganglia and the cortex, leading to progressive
movement disorders and severe psychiatric disturbances. Although the disorder was described
over 100 years ago, effective treatments do not exist. Genome editing using the precise and
potent CRISPR-Cas9 system represents an exciting therapeutic approach to treat HD. The
proposed study will employ the CRISPR-Cas9 system delivered via novel engineered capsid of
adeno-associated-virus (AAV), AAV-LC.V1.
Objective: We propose to determine efficacy and safety of the dual AAV-LC.V1 genetic therapy
in the brain using animal models. The results of these studies are essential components for our
Investigational New Drug (IND) application to the Food and Drug Administration (FDA) for clinical
testing of our HD program.
Specific Aims: Aim 1 will focus on in vitro screening a pair of gRNAs for the most frequent mutant
human HTT gene haplotypes. These studies will test the efficacy of knocking down the mutant
HTT allele as well as off-target editing. Aim 2 will determine the efficacy of knocking down the
mutant HTT allele in two murine models of HD via AAV-CRISPR. The vectors will be injected by
convection-enhanced delivery directly into the mouse brain (striatum and thalamus). To assess
overall therapeutic benefit, efficiency of editing at the molecular level will be tested in collected
tissues, while assessment of rescue from an HD phenotype will be evaluated by a battery of
behavioral tests. Aim 3 will examine toxicity and biodistribution of different doses of our AAV-
CRISPR system in rats in a GLP-compliant setting as required for IND-enabling studies. Tissues
will be collected at 3- and 9-months for histopathological evaluation to prepare the required GLP
toxicology report. As required by the FDA, acute and long-term efficacy, safety, and biodistribution
of the two-AAV-CRISPR vector system will be also assessed in the brains of non-human primates
(Aim 4). Many proposed experiments will be performed by specialized preclinical CROs in a GLP-
compliant setting.
Impact: By demonstrating the safety and efficacy of AAV-LC.V1-CRISPR gene therapy, the
proposed suite of studies may lead to clinical testing of this system to treat the progressive
neurodegeneration associated with HD.

## Key facts

- **NIH application ID:** 10840859
- **Project number:** 5U19NS132303-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Russell Lonser
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,396,185
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840859

## Citation

> US National Institutes of Health, RePORTER application 10840859, Research Project I: AAV-CRISPR to Treat Huntington's Disease (5U19NS132303-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10840859. Licensed CC0.

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