# JAX-Gladstone, SCGE Disease Models Studies Supplement

> **NIH NIH U01** · J. DAVID GLADSTONE INSTITUTES · 2022 · $200,000

## Abstract

PROJECT SUMMARY/ABSTRACT
We propose to use somatic cell genome editing by CRISPR/Cas9 approaches in vivo to treat two mouse models
of inherited peripheral neuropathy (Charcot-Marie-Tooth disease, CMT) in a collaboration between the
Gladstone Institutes (Conklin, U01-ES032673) and The Jackson Laboratory (JAX, Murray and Lutz, U42-
OD026635). CMT is a collection of incurable crippling peripheral neuropathies with overall prevalence of 1:2500
people. Certain CMT mutations result in dominant-negative alleles that could be corrected by allele-specific
silencing with CRISPR/Cas9. CMT type 2E (CMT2E) is caused by dominant mutations in the neurofilament light
chain gene (NEFL). We have used allele-specific genome editing to silence the severe NEFLN98S allele in patient-
derived iPSCs, reversing the disease phenotype. In Aim 1 we will extend our in vitro studies to an existing
NeflN98S mouse model of CMT2E. Similarly, CMT type 2D (CMT2D) is caused by dominant negative mutations
in glycyl tRNA-synthetase (GARS). We have shown that AAV9 delivery of allele-specific RNAi targeting the
mutant Gars mRNA was able to effectively prevent disease in two mouse models of CMT2D including the
GarsDETAQ allele. In Aim 2, we will test in vivo allele-specific genome editing in mice targeting the GarsDETAQ
allele. Together, these studies will establish the levels of genome editing that improve the neuropathy
phenotypes by measuring the editing efficiency, testing clinically relevant phenotypic outcomes, and profiling
toxicological and off-target effects. Vector design and packaging, as well as evaluation of editing efficiency will
be done at Gladstone. In vivo preclinical studies will be done at JAX.

## Key facts

- **NIH application ID:** 10620067
- **Project number:** 3U01ES032673-05S1
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Bruce R Conklin
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $200,000
- **Award type:** 3
- **Project period:** 2018-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620067

## Citation

> US National Institutes of Health, RePORTER application 10620067, JAX-Gladstone, SCGE Disease Models Studies Supplement (3U01ES032673-05S1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10620067. Licensed CC0.

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