# Therapeutic genome editing to treat Best disease

> **NIH NIH R01** · J. DAVID GLADSTONE INSTITUTES · 2020 · $472,500

## Abstract

PROJECT SUMMARY/ABSTRACT
A heterozygous hexanucleotide (GGGGCC) repeat expansion in a single allele of the C9orf72 gene is the most
frequent known genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two
fatal and irreversible neurodegenerative diseases. Given that there are no effective treatments for FTD (an
Alzheimer’s-related dementia) and ALS, novel therapeutic strategies are urgently needed. Targeting the
C9orf72 gene itself by CRISPR/Cas9 gene editing may provide a curative intervention.
This work proposes novel applications of CRISPR gene editing technology to edit or silence the pathogenic
C9orf72 disease gene in FTD/ALS patient derived induced pluripotent stem cells (iPSCs). Three editing
strategies will be evaluated for ability to correct the pathologic C9orf72 repeat expansion, including: (A) bi-
allelic excision of the repeat expansion, (B) SNP-based allele-specific inactivation of the mutant allele leaving
the normal allele intact (Aim 1) and (C) disruption of a regulatory promotor region to silence gene expression
(Aim 2). We will examine the ability of these editing strategies to correct disease pathology in cell types
relevant to disease – human cortical and motor neurons. We have developed rapid, robust methods to
generate neurons from human iPSCs derived from controls and patients. Analysis of edited control cell lines
will allow us to screen for unanticipated effects of precise gene edits on normal cellular function and fitness.
Our findings will not only advance our understanding of potential therapeutic approaches, but will also inform
our understanding C9orf72 biology, including C9orf72 gene regulation and potential mechanisms of disease.

## Key facts

- **NIH application ID:** 10123898
- **Project number:** 3R01EY028249-04S1
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Bruce R Conklin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,500
- **Award type:** 3
- **Project period:** 2017-09-30 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123898

## Citation

> US National Institutes of Health, RePORTER application 10123898, Therapeutic genome editing to treat Best disease (3R01EY028249-04S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10123898. Licensed CC0.

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