# C9orf72 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis(ALS): using patient cells and CRISPR to reveal therapeutic approaches

> **NIH NIH RF1** · J. DAVID GLADSTONE INSTITUTES · 2022 · $239,309

## Abstract

PARENT PROJECT SUMMARY/ABSTRACT
A hexanucleotide (GGGGCC) repeat expansion in a single allele of C9orf72 is the most common cause of
frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative of which
there is currently no cure. Since there are no effective treatments for FTD (an Alzheimer’s related dementia)
and ALS, there is a critical need for novel therapeutics. Targeting C9orf72 with CRISPR/Cas9 gene editing
presents a promising candidate therapy. Improving our understanding of the biology of C9orf72 will facilitate
employing gene editing strategies. This work utilizes novel applications of CRISPR to specifically edit or
silence the diseased allele in FTD/ALS patient-derived induced pluripotent stem cells (iPSCs). Completing
these aims generates a systematic evaluation of three complementary gene editing strategies for C9-FTD/ALS:
1) bi-allelic excision within the first intron harboring the repeat expansion (Aim 1), (2) allele-specific excision of
the mutant allele harboring the repeat expansion (Aim 2), (3) disruption of regulatory regions to selectively
silence theC9orf72 repeat expansion (Aim 3). Furthermore, we compare the ability of the editing strategies to
correct disease pathology in cell types relevant to disease–human cortical and motor neurons–made possible
by the fast and robust methods we developed to generate neurons from iPSCs derived from controls and
patients. Analysis of the editing outcomes in control cell lines enables us to screen for precise gene editing and
evaluate un anticipated effects on normal cellular function and fitness. Our findings will not only advance our
search for potential therapeutic approaches, but also inform our understanding of the biology of C9orf72
biology, including how the C9orf72 gene is regulated and the mechanisms underlying disease. This and our
future studies will develop a pipeline for systematically evaluating novel editing strategies that are potentially
curative for C9-FTD/ALS. My work will develop Aim 3 of the parent grant (Aim 1) and expand it further (Aim 2)

## Key facts

- **NIH application ID:** 10590420
- **Project number:** 3RF1AG072052-01S1
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Bruce R Conklin
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $239,309
- **Award type:** 3
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590420

## Citation

> US National Institutes of Health, RePORTER application 10590420, C9orf72 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis(ALS): using patient cells and CRISPR to reveal therapeutic approaches (3RF1AG072052-01S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10590420. Licensed CC0.

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