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CRISPR-Cas13 gene therapy and RNA editing for Facioscapulohumeral muscular dystrophy (FSHD)

Award Number: R01AR078395
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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CRISPR-Cas13 gene therapy and RNA editing for Facioscapulohumeral muscular dystrophy (FSHD) - Project Summary/Abstract Autosomal dominant Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, affecting 1 in 7,500 to 1 in 20,000 individuals. FSHD was formally classified as a major form of muscular dystrophy in 1954, but the pathogenic events leading to the disease have only recently started coming into focus. Today, it is now recognized that FSHD pathogenesis involves aberrant expression of the DUX4 gene, which encodes a myotoxic transcription factor. The emergence of DUX4 as a primary insult underlying FSHD represented a momentum shift in the field as it provided an important target for model development and therapy design. Indeed, as FSHD is currently untreatable, developing effective FSHD therapies is a critical need in the field. We hypothesized that an FSHD treatment should center on inhibiting toxic DUX4 expression in skeletal muscles. The objective of this proposal is to develop effective prospective FSHD therapies aimed at reducing or eliminating toxic DUX4 expression. To do this, we will use new cutting edge RNA silencing and RNA editing approaches for which technology emerged only within the last 2-3 years. These approaches only cut RNA and not DNA, and therefore pose no risk of permanent genome modification in host cells. Because these strategies are only newly emerged, they have never been tested in vivo using gene therapy approaches in an animal model of disease. We will do that here, and thus our proposal will provide first proof-of-principle for in vivo efficacy use of CRISPR-Cas13 and RNA editing technology. Specifically, in Aim 1 we will develop a new CRISPR/Cas13 gene therapy approach to cleave DUX4 mRNA before it can be made into protein. In Aim 2, we will develop RNA editing strategies that are designed to change the DUX4 transcript and render it incapable of producing toxic full- length forms of DUX4 protein. Finally, since these strategies are new and abundant off-target data are currently lacking, in Aim 3, we will assess the precision of RNA cleavage and editing approaches in human FSHD and control muscle cells. Upon completion of these Aims, we expect to produce pre-clinical data supporting the translation of new AAV-based RNA-targeted therapies for FSHD that can be ultimately used for translation toward our goal of clinical application. These data may also support the broader use of this technology for other genetic disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $501,784 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/24/2025	NON-COMPETING CONTINUATION	$501,784
														Subtotal = $501,784

Issue Date FY: 2024 ( Subtotal = $540,811 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/16/2024	NON-COMPETING CONTINUATION	$540,811
														Subtotal = $540,811

Issue Date FY: 2023 ( Subtotal = $620,756 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/3/2023	NON-COMPETING CONTINUATION	$620,756
														Subtotal = $620,756

Issue Date FY: 2022 ( Subtotal = $607,917 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/12/2022	NON-COMPETING CONTINUATION	$607,917
														Subtotal = $607,917

Issue Date FY: 2021 ( Subtotal = $624,920 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/13/2021	NEW	$624,920
														Subtotal = $624,920

Grand Total All Awards = $2,896,188

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CRISPR-Cas13 gene therapy and RNA editing for Facioscapulohumeral muscular dystrophy (FSHD)

Award Number: R01AR078395

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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