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CRISPR/Cas9 Technology in Restoring Dystrophin Expression in iPSC-Derived Muscle Progenitors

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Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD?

Romains Joubert¹, Virginie Mariot¹, Marine Charpentier²

¹NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK.

Journal of Personalized Medicine

|December 30, 2020

Summary

Gene editing aimed to disable DUX4 expression in facioscapulohumeral muscular dystrophy (FSHD) by targeting its poly(A) signal. However, DUX4 mRNA persisted, suggesting this gene editing approach may not be suitable for FSHD therapy.

Keywords:

CRISPR-Cas9 D4Z4 DUX4 FSHD TALEN facioscapulohumeral dystrophy gene editing muscle polyadenylation

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Area of Science:

Genetics
Molecular Biology
Neuromuscular Disorders

Background:

Facioscapulohumeral muscular dystrophy (FSHD) is a common adult-onset muscle disorder with no current treatments.
Aberrant DUX4 protein expression is implicated in FSHD pathogenesis, leading to muscle dysfunction and cell death.

Purpose of the Study:

To investigate the efficacy of gene editing strategies targeting the DUX4 polyadenylation (poly(A)) signal to permanently shut down DUX4 expression in FSHD.
To assess the feasibility of using transcription activator-like effector nucleases (TALEN) and CRISPR-Cas9 for FSHD gene therapy.

Main Methods:

In vitro gene editing of FSHD myoblasts using TALEN and CRISPR-Cas9 nucleases.
Targeting the DUX4 poly(A) signal sequence to disrupt gene expression.
Sequencing of over 150 TOPO clones to analyze editing outcomes.

Main Results:

Gene editing resulted in indels in only 4% of analyzed clones.
In two successful edits, the DUX4 poly(A) signal was eliminated at the genomic level.
Despite poly(A) signal elimination, DUX4 mRNA production continued due to an alternative upstream poly(A) signal.

Conclusions:

Targeting the DUX4 polyadenylation signal via genomic modification may not be an effective strategy for FSHD gene therapy.
The presence of alternative poly(A) signals complicates gene silencing approaches for FSHD.