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Development of therapeutic genome engineering in laminin-α2-deficient congenital muscular dystrophy
Dwi U Kemaladewi1,2, Ronald D Cohn2,3,4
1Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Abstract:
Muscular dystrophies are a heterogeneous group of genetic muscle diseases that are often characterized by pathological findings of muscle fiber degeneration and the replacement of muscle fibers with fibrotic/connective tissues. In spite of the genetic causes of many of these conditions having been identified, curative treatments are still lacking. Recently, genome engineering technologies, including targeted gene editing and gene regulation, have emerged as attractive therapeutic tools for a variety of muscular dystrophies. This review summarizes the genome engineering strategies that are currently under preclinical evaluation for the treatment of LAMA2-deficient congenital muscular dystrophy. In particular, we focus on the applications of CRISPR/Cas9 to correct a splice site mutation in LAMA2 and to up-regulate a disease-modifying gene LAMA1. Finally, the challenges faced in the clinical translation of these strategies are discussed.
Insights
Genome engineering offers new hope for muscular dystrophy. CRISPR/Cas9 technology is being explored to correct genetic defects in LAMA2-deficient congenital muscular dystrophy, potentially leading to effective treatments.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Muscular dystrophies are genetic muscle diseases causing degeneration and fibrosis.
- Despite identified genetic causes, curative treatments remain elusive.
- Genome engineering presents promising therapeutic avenues for muscular dystrophies.
Purpose of the Study:
- To review genome engineering strategies for LAMA2-deficient congenital muscular dystrophy.
- To highlight the application of CRISPR/Cas9 for LAMA2 mutation correction.
- To discuss the upregulation of LAMA1 as a therapeutic approach.
Main Methods:
- Focus on preclinical evaluation of genome engineering techniques.
- Detailed examination of CRISPR/Cas9 for splice site mutation correction in LAMA2.
- Exploration of gene regulation strategies to up-regulate LAMA1.
Main Results:
- CRISPR/Cas9 shows potential for correcting LAMA2 splice site mutations.
- Upregulating LAMA1 is investigated as a disease-modifying strategy.
- Preclinical data supports the viability of these genome engineering approaches.
Conclusions:
- Genome engineering, particularly CRISPR/Cas9, offers a promising therapeutic strategy for LAMA2-deficient congenital muscular dystrophy.
- Correction of LAMA2 mutations and LAMA1 upregulation are key targets.
- Challenges in clinical translation require further investigation.
