Promising gene therapy developed

Effective for DNM2 related diseases including SPG

Small interfering RNA (siRNA) technology, a form of gene therapy, has been used to create an effective treatment for DNM2 related Spastic Paraplegia (SPG) in both patient cell samples in the laboratory and in disease-affected mice.

This technology ‘silences’ the disease-causing allele variant, while leaving the healthy allele of the DNM2 gene unaffected.

Abstract

Dominant centronuclear myopathy (CNM) is a rare form of congenital myopathy associated with a wide clinical spectrum, from severe neonatal to milder adult forms. There is no available treatment for this disease due to heterozygous mutations in the DNM2 gene encoding Dynamin 2 (DNM2). Dominant DNM2 mutations also cause rare forms of Charcot-Marie-Tooth disease and hereditary spastic paraplegia, and deleterious DNM2 overexpression was noticed in several diseases.

The proof of concept for therapy by allele-specific RNA interference devoted to silence the mutated mRNA without affecting the normal allele was previously achieved in a mouse model and patient-derived cells, both expressing the most frequent DNM2 mutation in CNM. In order to have versatile small interfering RNAs (siRNAs) usable regardless of the mutation, we have developed allele-specific siRNAs against two non-pathogenic single-nucleotide polymorphisms (SNPs) frequently heterozygous in the population. In addition, allele-specific siRNAs against the p.S619L DNM2 mutation, a mutation frequently associated with severe neonatal cases, were developed.

The beneficial effects of these new siRNAs are reported for a panel of defects occurring in patient-derived cell lines. The development of these new molecules allows targeting the large majority of the patients harboring DNM2 mutations or overexpression by only a few siRNAs.

SOURCE:  Mol Ther Nucleic Acids. 2022 Aug 13;29:733-748. doi: 10.1016/j.omtn.2022.08.016. eCollection 2022 Sep 13. PMID: 36090755 © 2022 The Authors.

Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations

Swati Dudhal  1 Lylia Mekzine  1 Bernard Prudhon  1 Karishma Soocheta  1 Bruno Cadot  1 Kamel Mamchaoui  1 Delphine Trochet  1 Marc Bitoun  1

1. Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, France.

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