Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations - Plateforme d’immortalisation MyoLine – CRM Access content directly
Journal Articles Molecular Therapy - Nucleic Acids Year : 2022

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

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.
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Dates and versions

hal-03778880 , version 1 (16-09-2022)

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Swati Dudhal, Lylia Mekzine, Bernard Prudhon, Karishma Soocheta, Bruno Cadot, et al.. Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations. Molecular Therapy - Nucleic Acids, 2022, 29, pp.733-748. ⟨10.1016/j.omtn.2022.08.016⟩. ⟨hal-03778880⟩
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