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

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 m...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular therapy. Nucleic acids Vol. 29; pp. 733 - 748
Main Authors:	Dudhal, Swati, Mekzine, Lylia, Prudhon, Bernard, Soocheta, Karishma, Cadot, Bruno, Mamchaoui, Kamel, Trochet, Delphine, Bitoun, Marc
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 13-09-2022 Elsevier American Society of Gene & Cell Therapy
Subjects:	adhesion allele-specific silencing Biochemistry, Molecular Biology dominant centronuclear myopathy dynamin 2 endocytosis gene therapy Genomics Human health and pathology Life Sciences migration MT: RNA/DNA Editing Original RNA interference MT: RNA/DNA Editing allele-specific silencing dynamin 2 RNA interference dominant centronuclear myopathy migration gene therapy endocytosis adhesion
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. [Display omitted] Allele-specific siRNAs targeting two non-pathogenic DNM2 single-nucleotide polymorphisms frequently heterozygous in the population are effective to knock down several dominant DNM2 mutations and correct defects in centronuclear myopathy patient’s cells. These new molecules allow targeting the vast majority of patients with DNM2 mutations or overexpression by only a few siRNAs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally
ISSN:	2162-2531 2162-2531
DOI:	10.1016/j.omtn.2022.08.016