Prospects for the Etiotropic Treatment of Dysferlinopathy

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Abstract

Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such as Miyoshi myopathy with primary lesion of the distal fragments of the lower extremities and limb-gridle muscular dystrophy type 2B with primary lesion of the proximal fragments of both the lower and upper limbs, also distal myopathy with anterior tibial onset (DMAT). Nowdays, there are various pathogenetic and symptomatic treatments for hereditary muscular dystrophies but there are very few registered drugs for the etiological treatment of these diseases. This review discusses the main modern methods of gene therapy that can be used to treat dysferlinopathies, such as stop-codon passing, exon skipping, overexpression of other genes, gene transfer, splicosome-mediated trans-splicing, and also describes the latest experimental studies using these methods. In conclusion, exon-skipping and trans-splicing have been identified as the most optimal approaches in the treatment of muscular dystrophies, in particular dysferlinopathies.

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About the authors

Alisa V. Ivanova

Research Centre for Medical Genetics

Email: bioyoghurtneo@yandex.ru
ORCID iD: 0000-0002-8954-7330
SPIN-code: 9922-7412

Junior Researcher

Russian Federation, 115478, Moscow, Moskvorechie, 1

Svetlana A. Smirnikhina

Research Centre for Medical Genetics

Email: smirnikhinas@gmail.com
ORCID iD: 0000-0002-1558-3048
SPIN-code: 6884-6170

MD, PhD

Russian Federation, 115478, Moscow, Moskvorechie, 1

Alexander V. Lavrov

Research Centre for Medical Genetics

Author for correspondence.
Email: alexandervlavrov@gmail.com
ORCID iD: 0000-0003-4962-6947
SPIN-code: 4926-8347

Leading Research Scientist, MD, PhD

Russian Federation, 115478, Moscow, Moskvorechie, 1

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Supplementary files

Supplementary Files
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1. Covering letter

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2. Fig. 1. Dysferlin protein structure. Disferlin consists of seven C2 domains connected in series with Ca2 + binding activity, three Fer domains, two DYSF domains, one of which is located in the other, and a transmembrane T

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3. Fig. 2. The main directions of SMaRT: A - 5 'trans-splicing; B - 3 'trans-splicing; B - replacement of the internal exon. The pre-trans splicing molecule (PTM) complementarily binds to the target RNA and hides the endogenous splice site, while providing its own site, which, via the spliceosome, provides the therapeutic RNA sequence

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