THERAPEUTIC STRATEGIES FOR THE CORRECTION OF SPLICING IN HEREDITARY DISEASES: METHODS AND CLINICAL TRIALS

Abstract

Disorders of pre-mRNA splicing play a key role in the pathogenesis of a significant part of monogenic diseases, as they alter the composition of mature mRNA, reduce the synthesis of functional protein, and form clinical heterogeneity of the phenotype. In recent years, splicing correction has evolved from an experimental approach to a clinically applied strategy, primarily for spinal muscular atrophy and progressive Duchenne muscular dystrophy.

The purpose of this article is to analyze modern therapeutic approaches to splicing modification, their molecular mechanisms, limitations, and clinical research results.

The paper provides a review of Russian publications reflecting the development of antisense oligonucleotides, small splicing modifier molecules, and exon-skipping technologies.

It has been shown that the drugs providing the inclusion of exon 7 of the SMN2 gene in spinal muscular atrophy and the omission of individual exons of the DMD gene in Duchenne muscular dystrophy have the greatest evidence base. At the same time, there are problems of mutation specificity, the need for early initiation of therapy, uneven tissue delivery, and the high cost of long-term treatment.

It is concluded that the further development of the direction is associated with the personalization of the design of molecules, the standardization of clinical endpoints and the expansion of national patient registries.