Translational research and therapeutic perspectives in dysferlinopathies

Abstract

Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.

Figure 1

Binding partners of dysferlin. In normal myofibers, dysferlin is anchored by its C-terminal domain to the plasma membrane and membrane network to cytosolic vesicles. In these contexts, it associates with different partners according to its localization. Schematized here are the binding partners of dysferlin and their localization within the myofiber. ch, Channel.

Figure 2

Therapeutic strategies currently being tested. Dysferlinopathies are an ensemble of pathologies, due to mutations in the DYSF gene. Wide spectrums of mutations are responsible for the pathologies, including missense, nonsense, frameshift, deletion, insertion and splicing mutations. Currently, two main types of strategies are envisaged: gene transfer (AAV concatemerization, or minigene) and mRNA surgery (exon-skipping and trans-splicing strategies). Black arrows indicate strategies available for all gene mutations, whereas dashed arrows indicate mutation-specific strategies (mutations in exon 32 for exon skipping, 3′ mutations for trans-splicing). Inverted terminal repeats (ITRs) are the adeno-associated vector backbone.

Figure 3

A natural proof of exon skipping. Depicted is a family studied by Sinnreich et al. (72), in which the index case (identified by an asterisk) carries two mutant alleles. The family tree (A) and the nature of the two mutant alleles (B) are shown.