Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches

Abstract

Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by progressive muscle weakness, is caused by the absence or a decreased amount of the muscle cytoskeletal protein dystrophin. Currently, several therapeutic approaches to cure DMD are being investigated, which can be categorized into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin. Therapies that restore dystrophin expression include read-through therapy, exon skipping, vector-mediated gene therapy, and cell therapy. Of these approaches, the most advanced are the read-through and exon skipping therapies. In 2014, ataluren, a drug that can promote ribosomal read-through of mRNA containing a premature stop codon, was conditionally approved in Europe. In 2016, eteplirsen, a morpholino-based chemical capable of skipping exon 51 in premature mRNA, received conditional approval in the USA. Clinical trials on vector-mediated gene therapy carrying micro- and mini- dystrophin are underway. More innovative therapeutic approaches include CRISPR/Cas9-based genome editing and stem cell-based cell therapies. Here we review the current status of therapeutic approaches for DMD, focusing on therapeutic approaches that can restore dystrophin.

Nutraceutical and pharmaceutical cocktails did not preserve diaphragm muscle function or reduce muscle damage in D2‐mdx mice

“…Dystrophin deficiency results in progressive muscle wasting that culminates in respiratory or cardiac failure (Eagle et al., 2002). Some researchers are developing approaches to restore dystrophin protein (Shimizu‐Motohashi et al., 2019), whereas we and others are working to identify pharmaceutical and nutraceutical interventions with the potential for immediate application to mitigate disease pathology. In these experiments, we investigated the extent to which quercetin‐based cocktails preserved respiratory and diaphragmatic function and prevented histological damage in the D2‐mdx mouse model of DMD.…”

“…The absence of dystrophin is accompanied by a multitude of cellular dysfunctions, including increased oxidative stress, calcium mishandling, chronic inflammation and impaired autophagy (Bellinger et al., 2009; Kuznetsov et al., 1998; Spaulding et al., 2018). Development of therapeutics to restore dystrophin protein to dystrophic muscles is ongoing (Shimizu‐Motohashi et al., 2019), but immediate interventions are needed in order to protect and preserve muscle function. We and others are pursuing pharmaceutical and nutraceutical interventions to treat the secondary dysfunctions of DMD with the goal of using these agents to preserve muscle function, improve quality of life and prolong life expectancy (e.g.…”

Therapeutic targeting of alternative splicing

“…Włókna mięśniowe pozbawione dystrofiny ulegają łatwiej uszkodzeniu, co stopniowo prowadzi do utraty ich funkcji. Stwierdzono wiele różnych mutacji, które prowadzą do rozwoju DMD [31][32][33]. Często dochodzi do delecji fragmentu genu.…”

“…Dzieje się tak, ponieważ syntetyzowana wtedy dystrofina, która jest krótsza o fragment, który uległ delecji, może nadal częściowo pełnić swoje funkcje. W przypadku zmiany ramki odczytu syntetyzowane jest natomiast nieprawidłowe białko, które nie spełnia swojej roli [31]. W przypadku około połowy pacjentów delecje pojawiają się w obrębie regionu obejmującego eksony 45-55.…”

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

“…In humans, Duchenne muscular dystrophy (DMD) is the most common and most severe muscular dystrophy affecting children . Concerted efforts towards the development of new practical therapeutics (gene‐ and cell‐based therapies) have resulted in many new promising paradigms, some on the forefront of clinical utilization . But until recently, a critical barrier to progress in the field has been the stark difference in the severity of the muscular dystrophy observed between mice and humans, with mice showing minimal phenotypes.…”