Current and Emerging Therapies for Duchenne Muscular Dystrophy

Abstract

Coinciding with new standardized care guidelines, there are a growing number of therapeutic options to treat males with DMD. Treatment of the underlying pathobiology, such as micro-dystrophin gene replacement, exon skipping, stop codon read-through agents, and utrophin modulators showed variable success in animal and human studies. Symptomatic therapies to target muscle ischemia, enhance muscle regeneration, prevent muscle fibrosis, inhibit myostatin, and reduce inflammation are also under investigation. DMD is a complex, heterogeneous degenerative disease. The pharmacological and technological achievements made in recent years, plus timely supportive interventions will likely lead to an improved quality of life for many individuals with DMD.

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

“…At later stages of disease, cardiomyopathy develops, with heart failure or respiratory complications leading to death, on average in the mid-30s, even with modern treatment regimens. Therapy for DMD has benefited significantly from studies of genetic mouse models of muscular dystrophy, including the mdx model developed in the late 1980s (Crone and Mah, 2018). Current investigational therapies for DMD with ongoing research in DMD mouse models include exon skipping, micro-dystrophin or surrogate gene therapy, gene editing, inflammation blockers and stem cell delivery (Long et al, 2016;Min et al, 2019).…”

Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

“…Meanwhile, no treatment is available to stop this degenerative disease yet. Developing therapies aim at restoring the expression of dystrophin in muscle cells but, so far, the level stays too low to be beneficial to patients (7). The absence of both reliable biomarkers and effective therapies stress the need of better defining the first steps of DMD in Human to be able to 1) find specific markers of disease initiation in order to increase diagnosis sensitivity and, therefore, improve patient management by accelerating their access to better healthcare; and 2) develop alternative therapeutic approaches by finding targets that compensate the lack of dystrophin and complement current attempts at restoring its expression (8).…”

A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy

“…DMD is the most common type of muscular dystrophy, affecting approximately 1 in 3,500-5,000 male births (Emery, 1991; Mah et al, 2014). It first presents as motor difficulties in early childhood and progresses rapidly, leaving most affected boys in need of a wheelchair in their early teens and in need of respiratory aid in their 20s (reviewed in Crone and Mah, 2018). The disease is usually fatal in the third or fourth decade due to respiratory or cardiovascular failure.…”

“…Treatment options for DMD are still quite limited. The current standard of care is corticosteroid treatment, which delays the progression of muscle dysfunction but has serious side effects (Bushby et al, 2010; Crone and Mah, 2018; Kinnett et al, 2015). DMD gene therapy and gene editing approaches are very promising but face many challenges (Chamberlain and Chamberlain, 2017; Conboy et al, 2018; Duan, 2018; Min et al, 2019).…”

“…DMD gene therapy and gene editing approaches are very promising but face many challenges (Chamberlain and Chamberlain, 2017; Conboy et al, 2018; Duan, 2018; Min et al, 2019). Many small molecule approaches are being identified that could benefit DMD by modulating different pathological mechanisms downstream of the dystrophin mutation (Crone and Mah, 2018; Guiraud and Davies, 2017; Hoffman, 2019; Spinazzola and Kunkel, 2016). A current view in the DMD field is that a combination of therapies targeting different pathological mechanisms may ultimately be most beneficial for patients (Guiraud and Davies, 2017; Hoffman, 2019).…”