Advancing Cell Therapies for Duchene Muscular Dystrophy

What Is Duchene Muscular Dystrophy?

Duchene muscular dystrophy (DMD) is a rare neuromuscular disease caused by recessive mutations in the dystrophin gene that severely affect dystrophin protein expression and function. Different types of mutations in the dystrophin gene have been linked to DMD, including predominantly large deletions (i.e., involving one or more coding sequences), but also duplications, single nucleotide base changes, and small insertions/deletions (Duan et al. 2021).

Because the dystrophin gene is localized to the X-chromosome, females are generally asymptomatic carriers, and disease manifests almost exclusively in males, with a global prevalence of ~7 in 100,000 live male births (Crisafulli et al. 2020). In affected males, DMD disease’s onset occurs early and within the first 5 years of life, manifesting through motor difficulties (e.g., frequent falls). DMD is a progressive disease that results in increased skeletal muscle wasting; typically, 10-year-old patients are wheelchair-bound and rely on artificial respirators by 20 years of age. Additionally, since the functional muscle dystrophin isoform (Dp427m) is critical in cardiac muscle, patients develop cardiomyopathy by 10 years of age (Falzarano et al. 2015). Ultimately, DMD patients perish due to combined cardiac and respiratory failure at around 20-40 years of age.

Why Is Dystrophin So Crucial for Muscle Function?

Dystrophin is a large 427 kDa intracellular protein that sits close to the plasma membrane of muscle cells, acting as a bridge between sarcolemmal and cytoskeletal proteins. Through several structural domains, dystrophin interacts directly with critical cytoskeletal (e.g., actin), transmembrane (e.g., beta-dystroglycan), and cytosolic (e.g., dystrobrevin) proteins. Additionally, dystrophin indirectly associates with proteins within all cellular compartments, including critical extracellular proteins such as alpha-dystroglycan (alpha-DG) and laminin-211 (Dowling et al. 2021).

Dystrophin Complexome

Dystrophin Complexome:“The lower panel shows a model of the spatial configuration of the dystrophin complexome in skeletal muscle fibers. Shown is the dystrophin core complex consisting of the dystrophin isoform Dp427-M, dystroglycans (DG), sarcoglycans (SG), sarcospan (SSPN), syntrophins (SYN) and dystrobrevins (DYB), as well as the wider dystrophin-associated network that forms associations with the extracellular matrix, the sarcolemma, the cytoskeleton and the sarcomere. “Figure 1 lower panel, retrieved from (Dowling et al. 2021).

Through these protein interactions, dystrophin, as part of the dystrophin-associated glycoprotein complex (DGC), participates in various functions, such as cell signaling to sustain excitation-contraction coupling (EC coupling), cytoskeleton organization, muscle fiber stability, and lateral force transmission. Therefore, a lack of dystrophin expression and function leads to plasma membrane instability and several pathological changes in the muscle, including fiber degeneration, fibrosis, and chronic inflammation (Dowling et al. 2021).

A new cell therapy helping late-stage DMD patients

The progression of DMD disease is accelerated by inflammatory mechanisms, such as immune cell infiltration and concomitant increase in cytokines. Therefore, the go-to therapy to stave away DMD’s progress has been based on the use of steroids. Corticosteroids, such as Prednisone, have helped DMD patients improve muscle strength and function, and their long-term use provides cardiac and respiratory function benefits. Nevertheless, corticosteroid-based treatments are not without side effects, including metabolic, nervous systems, and gastrointestinal disturbances. Additionally, long-term corticosteroid treatments are not well tolerated by all patients, and some patients do not gain any clinical benefits (Falzarano et al. 2015).

A new progenitor cell-based approach to delaying the progression of DMD relies on the use of Cardiosphere-derived cells (CDCs). Cardiospheres comprise a heterogeneous cardiac cell population, including stem/progenitor cells, known to have regenerative potential. CDCs secrete a range of bioactive factors (e.g., non-coding RNA and microRNAs) effective in promoting angiogenesis and progenitor cell recruitment while suppressing cell death, fibrosis, and inflammation. Although these benefits were initially demonstrated in the context of heart disease, studies in a preclinical model of DMD, the mdx mouse, showed the value of CDCs to reverse cardiac and skeletal myopathy and concomitantly improve motor function. These findings were instrumental in driving the first clinical studies initiated in 2015 (HOPE-Duchenne (Halt cardiomyOPathy progrEssion in Duchenne-NCT02485938). These first Phase 1/2 studies aimed to evaluate the safety and efficacy of intracoronary infused Allogeneic Cardiosphere-Derived Cells (CAP-1002) treatment in DMD patients with cardiomyopathy. Guided by positive preclinical findings, these studies assessed the effects of CAP-1002 treatment on cardiac and skeletal muscle and demonstrated improved functions in both (Taylor et al. 2019).

In 2018 a new Phase 2 study (HOPE-2) was initiated to evaluate the safety and efficacy of CAP-1002 therapy administered intravenously in improving motor, pulmonary and cardiac functions in non-ambulatory and ambulatory DMD patients (NCT03406780). Unlike the original HOPE clinical studies, in HOPE-2, investigators administered multiple doses of CAP-1002 (i.e., a total of 4 doses, infused every 3 months) and executed a double-blind, randomized, placebo-controlled trial. Recently, findings from these Phase 2 studies demonstrated that CAP-1002 treatment improved upper limb function and cardiac function in late-stage DMD patients relative to placebo (McDonald et al. 2022).


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