Recent terminations of clinical trials of myostatin inhibitors in muscular dystrophy have raised questions about the predictiveness of mouse models for this therapeutic strategy.
A variety of ...myostatin inhibitors have been developed for preclinical and clinical studies. These inhibitors have ameliorated the phenotype of many but not all mouse models of muscular dystrophy. However, randomized double-blinded placebo controlled trials in both pediatric and adult muscular dystrophies have, as of yet, not demonstrated functional improvement.
The present article will review the preclinical promise of myostatin inhibitors, the clinical trial experience to date of these inhibitors in muscular dystrophy, and the potential reasons for the lack of observed translation.
Muscular dystrophies are a group of genetic muscle disorders that cause progressive muscle weakness and degeneration. Within this group, Duchenne muscular dystrophy (DMD) is the most common and one ...of the most severe. DMD is an X chromosome linked disease that occurs to 1 in 3500 to 1 in 5000 boys. The cause of DMD is a mutation in the dystrophin gene, whose encoded protein provides both structural support and cell signaling capabilities. So far, there are very limited therapeutic options available and there is no cure for this disease. In this review, we discuss the existing cell therapy research, especially stem cell-based, which utilize myoblasts, satellite cells, bone marrow cells, mesoangioblasts and CD133+ cells. Finally, we focus on human pluripotent stem cells (hPSCs) which hold great potential in treating DMD. hPSCs can be used for autologous transplantation after being specified to a myogenic lineage. Over the last few years, there has been a rapid development of isolation, as well as differentiation, techniques in order to achieve effective transplantation results of myogenic cells specified from hPSCs. In this review, we summarize the current methods of hPSCs myogenic commitment/differentiation, and describe the current status of hPSC-derived myogenic cell transplantation.
•Myogenic progenitor cells could provide a source for cell therapy for DMD to regenerate and replace the diseased tissue•An orchestration of signaling molecules directing the lineage determination sets the basis for PSC differentiation in vitro•There is a need to develop more cell therapy options (e.g iPSC) for DMD due to limited success of current ones•The review describes the most recent studies of hiPSC muscle lineage specification and the potential of their application
Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with ...improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.
The loss of skeletal muscle mass and size, or muscle atrophy, is a common human experience, linked to disability, for which there are no widely accepted pharmacological therapies. Piezo1 is a ...mechanosensitive cation channel that opens upon alteration of the plasma membrane lipid bilayer, such as through increased membrane tension. In this issue of the JCI, Hirata et al. identified Piezo1 and its downstream effectors, Krüppel-like factor 15 (KLF15) and interleukin-6 (IL-6), as an important signaling pathway in a murine model of disuse atrophy. Through genetic and pharmacological modulation of the pathway, the authors demonstrated that immobilization resulted in downregulation of Piezo1 and basal intracellular calcium concentration (Ca2+i), increasing expression of Klf15 and its downstream target Il6 and thereby inducing muscle atrophy. Piezo1 has been considered a therapeutic target for diverse disorders, including atherosclerosis and kidney fibrosis, and with this publication should now also be considered a viable target for disuse atrophy.
Introduction/Aims
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to ...bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics.
Methods
This multicenter, phase 1/2 trial enrolled 12 participants (aged 7‐21 years, who had limited ambulation or were nonambulatory) and comprised a 12‐week, double‐blind dose titration, then an open‐label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo.
Results
Participants received casimersen for a mean 139.6 weeks. Treatment‐emergent adverse events (TEAEs) occurred in all casimersen‐ and placebo‐treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen‐related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
Discussion
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN ...mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our “chemical-compound-based” strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFβ signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological “dual-SMAD” inhibition, the DMD-hiPSC-derived myoblasts and genetically corrected isogenic myoblasts form “rescued” multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human “DMD-in-a-dish” model using hiPSC-based disease modeling.
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•Isolation of functional myoblasts from multiple hiPSC lines using a defined system•Concordant but heterogeneous phenotypes among myoblasts from DMD patients•Genetic and pharmacological rescue of DMD-related phenotypes•Myotube formation in DMD-myoblasts and genetically corrected isogenic myoblasts
Choi et al. show that human iPSC (hiPSC)-derived myoblasts from Duchenne muscular dystrophy patients have aberrant phenotypes with patient-to-patient variability. The cells can be partially rescued by either genetic correction or chemical compound treatments.
The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding ...of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. Ann Neurol 2013;74:404–411
Facioscapulohumeral muscular dystrophy (FSHD) results from expression of the full-length double homeobox 4 (DUX4-FL) retrogene in skeletal muscle. However, even in cases of severe FSHD the presence ...of DUX4 is barely detectable. In this issue of the JCI, Bosnakovski et al. used an inducible, muscle-specific human DUX4 to reproduce the low-level, sporadic DUX4 expression of human FSHD muscle as well the myopathology seen in human FSHD disease. Notably, dysregulated fibroadipogenic progenitors accumulated in affected muscles, thus providing a mechanism for the replacement of muscle by fibrosis and fat.
Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced ...by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies.
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