Substitute dystrophin protein protects muscle in canines with DMD

Duchenne muscular dystrophy (DMD) is a severe, neuromuscular wasting disease that mainly affects boys. Variants in the DMD gene are responsible for the disease. Defects in its protein product, dystrophin, lead to impaired muscle function in striated and cardiac muscle. In a study published recently in Nature Medicine (, Song and colleagues show a protein related to dystrophin called utrophin acts as a protective gene therapy in mouse and canine animal models of DMD. The findings suggest that utrophin-based therapies may be able to treat dystrophin deficits. The researchers synthesized a transgene encoding a miniaturized form of utrophin and used adeno-associated viruses to systemically deliver the codon-optimized transgene. In a mouse model of DMD, intraperitoneal injection of the transgene in neonates was sufficient to suppress all tested signs of muscular dystrophy. Mice given the transgene exhibited serum creatine kinase levels and centrally nucleated myofibers—the most sensitive indicator of myoprotection—that were indistinguishable from those in wild-type mice. Treated mice also showed increased functional activity. Force grip tests revealed enhanced muscle performance similar to that of wild-type mice, as did measures of downhill treadmill running. Compared with untreated dystrophin-deficient mice, mice given the transgene voluntarily ran nearly twice as far. The transgene showed sustained expression in cardiac and skeletal muscles throughout the 4-month experiment, and treated mice showed no signs of toxicity. Together the results indicate that early overexpression of utrophin can relieve the DMD phenotype in small-animal models of the disease. To determine whether differences in small and large animals would limit the approach, Song and colleagues next administered the transgene to two canine models of DMD. Golden retriever muscular dystrophy (GRMD) dogs given the transgene as 4- to 7-day-old pups showed reduced myonecrosis and mononuclear infiltration as well as wild-type levels of sarcoglycan expression by the age of 6 weeks. The dogs also tolerated the treatment, displaying no signs of cell-mediated immunity against the virus capsid or the transgene protein. As most DMD patients are diagnosed after 2 years of age, the researchers additionally treated two nearly 2-month-old GRMD dogs. The transgene suppressed muscle injury and prevented muscle degeneration in the dogs while showing no signs of severe acute toxicity. Additional studies in German shorthaired pointer dogs with muscular dystrophy showed no cell-mediated immune response. Together the results indicate that the utrophin transgene provides comprehensive myoprotection without immune toxicity, and is a promising potential human therapy for DMD. —V. L. Dengler, News Editor

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Mechanosensitive ion channel variants lead to temporary hypomyelination

Defects in myelin, the fatty covering that insulates nerve fibers, lead to progressive degeneration of the brain’s white matter. The phenomenon characterizes leukodystrophies, a group of rare genetic disorders in which myelination proceeds abnormally. Patients with leukodystrophies typically present in early infancy with nystagmus and axial hypotonia, which eventually advances to ataxia and spasticity. Variants in the PLP1 gene, which encodes a structural myelin protein, underlie Pelizaeus–Merzbacher disease. Now, as recently reported in the American Journal of Human Genetics (, Yan and colleagues discovered that variants in TMEM63A, a mechanically activated ion channel highly expressed in oligodendrocytes, result in a disorder resembling Pelizaeus–Merzbacher disease in infancy that unexpectedly resolves. According to the authors, the findings suggest that mechanosensitive ion channels may play an underappreciated role in myelin development. Genome or exome sequencing was performed on four patients who presented in infancy with nystagmus, delayed motor development, and myelin deficits on serial magnetic resonance imaging (MRI) scans, as well as on their biological parents. All patients showed normal metabolism and dosage of 115 leukodystrophy-related genes, including PLP1. However, sequencing revealed heterozygous missense variants in TMEM63A in each of the four families, including one recurrent variant. Three variants arose de novo and one was paternally inherited. The three altered residues are highly conserved across vertebrate species, and a handful of prediction tools all indicate that the variants are damaging. Using patch clamp electrophysiology assays, the researchers tested the impact of the variants on ion channel activity. Whereas cells transfected with wild-type TMEM63A elicited stretch-activated currents in response to stimulation, cells transfected with any one of the variants failed to induce this response. The findings suggest that the variants result in loss of TMEM63A function. Unexpectedly, however, follow-up MRI scans showed that myelin deficits improved over time in all four individuals. Defects completely resolved in two patients, mild abnormalities persist in a third patient, and the fourth shows improved myelination. The researchers are uncertain how disruption of TMEM63A function leads to temporary myelination deficits. They propose that two homologs—TMEM63B and TMEM63C—may compensate for TMEM63A loss of function and suggest that the phenotype be referred to as infantile-onset transient hypomyelination. The scientists conclude that myelination can evolve normally even when the process begins later in development than usual. —V. L. Dengler, News Editor

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