Each data file was manually inspected to ensure that cursors and fits were assigned properly

Each data file was manually inspected to ensure that cursors and fits were assigned properly. Bone CT Tibias and L6 vertebrae from a subset mice were collected in this study. of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24?days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA. Introduction Spinal muscular atrophy (SMA) is usually a debilitating, frequently fatal neuromuscular disease and the most common genetic cause of infant mortality (1,2). SMA is usually caused by mutations in Survival of Motor Neuron 1 ((Survival of Motor Neuron 1) gene result in SMA (6); however, in humans a nearly identical gene, Both genes produce the same protein product, SMN. The primary difference between these genes is usually a non-coding CCT transition which creates an exonic splice silencer in is usually correctly spliced and produces full-length SMN protein, although the amount produced is usually insufficient to fully compensate for loss of Because the SMN locus is usually unstable, the copy number of can vary between individuals, with more copies (3C4) generally associated with milder forms of SMA (4,5,8). Multiple mouse models have been developed to enable preclinical studies of potential SMA therapeutic strategies. Because mice have only a single gene, deletion of which is usually embryonic lethal, various models have been designed to mimic the human locus. The SMN7 mouse, a model of severe SMA, lacks the sole endogenous copy of allele (9). In contrast, the C/C mouse, considered by some to be a milder model of disease, expresses a hybrid gene in which exons 7 and 8 of the endogenous gene have been replaced with exons 7 and 8 of human (10). The SMN7 mouse, in particular, displays patterns of muscle atrophy and motor neuron loss that more closely mimic the human disease (11). While a defining clinical feature of SMA is usually severe skeletal muscle atrophy, not all muscles are equally affected, with proximal muscles displaying generally greater atrophy and denervation than appendicular muscles (11,12). Interestingly, fast-twitch Type II muscle fibers display significantly greater atrophy than slow-twitch Type I fibers (3). The degree of muscle atrophy is usually directly related to the degree of innervation, with muscles innervated by nerves less affected by SMN loss displaying reduced atrophy (11,13,14). Although muscle atrophy is the predominant symptom of SMA, recent work has exhibited that patients also show reduced bone mineral density and an increased fracture risk, both in long bones and in vertebrae, a phenotype that is Meprednisone (Betapar) shared with mouse models of the disease (15C17). The majority of therapeutic approaches in SMA aim to increase full-length Meprednisone (Betapar) SMN protein levels, either in the central nervous system (CNS) or systemically. gene replacement therapy using adeno-associated viral vectors (AAV) has shown benefit in mouse models and in early clinical trials (18C20). Other approaches focus LAMC2 on modulating splicing, such that exon 7 is usually retained in a greater percentage of transcripts, leading to increased production of full-length SMN protein (21C24). At least two small molecule intronic splice silencer, thus facilitating exon 7 inclusion in both mouse models and clinically (25C30). The exhibited clinical benefit of this latter approach, including improvements in motor function and compound muscle action potential (CMAP), has led to regulatory approval for its use in individuals with all types of SMA (31). While each of these therapeutic approaches has shown significant pre-clinical and clinical efficacy, significant functional deficits remain in SMA patients following treatment, with the majority of patients significantly impaired compared with their healthy peers (18,26,27,32C37). Recently presented data from the NURTURE trial revealed that patients treated pre-symptomatically with nusinersen are achieving remarkable gains Meprednisone (Betapar) in motor function. Nevertheless, among patients with two copies of only 4 of 12 could stand unaided and 2 of 8 walk unaided (35). Patients with infantile onset SMA treated with the small-molecule SMN upregulator RG7916 also exhibited significant gains in function, with 57% of babies achieving CHOP-INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scores of 40 (out of a maximal score of 64), a milestone essentially never reached in untreated SMA Type 1 patients (34). Gene therapy with AAV-in infantile onset SMA has also had significant effects, with 10 of 12 patients reaching CHOP-INTEND scores of 50 and 2 of 12??60 (20). While these treatment effects result in significant improvements in patient function, there are nevertheless clear functional deficits remaining, with many patients failing to reach.

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