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  • With wide spread use of corticosteroids to combat inflammati

    2024-03-29

    With wide-spread use of corticosteroids to combat inflammation and allergies, even children are susceptible to corticosteroid-induced muscle wasting. Although non-steroidal SGRMs that spare muscle and bone, but have significant anti-inflammatory effects, have been preclinically developed and tested, they have not successfully entered clinical trials, making steroidal corticosteroids the only available option for a number of indications (van Lierop et al., 2012). SARMs have been shown to be effective in ameliorating multiple preclinical models of muscle wasting including glucocorticoid mediated muscle atrophy. (Jones et al., 2010). Duchenne muscular dystrophy (DMD): DMD is a genetic disorder that arises due to mutations in the cytoskeletal protein CZC-25146 (Emery, 1991, Rahimov and Kunkel, 2013). The dystrophin gene is located in the X chromosome and a number of its mutations cause truncated proteins that manifest clinically in the form of muscular dystrophy. Boys with DMD suffer from progressive muscle wasting and weakness and will become wheel-chair-bound often before reaching puberty. Boys with DMD suffer from cardiac and respiratory failures due to weakness in the heart and lung muscles, respectively, resulting in premature death (Frankel and Rosser, 1976, Politano et al., 1996). Recently, therapies to correct mutations using exon-skipping strategies have been developed with one of these molecules receiving approval from the Food and Drug Administration (FDA) (Lim et al., 2017). Although corticosteroids are the standard of care to combat inflammation in DMD, with the exception of the novel exon skipping drug there are currently no disease-modifying therapeutic agents, available to treat DMD. Regrettably prolonged use of corticosteroids results in undesirable side-effects such as muscle wasting. One of the strategies suggested to combat DMD is the use of SARMs. Recently, the SARM GLPG0492 was tested in dystrophin-mutated mdx mouse preclinical models of DMD. GLPG0492 increased body weight, muscle mass and function in mdx mice that were either sedentary or were stressed by exercise (Cozzoli et al., 2013). These data support the use of SARMs for the treatment of DMD either alone or as combination with exon-skipping drugs or other strategies such as NFkB CZC-25146 or myostatin inhibitors. Combination therapies capable of increasing muscle mass could potentially extend the survival of the DMD afflicted boys. Considering the function of AR on secondary sexual tissues, any SARM considered for clinical evaluation in children with DMD should exhibit a broad tissue-selectivity and impeccable safety profile. Stress urinary incontinence (SUI): The levator ani muscle in the pelvic floor is an AR-enriched muscle. Preclinical screening of SARMs often includes determining their ability to increase levator ani muscle weight, which is used as a surrogate for anabolic activity. The levator ani muscle and the pelvic floor muscles in women become weak due to ageing, child birth, and depletion of circulating hormones post-menopausally. Currently no treatment options are available for SUI. Since women are highly susceptible to uterine hyperplasia and virilization, steroidal androgens are not an appropriate choice to treat SUI. SARMs capable of selectively building pelvic floor muscles with reduced virilizing and uterine proliferative side-effects would be preferred and better tolerated for SUI. Preclinically, we demonstrated that treatment of ovariectomized mice with SARMs resulted in restoration of the pelvic muscles to their sham-operated weight (Ponnusamy et al., 2016). Additionally, the induction of several genes associated with muscle catabolism was inhibited. This study supported the clinical evaluation of enobosarm for SUI. Osteoporosis. The ability of SARMs to increase both muscle and bone strength in animal models suggests that they may provide a unique dual approach to osteoporosis therapy (Mohler et al., 2005) (Gao et al., 2005, Kearbey et al., 2007, Hanada et al., 2003, Hamann, 2004). Currently osteoporosis is primarily treated with anti-resorptive agents that prevent further breakdown of bone by the body. Anti-resorptive agents potentially prevent further bone turn-over, but will be unable to increase bone mass. In preclinical models, AR agonists such as DHT and SARMs have prevented bone loss in both castrated male rats and ovariectomized female rats. They also increased cortical and trabecular bone mineral density above baseline in these experimental conditions (Mason and Morris, 1997). SARMs have been shown not only to prevent loss of bone (i.e., treatment begins at time of surgery) in ovariectomized and castrated rats, but also to increase bone strength (Kearbey et al., 2007, Hanada et al., 2003).