in a study with 8 sbma patients, moderate-intensity exercise was not well tolerated, and exercise frequency was decreased prior to the end of the training program. levels of creatine kinase (ck), a biomarker of muscle degeneration, were found to increase during intense exercise, indicating primary myopathy. in a study of home-based functional exercise with 50 sbma patients, both the low-intensity exercise and stretching control groups tolerated exercise well, but there was no significant difference in primary and secondary outcomes between the two groups. however, subgroup analysis did show benefit for a low-functioning group, suggesting there may be a role for exercise in these patients. in a third study, high-intensity interval training (hiit) for less than one hour per week, improved both vo2max and performed workload, without increasing ck levels, self-rated fatigue and pain. overall, these results suggest that exercise programs should be individually tailored, and sbma patients must be carefully monitored for maladaptive biomarkers (increasing ck levels) to prevent muscle damage and worsening of disease phenotypes. history sbma was first described in japanese literature in 1897 by hiroshi kawahara in a case report detailing progressive bulbar palsy in two brothers. information on the clinical course, x-linked inheritance patterns, and key pathologic features was later documented by william r. kennedy in 1968. onset of disease in mid-life and lack of symptoms in heterozygous female carriers was further described by anita harding in 1982. in 1986, the causative gene of sbma was shown to be present on the proximal arm of the x chromosome by kurt fischbeck, though the exact gene causing sbma had not yet been characterized. in 1991, it was discovered that the ar gene is involved in the disease process, and that expansion of a cag repeat in the ar gene causes disease. research directions research in sbma is broad, and covers a number of aspects of the disorder. below is a summary of a few areas of ongoing research in sbma: aggregation the polyglutamine androgen receptor does not fold properly, and subsequently forms protein aggregates with other proteins. this is a gain of new function conferred by the polyglutamine tract, as the non-polyglutamine expanded androgen receptor does not form these aggregates. several proteins key to normal cellular function have been found to be sequestered within these aggregates, including creb-bp, hsp70, hsp40, and components of the ubiquitin proteasome system. it is thought that loss of sufficient supply of these and other key proteins contributes to the pathogenesis of the disease, though further research is ongoing. post-translational modifications following its transcription and translation, the androgen receptor is modified with a number of post-translational modifications, including phosphorylation, methylation, acetylation, and sumoylation. the polyglutamine androgen receptor has been found to have different levels of some these post-translational modifications. further, altering the levels of certain post-translational modifications of the mutant androgen receptor has altered the degree of toxicity in cellular and animal models, suggesting they may be a target for further research and therapeutic development. leuprorelin leuprorelin, a gnrh agonist which blocks the synthesis of testosterone when given continuously, was initially shown to be effective at improving motor function in mouse models of sbma. a small pilot study was performed in which five sbma patients were given subcutaneous injections of leuprorelin every four weeks for six months, with serial scrotal skin biopsies performed. nuclear accumulation of polyglutamine androgen receptor was significantly reduced in patient scrotal biopsies. additionally, serum ck, a marker of muscle deterioration, and testosterone levels were both reduced in patients receiving leuprorelin. notably, in this study patients were not randomized to treatment groups or placebo controlled. a subsequent larger study consisted of fifty sbma patients randomized to either leuprorelin treatment or placebo. this trial spanned 48 weeks of treatment with treatment occurring every four weeks initially. following treatment, thirty-four patients had an open-label follow-up spanning an additional ninety-six weeks with treatment continuing every twelve weeks. at the forty-eight week mark, there was no significant difference in the als functional rating scale, the primary outcome measure of the study, between placebo and leuprorelin treated groups. there was improvement in swallowing a barium contrast marker, a secondary endpoint of the study, at forty-eight weeks. further, there was improvement in the als functional rating scale at the 96 and 144 week marks, suggesting a longer period may be needed to see effects of leuprorelin. a larger, multi-center, placebo-controlled, double blind study was then conducted which contained 199 sbma patients who were randomized to either placebo or leuprorelin treatment. the study spanned forty-eight weeks with leuprorelin treatment every 12 weeks, with ability to swallow a barium contrast marker as the primary endpoint. in this study, there was not a significant difference in barium swallow at forty-eight weeks. there was also no difference in other video fluorography measurements, supporting the lack of improvement in swallow function in the treatment group. other secondary measures, such as number of ar positive scrotal cells and serum ck level were significantly different in the treatment group. though the primary endpoint of the study did not show an effect of leuprorelin on sbma patients, a subgroup analysis performed on patients who had symptoms for ten years or less did show improved swallowing function, and it was suggested that treatment may be more effective in patients who have shown symptoms for shorter periods of time or with less advanced disease. a recent follow-up open-label study compared thirty-six patients treated with leuprorelin to nontreated controls over eighty four months, and found that the treated group showed slower decline in motor function than the non-treated group. significantly differing endpoints of this study included the als functional rating scale, the limb norris score, and the norris bulbar score. dutasteride dutasteride is a 5α-reductase inhibitor which blocks the conversion of testosterone into dihydrotestosterone, reducing overall androgen receptor activation. fifty patients were recruited to a randomized, placebo controlled trial spanning two years, with a primary endpoint of quantitative muscle assessment. no significant difference was found in quantitative muscle assessment between the placebo and dutasteride groups at the two year mark. secondary outcomes including barium swallow and manual muscle testing also showed no significant difference between groups. bvs857 igf-1, a signaling molecule downstream of growth hormone, has well established functions promoting skeletal muscle growth. in preclinical studies on mouse models of amyotrophic lateral sclerosis, igf-1 was shown to be protective against motor neuron death. a double blind, placebo-controlled clinical trial was performed with eighteen sbma patients receiving bvs857, a mimetic of igf-1, with nine placebo controls. the study found increased thigh muscle volume improved lean body mass following 12 weeks of treatment in the bvs857 group compared to placebo. however, eleven of eighteen patients were found to have an immune response against bvs857, with five patients developing neutralizing antibodies, posing a challenge for long-term treatment. society and culture in 2000, the kennedy's disease association was founded by susanne and terry waite and patrick griffin to help find effective treatments and a cure for sbma. the organization is managed and operated by an all-volunteer board of directors, and grown to over 1,600 associates from over 50 countries. donations from patients and families provide funding to support research (90%), education (5%) and operating expenses (5%). kda has awarded grants and fellowships to researchers in the united states, canada, britain, italy, and japan to support both basic research and clinical trials on the causes and potential treatments for sbma. the kda website states that they focus on providing “seed-money” to post-doc and other young researchers to start working on sbma, collecting preliminary data that can be used to support larger proposals to governmental and philanthropic organizations. in 2022, the kda waite-griffin fellowship was established to encourage young researchers to include research on sbma in their future career plans.