The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: (1) We examined the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls. In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. Lung areas, diaphragm, and chest wall motion were measured throughout the breathing cycle. The lung areas at maximal inspiration and expiration were reduced in DMD patients relative to controls. The change in the lung area between inspiration and expiration correlated with percent predicted forced vital capacity (FVC) in patients and was not significantly different between groups. The diaphragm position, length, contractility, and motion were not significantly different between groups. Chest wall motion was reduced in patients compared to controls. Cine breathing MRI allows independent and reliable assessment of the diaphragm and chest wall dynamics during the breathing cycle in DMD patients and controls, and may be a useful imaging biomarker in future clinical trials. (2) We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in SBMA patients. SBMA patients have low IGF-1 levels, and studies of IGF-1 showed benefit in a transgenic model of SBMA. A study of BVS857 in healthy volunteers showed it to be well tolerated. This was a randomized, double-blind, and placebo-controlled study in SBMA patients recruited at neuromuscular centers in Denmark, Germany, Italy, and three sites within the US. Eligible patients were age 18 years or older with a confirmed genetic diagnosis of SBMA, ambulatory, with symptomatic weakness, and serum IGF-1 levels of 170 ng/mL. Following a safety and tolerability evaluation with 8 SBMA patients, BVS857 was administered weekly for 12 weeks to 27 patients, with 2:1 drug to placebo randomization by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. For the primary outcome measure of TMV, the ratio of post-baseline to baseline at week 13 was analyzed by analysis of covariance per protocol. 27 patients were randomly assigned to treatment groups and 25 were included in the preliminary efficacy analysis. BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo with a geometric-mean ratio of 104, and a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients, respectively. There were no significant differences in reported adverse events between the BVS857 and placebo groups. There were also no differences in measures of muscle strength and function. Immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to endogenous IGF-1 in 5 patients. TMV remained stable in BVS857-treated SBMA patients after 12 weeks of dosing. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies may help to further evaluate the efficacy of activating the IGF-1 pathway in SBMA. (Lancet Neurol, in press)
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