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) completion of a phase 2 clinical trial to test the feasibility of dutasteride treatment for spinal and bulbar muscular atrophy (SBMA), (2) initiation of a randomized, controlled trial of exercise in SBMA, (3) development of a protocol for evaluation of skeletal and cardiac imaging with a trial of oligonucleotide therapy in Duchenne muscular dystrophy (DMD). SBMA is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment.
We aim ed to assess the efficacy and safety of the 5-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. We undertook a randomized, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned to receive dutasteride (0.5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. 50 men were randomly assigned to treatment groups, and 44 were included in the efficacy analysis. At 24 months, the placebo group showed a decrease of 4.5% from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1.3%;the difference between groups was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the SF-36v2 questionnaire, favored dutasteride whereas the mental component summary favored placebo. The dutasteride group had fewer patients reporting falls than did the placebo group;there were no other significant differences in reported adverse events. Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of positive effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials. The role of exercise in motor neuron disease is controversial. We recently started a study to examine the safety and efficacy of exercise in SBMA.
We aim to enroll 80 men with genetically confirmed SBMA. This is a randomized, evaluator blinded, trial with 25 subjects in each exercise arm. Following informed consent, the subjects undergo initial medical and physical evaluations followed by a series of neurological tests and blood work over a two-day outpatient visit at the NIH. The subjects provide blood work for analysis of hormonal levels and assessment of any potential muscle damage. On the second day of their visit, the subjects are randomized and taught a series of either functional or stretching exercises that they engage in as part of the study and control arms, respectively. Following the baseline visit to NIH, the subjects are monitored throughout the study with telephone contacts and other measures including video recording to monitor their progress and compliance. The subjects return to the NIH at the end of a 12 week period at which time the physical and laboratory testing is repeated. The primary outcome measure used is the Adult Myopathy Assessment Tool . Secondary outcome measures are QMA, the Timed Up and Go test, a quality of life measure (SF-36v2), adverse event questionnaires, a Computerized Dynamic Posturography assessment of balance, accelerometer measurements of exercise effort, and progressive height sit-to-stand testing. Several exploratory biomarkers that may be affected by exercise are being evaluated, including insulin-like growth factor-1 (IGF-1), IGF binding protein 3, testosterone, growth hormone, and creatine kinase. Beck Depression Inventory testing is also being used to determine if the subjects mood is affected by exercise. DMD is the most frequent inherited fatal childhood disease. Antisense oligonucleotide-induced exon skipping is a promising therapeutic strategy for DMD that is currently being explored in clinical trials. Magnetic resonance imaging (MRI) and ultrasound imaging methods are sensitive to key processes in dystrophic muscle such as edema and fat infiltration and therefore could serve as a biomarker of disease progression and therapeutic response. We have developed a study protocol to explore the potential of these imaging biomarkers for assessing the effects of the oligonucleotide GSK2402968 in ambulatory boys with DMD. The primary objective is to assess longitudinal changes in skeletal muscle structural MRI measures reflecting fat and edema in the lower extremities in ambulatory boys with DMD receiving GSK2402968 or placebo.
We aim to enroll up to 65 ambulatory boys with DMD. Healthy volunteer/control boys (up to 20) matched for the age-range will be recruited to obtain pilot data for imaging studies. This prospective study of skeletal muscle, cardiac, and diaphragm imaging at the NIH will be offered to all subjects participating in a phase 2, double blind, exploratory parallel-group, placebo-controlled clinical study in ambulatory subjects with DMD resulting from a mutation that can be corrected by exon 51 skipping induced by GSK2402968. Subjects will travel with a family member to the NIH for MRI and ultrasound assessments during the screening phase of the parent study and additionally, if randomized, then at the following time points in the parent study: at 12 weeks, and 24 weeks during the blinded treatment period;and finally, after completion of 24 week post-treatment phase (at 48 weeks). If not randomized, the subjects will have a one-time evaluation during the screening phase of the parent study. Pilot data also will be obtained from healthy boys for comparisons to allow exploration of MRI and ultrasound measures specific to pathology in the ambulatory boys with DMD. The primary outcome measure for the study is MRI-detected change in skeletal muscle fat in the lower extremities from baseline in boys with DMD receiving GSK2402968 or placebo. Secondary outcome measures include changes in the following outcome measures at 12, 24, and 48 weeks from baseline in boys with DMD receiving GSK2402968 or placebo: relative muscle fat/water assessed by skeletal muscle MRI T1 imaging, muscle edema assessed by T2 imaging, and cardiac function and myocardial fat and edema as measured by cardiac MRI. Exploratory outcome measures include changes in muscle water diffusivity as assessed by diffusion MRI;the effects of exercise on selected MRI measures in leg muscles, muscle ultrasound to monitor changes in skeletal muscle volume, echogenicity, and stiffness;and MRI assessment of diaphragm motion.

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Guber, Robert D; Kokkinis, Angela D; Schindler, Alice B et al. (2017) Patient-Identified Impact of Symptoms in Spinal and Bulbar Muscular Atrophy. Muscle Nerve :
Mankodi, Ami; Azzabou, Noura; Bulea, Thomas et al. (2017) Skeletal muscle water T2 as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy. Neuromuscul Disord 27:705-714
Mankodi, Ami; Bishop, Courtney A; Auh, Sungyoung et al. (2016) Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy. Neuromuscul Disord 26:650-658
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