CLINICAL STUDY OF SPINAL MUSCULAR ATROPHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spinal Muscular Atrophy (SMA) is one of the most devastating neurological diseases of childhood. Affected infants and children suffer from progressive muscle weakness caused by degeneration of lower motor neurons in the spinal cord and brainstem. Clinically, four phenotypes are distinguished within the continuous spectrum of disease severity based on the age of onset and the highest motor milestone ever achieved. SMA is caused by homozygous deletion of the survival motor neuron-1 (SMN1) gene. A related gene, SMN2, produces low levels of full-length SMN protein due to inefficient splicing. There is an inverse correlation between SMN copy number and disease severity, presumably mediated by levels of full-length SMN protein. Therefore, increasing the amount of full-length SMN protein is a promising treatment strategy. Several drugs targeting splicing efficiency have resulted in increased SMN protein in preclinical assays and are now awaiting clinical testing. With the future objective to conduct clinical trials in SMA, the proposed project has 3 specific aims: 1) to characterize the patient population from a clinical and molecular point of view; (2) to establish a web-based database that will serve to enroll the patient population and that will facilitate timely recruitment for future clinical trials; and (3) to plan for clinical trials by (a) developing reliable outcome measures, (b) establishing the infrastructure needed to carry out efficient clinical trials, and (c) convening meetings of preclinical and clinical researchers involved in SMA drug development to select candidate drugs. We have established a Pediatric Neuromuscular Clinical Research Network (PNCR) to evaluate patients at three sites: New York, Boston and Philadelphia. Data management (including fully web-based data repository) and statistical analyses will be carried out at the University of Rochester by a group experienced in clinical trials of neuromuscular disease. We will cha