Journal
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
Volume 10, Issue -, Pages 348-360Publisher
CELL PRESS
DOI: 10.1016/j.omtm.2018.08.005
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Funding
- SMA Europe
- NIH/NINDS grant [R21NS093175]
- Sims' Fund to Cure SMARD
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS093175] Funding Source: NIH RePORTER
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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive disease caused by the loss of the ubiquitously expressed IGHMBP2 gene. SMARD1 causes degeneration of alpha-motor neurons, resulting in distal muscle weakness, diaphragm paralysis, and respiratory malfunction. We have reported that delivery of a low dose of AAV9-IGHMBP2 to the CNS results in a significant rescue of the SMARD1 mouse model (nmd). To examine how a delivery route can impact efficacy, a direct comparison of intravenous (IV) and intracerebroventricular (ICV) delivery of AAV9-IGHMBP2 was performed. Using a low-dose, both IV and ICV delivery routes led to a significant extension in survival and increased body weight. Conversely, only ICV-treated animals demonstrated improvements in the hindlimb muscle, neuromuscular junction, and motor function. The hindlimb phenotype of IV-treated mice resembled the untreated nmd mice. We investigated whether the increased survival of IV-treated nmd mice was the result of a positive impact on the cardiac function. Our results revealed that cardiac function and pathology were similarly improved in IV- and ICV-treated mice. We concluded that while IV delivery of a low dose does not improve the hindlimb phenotype and motor function, partial restoration of cardiac performance is sufficient to significantly extend survival.
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