Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children that is caused by mutations in the IGHMBP2 gene (11q13) and lacks a cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy rescued the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. In this study, we report rescue of the disease phenotype in a SMARD1 mouse model following therapeutic delivery of an AAV9 construct encoding the wild-type IGHMBP2 via systemic injection to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and lifespan (450% increase), ameliorating pathological features in the CNS, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1 induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.