Novel mouse models for spinal muscular atrophy with respiratory distress type I : characterizing disease relevant models and evaluating therapeutic potential
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Spinal muscular atrophy with respiratory distress type I (SMARD1) is a rare neurodegenerative disease caused by loss-of-function mutations in the immunoglobulin µ-DNA binding protein 2 (IGHMBP2). SMARD1 is defined by severe respiratory impairment due to progressive diaphragm weakness followed by distal to proximal spread of muscle atrophy. This is caused degeneration of lower alpha motor neurons. Clinical onset typically occurs ~6 weeks to ~6 months of age and is followed by rapid disease progression and mortality within 2 years. There is currently no SMARD1-specific therapeutics available, and patients rely on palliative care measures such as use of an artificial mechanical ventilator. SMARD1 is thought to be an excellent candidate for AAV9-mediated gene therapy; however, the pipeline for treatment approval remains in the pre-clinical stage. In this work we assess and develop two areas in SMARD1 that remain poorly understood. First, we evaluate the therapeutic window for SMARD1 FVB-nmd2J mice by delivering our ssAAV9-IGHMBP2 at different dosages and neonatal timepoints. This allows us to properly compare the extent of phenotypic and cellular pathology rescue preand post-symptomatically in vivo. We confirm from this study that the earlier the treatment of ssAAV9-IGHMBP2 results in a higher extent of rescue. Additionally, we characterize one of the novel mouse lines created that carries a missense-derived patient mutation, D565N (D564N in mice). We determined this mutation results in severe phenotypic and cellular pathology defects in homozygous offspring, and, notably, results in respiratory impairments. We also observed that high dose delivery of ssAAV9- IGHMBP2 to this missense mutation-based mouse model results in substantial rescue. These insights help further our understanding about SMARD1, as well as further preclinical insights for developing a gene replacement therapeutic option.
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Ph. D.