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Nizzardo M, Simone C, Rizzo F, et al. Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Sci Adv. 2015;1(2):e1500078doi: 10.1126/sciadv.1500078.
Nizzardo, M., Simone, C., Rizzo, F., Salani, S., Dametti, S., Rinchetti, P., Del Bo, R., Foust, K., Kaspar, B. K., Bresolin, N., Comi, G. P., & Corti, S. (2015). Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Science advances, 1(2), e1500078. https://doi.org/10.1126/sciadv.1500078
Nizzardo, Monica, et al. "Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model." Science advances vol. 1,2 (2015): e1500078. doi: https://doi.org/10.1126/sciadv.1500078
Nizzardo M, Simone C, Rizzo F, Salani S, Dametti S, Rinchetti P, Del Bo R, Foust K, Kaspar BK, Bresolin N, Comi GP, Corti S. Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Sci Adv. 2015 Mar 13;1(2):e1500078. doi: 10.1126/sciadv.1500078. eCollection 2015 Mar. PMID: 26601156; PMCID: PMC4643829.
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Sci Adv. 2015 Mar 13;1(2):e1500078. doi: 10.1126/sciadv.1500078. eCollection 2015 Mar.

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

Science advances

Monica Nizzardo, Chiara Simone, Federica Rizzo, Sabrina Salani, Sara Dametti, Paola Rinchetti, Roberto Del Bo, Kevin Foust, Brian K Kaspar, Nereo Bresolin, Giacomo P Comi, Stefania Corti

Affiliations

  1. Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, and Neurology Unit, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  2. Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
  3. Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA. ; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. ; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA.

PMID: 26601156 PMCID: PMC4643829 DOI: 10.1126/sciadv.1500078

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, 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.

Keywords: Spinal Muscular atrophy with Respiratory Distress Type 1; gene therapy

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