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.
Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model / M. Nizzardo, C. Simone, F. Rizzo, S. Salani, S. Dametti, P. Rinchetti, R. Del Bo, K. Foust, B.K. Kaspar, N. Bresolin, G.P. Comi, S. Corti. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 1:2(2015 Mar), pp. e1500078.1-e1500078.10.
|Titolo:||Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model|
NIZZARDO, MONICA (Primo)
SIMONE, CHIARA (Secondo)
COMI, GIACOMO PIETRO (Penultimo)
CORTI, STEFANIA PAOLA (Ultimo)
|Parole Chiave:||Spinal Muscular atrophy with Respiratory Distress Type 1; gene therapy|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
Settore MED/03 - Genetica Medica
Settore BIO/11 - Biologia Molecolare
Settore MED/50 - Scienze Tecniche Mediche Applicate
Settore BIO/05 - Zoologia
|Data di pubblicazione:||mar-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1126/sciadv.1500078|
|Appare nelle tipologie:||01 - Articolo su periodico|