PMID- 26601156
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151125
LR  - 20181113
IS  - 2375-2548 (Print)
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 1
IP  - 2
DP  - 2015 Mar
TI  - Gene therapy rescues disease phenotype in a spinal muscular atrophy with 
      respiratory distress type 1 (SMARD1) mouse model.
PG  - e1500078
LID - 10.1126/sciadv.1500078 [doi]
LID - e1500078
AB  - 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.
FAU - Nizzardo, Monica
AU  - Nizzardo M
AD  - 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.
FAU - Simone, Chiara
AU  - Simone C
AD  - 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.
FAU - Rizzo, Federica
AU  - Rizzo F
AD  - 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.
FAU - Salani, Sabrina
AU  - Salani S
AD  - 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.
FAU - Dametti, Sara
AU  - Dametti S
AD  - 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.
FAU - Rinchetti, Paola
AU  - Rinchetti P
AD  - 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.
FAU - Del Bo, Roberto
AU  - Del Bo R
AD  - 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.
FAU - Foust, Kevin
AU  - Foust K
AD  - Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
FAU - Kaspar, Brian K
AU  - Kaspar BK
AD  - 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.
FAU - Bresolin, Nereo
AU  - Bresolin N
AD  - 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.
FAU - Comi, Giacomo P
AU  - Comi GP
AD  - 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.
FAU - Corti, Stefania
AU  - Corti S
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20150313
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
PMC - PMC4643829
OTO - NOTNLM
OT  - Spinal Muscular atrophy with Respiratory Distress Type 1
OT  - gene therapy
EDAT- 2015/11/26 06:00
MHDA- 2015/11/26 06:01
PMCR- 2015/03/13
CRDT- 2015/11/25 06:00
PHST- 2015/01/20 00:00 [received]
PHST- 2015/02/15 00:00 [accepted]
PHST- 2015/11/25 06:00 [entrez]
PHST- 2015/11/26 06:00 [pubmed]
PHST- 2015/11/26 06:01 [medline]
PHST- 2015/03/13 00:00 [pmc-release]
AID - 1500078 [pii]
AID - 10.1126/sciadv.1500078 [doi]
PST - epublish
SO  - Sci Adv. 2015 Mar 13;1(2):e1500078. doi: 10.1126/sciadv.1500078. eCollection 2015 
      Mar.