Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice.
Spinal muscular atrophy (SMA) is the most common genetic disease leading to infant mortality. This neuromuscular disorder is caused by the loss or mutation of the telomeric copy of the 'survival of motor neuron' (Smn) gene, termed SMN1. Loss of SMN1 leads to reduced SMN protein levels, inducing degeneration of motor neurons (MN) and progressive muscle weakness and atrophy. To date, SMA remains incurable due to the lack of a method to deliver therapeutically active molecules to the spinal cord. Gene therapy, consisting of reintroducing SMN1 in MNs, is an attractive approach for SMA. Here we used postnatal day 1 systemic injection of self-complementary adeno-associated virus (scAAV9) vectors carrying a codon-optimized SMN1 sequence and a chimeric intron placed downstream of the strong phosphoglycerate kinase (PGK) promoter (SMNopti) to overexpress the human SMN protein in a mouse model of severe SMA. Survival analysis showed that this treatment rescued 100% of the mice, increasing life expectancy from 27 to over 340 days (median survival of 199 days) in mice that normally survive about 13 days. The systemic scAAV9 therapy mediated complete correction of motor function, prevented MN death and rescued the weight loss phenotype close to normal. This study reports the most efficient rescue of SMA mice to date after a single intravenous injection of an optimized SMN-encoding scAAV9, highlighting the considerable potential of this method for the treatment of human SMA.
UPMC-AIM UMR S974, INSERM U 974, CNRS UMR 7215, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, France.
Elisa
E
Dominguez
Thibaut
T
Marais
Nicolas
N
Chatauret
Sofia
S
Benkhelifa-Ziyyat
Sandra
S
Duque
Philippe
P
Ravassard
Romain
R
Carcenac
Stéphanie
S
Astord
Aurélie
A
Pereira de Moura
Thomas
T
Voit
Martine
M
Barkats
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D016896:Treatment Outcome
D055533:Survival of Motor Neuron 1 Protein