Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice
Open Access
- 30 November 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 20 (4), 681-693
- https://doi.org/10.1093/hmg/ddq514
Abstract
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.Keywords
This publication has 50 references indexed in Scilit:
- Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor NeuronsMolecular Therapy, 2009
- Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytesNature Biotechnology, 2008
- Self-complementary AAV Vectors; Advances and ApplicationsMolecular Therapy, 2008
- Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific DiseaseNeuron, 2005
- Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophyJCI Insight, 2004
- Codon optimization improves heterologous expression of a Schistosoma mansoni cDNA in HEK293 cellsZeitschrift für Parasitenkunde, 2002
- Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2Genetics in Medicine, 2002
- Multiple Effects of Codon Usage Optimization on Expression and Immunogenicity of DNA Candidate Vaccines Encoding the Human Immunodeficiency Virus Type 1 Gag ProteinJournal of Virology, 2001
- Identification and characterization of a spinal muscular atrophy-determining geneCell, 1995
- The Genetic Component in Child MortalityArchives of Disease in Childhood, 1970