Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice

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.

Spinal Muscular Atrophy: Journeying From Bench to Bedside

“…In part, this is a consequence of the identification of new serotypes, for example adenoassociated virus (AAV)9, of the adenoassociated virus which are reported to efficiently penetrate BBB of neonatal mice and infect multiple cell types [102]. Such a vector harboring SMN1 infected not only neurons, but also peripheral tissue, dramatically rescuing the SMA phenotype in severely affected model mice [80,103,104]. The promise of this strategy in preclinical murine models has prompted the development of protocols that can be applied to larger models and eventually SMA patients.…”

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

“…Several groups are currently evaluating the pre-clinical efficacy of scAAV which have been shown to efficiently infect motor neurons [Foust et al, 2010;Passini et al, 2010;Valori et al, 2010;Dominguez et al, 2011]. Two distinct routes of administration, intravenous (IV) and IT injections, have been tested in pre-clinical models: a better outcome, in terms of survival of the affected mice, has been achieved by IV compared to IT [Foust et al, 2010;Passini et al, 2010;Valori et al, 2010;Dominguez et al, 2011]. However, this therapeutic approach presents some issues: while IT administration could limit the spreading of scAAV infection outside the CNS, potentially reducing the risk of immunization against the virus, it precludes provision of SMN to peripheral tissues.…”

Targeting RNA-Splicing for SMA Treatment

“…Not surprisingly, extensive efforts have been undertaken to examine constructs and vectors that can safely boost SMN expression in motor neurons of SMA models Dominguez et al, 2011;Foust et al, 2010;Glascock et al, 2011;Passini et al, 2010). This has been one of the mainstream objectives in the search for drugs to treat SMA.…”