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

TLDR

Spinal muscular atrophy is the most common genetic disease causing infant mortality, arising from loss or mutation of the SMN1 gene, which reduces SMN protein, leading to motor neuron degeneration and progressive muscle weakness, and currently lacks an effective delivery method to the spinal cord. The study aims to evaluate gene therapy that reintroduces SMN1 into motor neurons as a promising treatment for SMA. Researchers performed a postnatal day‑1 systemic injection of self‑complementary AAV9 vectors encoding a codon‑optimized SMN1 sequence with a chimeric intron under a PGK promoter to overexpress human SMN protein in a severe SMA mouse model. The therapy rescued 100 % of mice, extending median survival from 13 to 199 days and life expectancy from 27 to over 340 days, fully restoring motor function, preventing motor neuron death, normalizing weight, and representing the most efficient rescue achieved with a single intravenous injection, underscoring its potential for human SMA.

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.