Decreasing Disease Severity in Symptomatic,Smn^−/−;SMN2^+/+, Spinal Muscular Atrophy Mice Following scAAV9-SMN Delivery

Abstract

Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present, SMN2. SMN2 is retained in all SMA patients and encodes the same protein as SMN1. However, SMN1 and SMN2 differ by a silent C-to-T transition at the 5' end of exon 7, causing alternative splicing of SMN2 transcripts and low levels of full-length SMN. SMA is monogenic and therefore well suited for gene-replacement strategies. Recently, self-complementary adeno-associated virus (scAAV) vectors have been used to deliver the SMN cDNA to an animal model of disease, the SMND7 mouse. In this study, we examine a severe model of SMA, Smn -/-;SMN2 + / + , to determine whether gene replacement is viable in a model in which disease development begins in utero. Using two delivery paradigms, intracerebroventricular injections and intravenous injections, we delivered scAAV9-SMN and demonstrated a two to four fold increase in survival, in addition to improving many of the phenotypic parameters of the model. This represents the longest extension in survival for this severe model for any therapeutic intervention and suggests that postsymptomatic treatment of SMA may lead to significant improvement of disease severity.

SMN-Inducing Compounds For The Treatment Of Spinal Muscular Atrophy

“…administration of scAAV9–SMN, icv. administration was shown to produce a greater degree of rescue in SMA [100,107]. Similar conclusions were also drawn regarding icv.…”

“…Similar conclusions were also drawn regarding icv. administration in an even more severe model of disease that typically dies at approximately P5 [107]. While the extension in survival did not achieve the 150–250 days seen with the less severe model, this work demonstrated that delivery of the scA AV9-SMN vector can significantly extend survival even in severely symptomatic SMA animals.…”

Spinal muscular atrophy: An update on therapeutic progress

“…On the other hand, experiments conducted in Taiwanese type I SMA mice yielded variable results and less promising survival benefits with ICV administration of SMN1 sequence (Fig. 1) [82]. These findings underscore the caution that must be exercised when extrapolating the results of pre-clinical studies conducted in a specific mouse model to design clinical trials in humans.…”

Systemic Delivery of Tyrosine-Mutant AAV Vectors Results in Robust Transduction of Neurons in Adult Mice

“…However, while intravenous injections of AAV9 vectors achieved efficient transduction of spinal motor neurons in fetal, neonate, and adult mice, as well as in adult cats and pigs [9–13, 15, 16], most of the transduced cells were astrocytes in adult mice and nonhuman primates [9, 14, 16]. Thus, extensive gene delivery to neurons in the adult CNS remains challenging.…”