RETRACTED ARTICLE: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN

Abstract

Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function1. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect ~60% of motor neurons when injected intravenously into neonatal mice2–4. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA.

Repair of pre-mRNA splicing

“…Two recent reports have demonstrated that different adeno-associated virus (AAV) vectors expressing SMN cDNA can reach motoneurons and partly rescue newborn mice that would otherwise show a severe SMA phenotype. 109,110 Moreover, neural stem cell therapy may also be an option for treating SMA.…”

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

“…The issue of a "therapeutic window" is widely discussed in the scientific community since data arising from pre-clinical studies are complex and data from similar human studies are nonexistent. Some pre-clinical studies support the existence of a critical therapeutic window, since increases in SMN levels at post-natal day 1 (P1) rescue the majority of SMA mice, but this rescue is absent if SMN levels are restored later [Foust et al, 2010;Le et al, 2011]. However, other studies did not confirm these findings [Lutz et al, 2011].…”

“…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.…”

“…Additionally, while SMN2 full length transcript levels are lower in patients compared to controls and are grossly related to phenotypic severity, this observation was not recapitulated for SMN protein, which is significantly reduced only in the most severely affected patients [Sumner et al, 2006;Tiziano et al, 2010a;Tiziano et al, 2010b;Piepers et al, 2011;Crawford et al, 2012;Tiziano et al, 2013]. This being said, studies in SMA mice suggest that as little as 70% of control SMN protein might be sufficient to revert disease pathology if introduced during the pre-symptomatic period [Foust et al, 2010].Clinical Outcomes: How to Evaluate the Efficacy of a Treatment?The wide phenotypic spectrum of the disease, coupled with the wide age range of patients, poses significant challenges as it is clear that the same outcome measures can hardly be used in children and adults with chronic SMA. The identification of unbiased primary TIZIANO ET AL.…”

Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

“…For decades, herpes simplex viruses (HSVs) have been known to enter the CNS by retrograde axonal transport, and HSV has been engineered for remote gene transfer in animal models of disease (15,16). Engineered viruses and protein chimeras have also been used successfully in animal models to transfer therapeutic genes for conditions such as spinal cord injury, spinal muscular atrophy, chronic pain, and amyotrophic lateral sclerosis (17)(18)(19)(20)(21). However, virus-mediated gene therapy has been limited in clinical translation due to issues of immunogenicity, vector safety, and cost of production.…”