Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.

A Negatively Acting Bifunctional RNA Increases Survival Motor Neuron Both In Vitro and In Vivo

“…This virus is an ideal candidate for gene therapy as it is replication deficient and certain AAV serotypes have been shown to have high tropism for both muscles and neurons and can use retrograde transport to travel from muscle to neurons in vivo. Previous studies have successfully used the retrograde transport ability of a pseudotyped lentivirus to deliver SMN cDNA (Azzouz et al, 2004). Although these data have direct implications for SMA therapy, they could also be transitioned to be applicable to many disease states in which it would be desirable to skip an exon, such as in muscular dystrophy, where skipping an exon or set of exons may return the proper reading frame.…”

Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts

“…The blot was then stripped and re-probed against actin as a loading control motor neuron death occurs early in prenatal development and, in turn, this SMN-deWciency eVectively predetermines the fate of motor neurons. This model could account for why recent avenues into SMA therapies show elevated SMN protein levels, but result in a less robust eVect regarding overall survival and correction of the disease phenotype (Azzouz et al 2004;Haddad et al 2003). Regardless of the therapeutic mechanism, it will be critical to address when SMN levels must be elevated and what the speciWc role of SMN is in aVected tissues.…”

Stimulating Full-Length SMN2 Expression by Delivering Bifunctional RNAs via a Viral Vector

“…Potentially the developmental signal that will eventually trigger motor neuron death occurs early in prenatal development and, in turn, this SMN deficiency effectively predetermines the fate of motor neurons. This model could account for why recent avenues into SMA therapies show elevated SMN protein levels but result in a less robust effect regarding overall survival and correction of the disease phenotype [34,35]. While the experiments described in this report have immediate implications for the development of an SMA therapy, the results could be used as a model for a broad range of genetic disorders in which correcting a splicing defect would restore functionality to a disease-causing gene by effectively being able to promote the inclusion of specific exons that are misprocessed in the disease state.…”