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.

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

“…The lentiviral vector for delivery of hPGC-1α in our study was well tolerated, did not trigger adverse effects, and allowed sustained expression of the transgene for months. Successful proof-of-principle studies of gene therapy using similarly pseudotyped lentiviral vectors have been demonstrated in animal models of ALS (34,35), spinal muscular atrophy (36), and spinal nerve injury (37). In addition, we have developed and tested a similar vector for dopamine replacement therapy in late stage Parkinson's disease patients in a phase I/II clinical trial, showing long-term expression and improved motor behavior in treated patients (38).…”

Repair of pre-mRNA splicing

“…This will require appropriate transfer vectors. Some initial success was obtained by Azzouz, Mazarakis and coworkers by using lentiviral vectors, 152,153 but recent results indicate that self-complementary AAV9 vectors can efficiently transduce motoneurons, when injected into presumably also not concentrated in the nucleus, underlining the importance of a snRNA backbone for RNA stability and nucleoplasmic accumulation.…”

New Vectors for Stable and Safe Gene Modification

“…Although EIAV-based vectors are about 10-fold less efficient in several human cell lines than HIV-1 based vectors (Ikeda et al, 2002), they have demonstrated good efficiency for treatment of neuromuscular pathologies in animal models (Azzouz et al, 2004;Yip et al, 2006). In addition, they are able to transduce human HSCs (Siapati et al, 2005) and are very efficient in vivo.…”