Targeted lentiviral-mediated delivery of progranulin cDNA in a genetic model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatally progressive neurodegenerative disease characterized by the loss of motor neurons in both the brain and spinal cord. Neuronal cell death leads to a lack of muscle innervation which eventually gives rise to paralysis. Patients typically survive less than five years following the initial onset; with respiratory complications ultimately causal in death. The majority of ALS cases are of unknown etiology, with around 5% linked to aberrant genetic mutations. The most well characterized mutations account for approximately 1-2% of all ALS cases, and are linked to the genetic locus for superoxide dismutase-1 (SOD1). The severity of disease and the concomitant lack of effective therapeutic options necessitate significant research efforts in search of viable treatment options that would significantly impede and/or reverse the ultimate loss of motor neurons. Progranulin (PGRN) may be one such an option since the protein is a secreted growth factor that has demonstrated neuroprotective outcomes in models of Alzheimer’s- and Parkinson’s disease and may generally be important in the long term survival of neurons. Employing a lentiviral-mediated delivery mechanism at a stage prior to disease onset, we set out to assess the potential neurotrophic properties of exogenously delivered PGRN cDNA when targeted to neuronal subsets within the lumbar spinal cord of mice expressing mutant SOD1. The resultant outcomes at both the behavioural and neuropathological levels did not demonstrate any significant protective effect from the lentiviral delivery of exogenous PGRN. PGRN-treated cohorts did not exhibit an increase in overall survival, a decrease in gliosis, or an increase in neuronal viability when compared to the GFP-lentiviral-injected control groups. This study suggests that PGRN delivery at an early stage of ALS neurodegeneration preceding the phenotypic expression of disease may not be a viable therapeutic option in ameliorating the ALS degenerative cascade. Technical caveats to this interpretation are discussed. One of these includes the unexpected reduction in the copy number of the mSOD1 gene in transgenic mice, which ultimately presenting with a protracted progression of the disease. The present study thus additionally underscores some of the challenges faced in pre-clinical therapeutic development using murine ALS models.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat