Supraphysiological expression of survival motor neuron protein from an adenovirus vector does not adversely affect...

Spinal muscular atrophy (SMA) is the most common inherited neurodegenerative disease that leads to infant mortality. It is caused by mutations in the survival motor neuron (SMN) protein resulting in death of alpha motor neurons. Increasing evidence suggests that several other tissues are also affected in SMA, including skeletal and cardiac muscle, liver, and pancreas, indicating that systemic delivery of therapeutics may be necessary for true disease correction. Due to the natural biodistribution of therapeutics, a level of SMN several-fold above physiological levels can be achieved in some tissues. In this study, we address whether supraphysiological levels of SMN adversely affects cell function. Infection of a variety of cell types with an adenovirus (Ad) vector encoding SMN leads to very high expression, but the resulting protein correctly localizes within the cell, and associates with normal cellular partners. Although SMN affects transcription of certain target genes and can alter the splicing pattern of others, we did not observe any difference in select target gene splicing or expression in cells overexpressing SMN. However, normal human fibroblasts treated with Ad-SMN showed a slight reduction in growth rate, suggesting that certain cell types may be differently impacted by high levels of SMN.