Development of a Novel Strategy to Treat Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by reduced levels of the survival motor neuron (SMN) protein, which results in degeneration of motor neurons, leading to muscle weakness, and, ultimately, death. To provide an effective therapy for SMA, SMN expression must be restored in motor neurons. The goal of our research is to develop protein-based therapeutics for SMA. Protein transduction domain (PTD), from the human immunodeficiency virus-transactivator of transcription (HIV-TAT), mediates the transduction of any polypeptide to which they are fused. We produced bacterial expression cassettes of PTD-SMN. The PTD-SMN is able to transduce cells in vitro, reaching the nucleus and forming punctate structures similar to that of endogenous SMN. Internalization of PTD-SMN results in an increased nuclear-staining foci (gems) number. Importantly, this PTD-SMN co-localizes with coiled bodies, indicating PTD-SMN is able to localize to the correct region of the nucleus. However, we were unable to detect interaction of PTD-SMN with SMN known binding partners, suggesting that majority of PTD-SMN has low activity. Our results suggest that PTD-SMN produced from a prokaryotic source may be useful for SMA therapy, but optimization of protein production is required before this therapy can reach its full potential.