Peptide-conjugated Morpholino for treatment of Spinal Muscular Atrophy

The project objective is to contribute to the development of a stem cell therapy for SMA, which is a common motor neuron degeneration disorder, characterized by progressive muscle weakness and paralysis, and eventually leading to death. It is caused by mutations in the SMN gene. Results from recent studies with ASO and MO in animal models were promising; thus, this may be an effective treatment for SMA patients. However, low systemic distribution to affected tissues such as the brain and spinal cord, poor delivery of oligonucleotides into cells, and the narrow therapeutic window may hamper the transition into clinical trials. To overcome these issues we propose to investigate the potential of CPPs, which have enhanced tissue delivery in other diseases, including DMD, leading to improved systemic distribution, pharmacological properties, and efficacy compared to unconjugated-MO. We will conjugate 3 different CPP types with our already validated MO sequence and we will test them in pilot groups of SMAΔ7 mouse models, selecting the most efficient in terms of delivery. We will then compare the efficacy of CPP-conjugated MO with unconjugated-MO in presymptomatic and symptomatic SMA mice. We will perform survival and neuropathological analyses of treated SMA mice. Data from this project will be evaluated based on two clinically meaningful outcomes: 1) the possibility to use a non-invasive systemic injection and 2) the ability to treat the disease in the symptomatic phase, expanding the therapeutic window. We expect that the results from these experiments will provide novel valuable information to the SMA field. If successful, this approach can be further optimized and developed for SMA clinical trials.