TRANS-SPLICING TO REPAIR CYSTIC FIBROSIS MRNA

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The ultimate objective of this proposal is to develop a new general mechanism to reprogram any human or eukaryotic gene at the pre- messenger RNA level. Specifically, this proposal will develop our patented technology, spliceosome mediated RNA trans-splicing (SMaRT[TM]), towards the production of a practical gene therapy for the treatment of Cystic Fibrosis. In Phase 1, we produced a series of pretherapeutic RNA molecules (PTMs) that are capable of initiating SMaRT reactions with mutant Cystic Fibrosis Transmembrane Regulator (CFTR) pre-mRNA, repairing the mRNA and expressing full length CFTR protein in cultured cells. The goal in Phase 2 is to identify an optimal PTM that can repair mutant CFTR mRNA, appropriately express normal CFTR protein, and restore chloride channel function in the most clinically relevant models of Cystic Fibrosis. This lead PTM therapeutic candidate will enter full preclinical testing in Phase 3 and ultimately, human clinical trials if results warrant. Many other genetic diseases may also be amenable to SMaRT[TM] therapeutics. Trans-splicing PTMs could improve many aspects of gene therapies by conferring intra-cellular specificity, decreasing the size of the delivered gene, and acquiring the regulated expression of the endogenous target gene. PROPOSED COMMERCIAL APPLICATIONS: Development of RNA molecules capable of repairing mutant CFTR by trans-splicing could lead to a therapeutic for Cystic Fibrosis that could slow or halt disease progression. There is a clinical need to serve and treat this market of approximately 30,000 affected individuals in the U.S. alone. Additionally, the development of effective spliceosome mediated RNA trans-splicing technology would be of utility in many gene transfer applications including the treatment of other genetic diseases, infections by splicing viruses ( HIV, EBV, papilloma, etc) and cancer.