SMaRT Spliceosome-Mediated RNA Trans-splicing

American Society of Gene Therapy News Release: "Current gene transfer methods rely on the efficient transfer of cDNAs to effect phenotypic change. A study presented at the American Society of Gene Therapy Annual Meeting demonstrated a new approach to gene therapy. The researchers developed in vivo data supporting a novel method for genetic repair based on the correction of mutant pre-mRNA.

Christopher Walsh, MD, and Hengjun Chao, MD, at the University of North Carolina at Chapel Hill and Gary Mansfield, MD, and collaborators at Intronn Inc, Rockville, MD, made use of a natural mechanism that splices out introns and joins together the protein-coding exons. The normal process is called 'cis-splicing.' The researchers developed a new technology, called 'Spliceosome-mediated RNA trans-splicing (SMaRT),' to correct the hemophilia phenotype in Factor VIII knock out mice. A gene therapy vector is made by inserting their 'trans-splicing cassette' into a viral vector.

The researchers found that when they injected their vector into the hemophiliac mice, a significant increase in functional Factor VIII was found in the bloodstream of the mice. This factor allowed the mice to survive the bleeding trauma, which is lethal to untreated hemophilia mice. They demonstrated that the mutant FVIII RNA was repaired and that 'RNA repair' occurred via trans-splicing.This novel RNA repair method can provide a new approach in gene therapy for many genetic diseases, which are difficult to deal with by current gene transfer methods."