Science has come one step closer to developing practical methods of gene therapy. Viable gene therapy means treatment for currently untreatable diseases including the vast amount of genetic disorders affecting millions world-wide.

A new study has taking this idea to the next level. Researchers from VIRxSYS, a biotech company working on practical methods of gene therapy and developing an HIV vaccine, have demonstrated ability to use RNA therapy to reverse hemophilia in mice. Published in Molecular Therapy, this study describes a new RNA therapy technique in which implanted RNA molecules can implant genetic sequences in albumin genes to produce other proteins. This technology is known as mediated RNA trans-splicing, or SMaRT™ and is the brainchild of VIRxSYS.

Using their technique, scientists were able to produce beneficial proteins including Factor VIII (mutated in patients with hemophilia A), and apoA-I, which is responsible for producing the main protein in good cholesterol (HDL). By being able to produce Factor VIII, researchers were able to reverse hemophilia in mice, and suggest uses for other therapeutic compounds that could be made in vivo using RNA therapy.

"Two of the RNA molecules that were spliced into albumin are normally produced in the liver. These are the apoA-I, which produces the principal protein in good cholesterol, and Factor VIII, which makes the protein missing in patients with hemophilia A,” said Gerard J. McGarrity, Ph.D. , VIRxSYS Executive Vice President of Scientific and Clinical Affairs. “We instructed the liver to make more apoA-I protein than it normally does, and in separate experiments we instructed the liver to make the correct form of Factor VIII instead of a mutated form. The work is at an early stage, but we are definitely teaching old genes some new tricks."

Hemophilia is a blood disorder in which clotting does not occur normally. Hemophilic patients take a much longer time for their blood to clot, and are at risk from severe blood loss even from simple lesions or cuts. Some patients with hemophilia may also experience internal bleeding, which can cause tissue and organ damage and possible death. Factor VIII is missing or mostly ineffective in patients with hemophilia, and is an inherited genetic disorder. According to the National Institutes of Health (NIH) there are about 18,000 people in the US with hemophilia and 400 babies are born with the disorder each year.

Albumin is the most abundantly expressed gene in the liver and serves as a high-quality base for RNA splicing. Results of the study showed that each of the gene sequences spliced into the albumin gene were expressed in high concentrations by liver cells and was not expressed in other cells, avoiding an immune response. Despite the newness of mediated RNA trans-splicing, VIRxSYS plans to enter human clinical trials testing this technology in late 2010.

References:

Wang J, Mansfield SG, Cote CA, Jiang PD, Weng K, Amar MJ, Brewer BH Jr, Remaley AT, McGarrity GJ, Garcia-Blanco MA, Puttaraju M. "Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo." Molecular Therapy. 2009; 17(2):343-51; doi:10.1038/mt.2008.260.

NIH

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