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Fellowship Research Project Funded in 2008

RNA splicing mediated therapies for Hemophilia

Dr. Kelly Aukema
Postdoctoral Fellow,
Michael Smith Foundation for Health Research
University of Northern British Columbia
Prince George, British Columbia

Hemophilia, an inherited bleeding disorder caused by defects in a clotting factor, affects roughly 1 in 10,000 Canadians. Alternative treatments for Hemophilia are desirable as current therapies, consisting of clotting factor replacement injections, are extremely expensive, totaling up to $1 million per person annually. Furthermore, the effectiveness of clotting factor injection is limited by immune response as up to 35% of patients treated develop antibodies to the injected factor.

RNA splicing offers a viable alternative treatment. Hemophilic mice have been successfully treated by repairing the genetic defect at the level of the messenger RNA. Taking advantage of a rare side reaction of the existing cellular RNA splicing machinery, a corrective RNA fragment can be spliced into a defective clotting factor messenger RNA by a mechanism called trans-splicing.

Mammalian RNA splicing is coupled to DNA transcription, and this coupling may be a mechanism employed by the cell to deter trans-splicing, as uncontrolled trans-splicing in a normal context is likely detrimental to the cell. This raises the possibility that the efficiency of trans-splicing, and therefore splicing-based therapies, may be improved if splicing could be slowed to allow transcription to finish before splicing begins.

As a CHS fellow working towards improving splicing-based therapies for hemophilia, I will investigate the function of the U6 RNA, considered one of the most important components of the splicing machinery because of its location in the catalytic core, as effective means for slowing pre-mRNA splicing. Specifically, I propose to investigate the incorporation of U6 into the splicing complex as potential rate adjustable step in splicing. I propose to determine the timing of the conformational change in U6 that precedes its incorporation into the catalytically active splicing complex, and I will test our extensive collection of mutations in Prp24, the protein that catalyzes the conformational change in U6, for their ability to alter the rate of U6 conformational change.