RE(ACT) Congress 9-12 March 2016, Barcelona. 3rd International Congress on Research of Rare and Orphan Diseases. 9th to 12th March 2016. Crowne Plaza Barcelona - Fira Center, Barcelona, Spain: Abstracts

Abstract

The genetic analysis of monogenic disorders has over the past 3 decades resulted in the identification of thousands of genes which either cause or impact these conditions; most of these disorders have no therapies. The modulation of the transcripts and proteins encoded by these genes might be anticipated to have therapeutic utility, either by their upregulation (e.g. of mutated recessive disease genes encoding proteins with residual enzymatic activity, of genes that are sequentially similar to, and that functionally recapitulate, mutated recessive disease genes or of genes that cause disease when haploinsufficient) or downregulation (e.g. of mutated dominant genes which confer a gain of pathologic function or of genes which, when present in increased number, cause disease). Moreover, it is known that small molecules including clinically approved drugs can affect the human transcriptome. Given the number of genes that cause or effect inherited human conditions and the substantial subset of the transcriptome that is impacted by drugs, we believe that there are likely genes which are both modifiers of rare disease and responsive to pharmacologic modulation. The enhanced CARE for RARE project in Canada is therefore exploring whether previously unknown off-target effects of clinically approved drugs may lead to new therapies. We have screened ∼ 80 rare conditions, (haploinsufficient, rescuing paralogous genes and hypomorphic mutation with residual function) using this approach. There are currently 5 conditions which show some induction (GLUT1, SMAD3, DDHD2, NEU1, HPRT) ; the most promising results and lessons learned from this approach shall be presented.