Developing genetic therapies for polyglutamine disorders

Abstract

In this thesis various genetic therapies to reduce polyglutamine-induced toxicity are discussed. Although polyglutamine disorders are caused by CAG triplet repeat expansions in different genes, they all result in gain of toxic polyglutamine protein function and subsequently neurodegeneration. The polyglutamine disorders have a monogenic cause and thus far no therapies are available to delay the age of onset or slow the disease progression. These expanded polyglutamine proteins are known to undergo proteolytic processing and this results in polyglutamine-containing protein fragments that are considered to be the main toxic entities in polyglutamine disorders. In this thesis various novel genetic therapies for polyglutamine disorders are proposed. By targeting the polyglutamine-encoding transcripts, translation of mutant polyQ protein is reduced or the polyglutamine protein is modified. This is achieved by targeting the CAG repeat directly (chapter 3), removing the motifs that are implicated in the formation of polyglutamine fragments (chapter 4), or by removal of the CAG repeat-encoding exon (chapter 5).Vereniging van Huntington Prosensa Therapeutics B.V.UBL - phd migration 201