WP4: New therapeutic strategies

Main aim: To evaluate or validate newly-developed therapeutic strategies for selective polyQ huntingtin, ataxin-1 and ataxin-3 lowering in generated iPSC models.

WP leader: Harm Kampinga (UMCG)

Objectives: Since the polyQ disorders are all monogenic dominant diseases, decreasing the levels of the mutant protein (polyQ Htt, ataxin-1 or ataxin-3) by reducing its synthesis, via lowering of mutant RNA and/or improving selective degradation by protein quality control pathways will prevent or delay onset of disease.  The recently halted Roche trial targeting Htt-RNA had multiple caveats, including being costly and invasive, but also likely to the limited efficacy (deep brain penetrance) and being non-allele specific (entailing the risk of losing the essential function of the wildtype allele). This further underscores the importance of novel/alternative mutant polyQ lowering approaches that we aim to develop and validate in this work package. Whereas our models may also be a source for validation of alternative RNA-based strategies including those by Vico and uniQure, the discovery part in the workpackage will focus on selective degradation of the mutant proteins. Hereto, two strategies will be explored to accelerate selective degradation of the mutant protein in its earliest possible phase. For each of these, proof-of-concept evidence exists, and involved enzymes and mechanisms have recently been identified by the involved researchers