Drugging unconventional targets: insights from Huntington's disease

Abstract

Classical targeted drug discovery is based on targeting druggable targets, typically kinases and receptors of which the function can be agonized or antagonized. This strategy meets difficulties in cases such as Huntington's disease (HD) and similar neurodegenerative disorders, where the pathological function of the protein causing the disease is not clear. HD is caused by mutant HTT protein (mHTT) containing an expanded polyglutamine (polyQ) stretch, but the function of mHTT and how mHTT causes HD are unknown, thus preventing efforts to screen for mHTT 'inhibitors'. However, HD is appealing for drug discovery because the genetic mutation is clear, as compared with other major neurodegenerative disorders. Although mHTT is not a conventional 'druggable' target, one approach that appears promising is lowering its level, which might be applicable to other neurodegenerative disorders and proteinopathies linked to aberrant accumulation of proteins. Here we review mHTT lowering strategies that might provide promising avenues for drugging such diseases.

Keywords: RNA interference; antisense oligonucleotides; high-throughput screening; neurodegenerative disorder; protein degradation; proteinopathies.