The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease

Abstract

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene. There are currently no effective treatments for this devastating disease. Given its monogenic nature, disease modification therapies for HD should be theoretically feasible. Currently, pharmacological therapies aimed at disease modification by altering levels of HTT protein are in late-stage preclinical development. Here, we review current efforts to develop new treatments for HD based on our current understanding of HTT function and the main pathological mechanisms. We emphasize the need to enhance translational efforts and highlight the importance of aligning the clinical and basic research communities to validate existing hypotheses in clinical studies. Human and animal therapeutic trials are presented with an emphasis on cellular and molecular mechanisms relevant to disease progression.

Figure 1. Cellular mechanisms implicated in HD pathogenesis.

The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. HTT itself is depicted as a “solenoid,” based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signaling mechanisms. mHTT, mutant HTT protein.