Gene therapy in mouse models of huntington disease

Abstract

Huntingtin, the protein that when mutated causes Huntington disease (HD), has many known interactors and participates in diverse cellular functions. Mutant Htt (mHtt) engages in a variety of aberrant interactions that lead to pathological gain of toxic functions as well as loss of normal functions. The broad symptomatology of HD, including diminished voluntary motor control, cognitive decline, and psychiatric disturbances, reflects the multifaceted neuropathology. Although currently available therapies for HD focus on symptom management, the autosomal dominant cause and the adult onset make this disease an ideal candidate for genetic intervention. A variety of gene therapy approaches have been tested in mouse models of HD, ranging from those aimed at ameliorating downstream pathology or replacing lost neuronal populations to more upstream strategies to reduce mHtt levels. Here the authors review the results of these preclinical trials.

Figure 1

Happ1 gene therapy improves body weight of N171-82Q Huntington disease (HD) model mice. The green fluorescent protein (GFP)–treated N171-82Q mouse (left) displays reduced body weight, hunched posture, and piloerection (ruffled coat), whereas the Happ1-treated N171-82Q mouse (right) displays normal body weight and appearance. The mice shown are male littermates.