Therapeutic Advances for Huntington's Disease

Abstract

Huntington's disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

Keywords: CAG repeat; Huntington’s disease; mutant huntingtin (mHTT); neurodegeneration; therapeutics.

Figure 1

Mechanism of Toxicity of Huntingtin (HTT) gene. NO (Nitric Oxide), CAG (cytosine-adenine-guanine).

Figure 2

Recent advancement in the therapeutics for Huntington’s disease. TBZ (Tetrabenazine); EPA (eicosapentaenoic acid); MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); SAHA (suberoylanilide hydroxamic acid); HDACi4b (histone deacetylase inhibitors); RNAi (RNA interference); ASO (antisense oligonucleotide); ZFP (zinc finger protein); CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats); miRNA (micro RNA); siRNA (small interfering RNA).