Huntington disease: pathogenesis, biomarkers, and approaches to experimental therapeutics

SummaryHuntington disease (HD) is characterized by motor, cognitive and behavioral abnormalities that typically emerge in adulthood in persons who have inherited the mutant gene. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest predictive genetic testing. Thus, it has been possible to develop imaging biomarkers of HD progression, not just in the period of manifest illness, but also in the prodromal or “premanifest” period. Striatal atrophy is the most studied, and shows steady progression beginning in the prodromal period beginning up to 15 years before predicted onset, and continuing through the period of manifest illness. Therapeutic targets for HD include the huntingtin protein itself, either by reducing its levels with antisense oligonucleotides or siRNA, or potentially by intervening via posttranslational modifications such as phosphorylation, acetylation, SUMOylation, or proteolytic cleavage. Other strategies involve bolstering the cell's ability to deal with abnormal proteins, either via chaperones or protein degradation machinery. It may be possible to counteract the abnormal transcription caused by mutant huntingtin, with histone deacetylase inhibitors, or to enhance relevant gene products such as Brain Derived Neurotrophic Factor (BDNF). Another tactic is to enhance cellular metabolic defenses, such as with creatine or Coenzyme Q10. Strategies are being devised to use biomarkers, and administer therapeutic agents which can be given safely for long periods of time during the proodromal period, with a goal not just to slow progression, but to delay, or conceivably even prevent, the onset of clinical HD.