Orphan drugs in development for Huntington's disease: challenges and progress

Abstract

Huntington's disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine) repeat in the huntingtin (HTT) gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and advanced strategies to develop novel treatments in Huntington's disease are examined.

Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date

“…In accordance with the original descriptions of HD, and taking into account both the prominence of chorea and the selective degeneration of the brain striatum as a key feature of the disease, therapeutic approaches to HD have included either the control of behavioral changes (eg, neuroleptics, benzodiazepines, and mood stabilizers) 13 , 14 or attempts to reduce choreic movements with tetrabenazine, the only approved drug that inhibits dopamine release with a specific indication for chorea. 13 – 15 However, knowledge of the natural history of HD has increased in recent years. The development of experimental HD models and new psychiatric drugs (eg, atypical neuroleptics and antidepressants), as well as novel findings regarding the neuropathology of the disease, 16 have influenced HD management guidelines.…”