Huntington's disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation

Abstract

Purpose of review: Ten years of intensive research are now beginning to bring candidate neuroprotective therapies to clinical trials. This review describes recent progress in basic, preclinical, and clinical research that underlies current and potential neuroprotective trials.

Recent findings: Basic research continues to elucidate the proteolytic processing of huntingtin into toxic fragments and has examined the toxic potential of huntingtin monomers versus oligomers versus insoluble aggregates. Energy depletion has been reinvigorated as a therapeutic target by studies identifying very early mitochondrial alterations. Toxic interactions between mutant huntingtin and a variety of transcription factors have emerged as a major focus with a variety of studies suggesting transcriptional dysfunction to be a central mechanism in Huntington's disease. Progress in preclinical research included therapeutic leads identified by compound library screens, by designing polypeptides that can interact with huntingtin, and by testing compounds in transgenic mice with the potential for affecting some of the mechanisms thought to underlie neurodegeneration. While early results of neurotransplantation are generating increasing controversy, a variety of compounds discovered to benefit transgenic mice are working their way into clinical trials in symptomatic patients. Studies in presymptomatic individuals at risk for developing Huntington's disease are underway to enable the testing of agents with the potential for delaying or preventing onset of symptoms.

Summary: While laboratory research continues to advance and provide therapeutic leads, clinical trials are needed to test existing leads and guide further progress. With any luck, some of these tests will begin to identify treatments that make a difference for families with the disease.