Current medical care focuses primarily on symptom management, optimizing functions that are in continual decline, and the provision of ever-increasing levels of assistance. Symptomatic therapies using existing medications can help specific symptoms, such as depression, emotional dyscontrol, obsessive thinking, psychosis, chorea, rigidity, dysphagia, and weight loss. While medications, counseling, and rehabilitative modalities may improve the quality of life (QOL) for HD patients, there is no evidence that they appreciably slow the progression of the disease.To date, there is no clinically proven treatment for HD. The development of transgenic and knock-in mouse models of HD that replicate the phenotype observed in HD patients has been instrumental in identifying potential therapeutic candidates. Many potential therapies that separately target the previously mentioned mechanisms have now been tested in genetic models of HD, some of which significantly improved the clinical and neuropathological phenotype of HD mice and, as such, are immediate candidates for human clinical trials in HD patients since they are US Food and Drug Administration (FDA) approved compounds. This pre-clinical success been translated to early phase clinical studies in order to determine optimal dose ranges for HD patients and provide useful biomarkers.

Agents disrupting pathologic interactions of mutant huntingtin, either soluble or within aggregates, may target early pathogenic processes in HD. Proteolysis of mutant huntingtin and transglutaminase upregulation are thought to be proximal events in HD whereby abnormal and toxic fragments of huntingtin are released forming protein aggregates in neurons.These aggregates persist, indicating protein misfolding and failed proteolysis. In addition, transglutaminase upregulation catalyzes the formation of gamma-glutamyl isopeptide bonds between polyglutamine tracts, rendering the resulting cross-linked protein complexes insoluble. The resulting huntingtin aggregates sequester proteins including chaperones, proteasomal proteins, normal huntingtin, and transcription factors, which disturb protein homeostasis.

While the role of huntingtin aggregates continues to be debated, the evidence points to a proximal toxicity residing in mutant huntingtin, its proteolytic fragments, and their interactions with other proteins. Two such agents currently in clinical trials that inhibit mutant huntingtin aggregation and proteolysis are cystamine and minocycline, respectively. Cystamine is an aminothiol molecule that has multiple mechanisms of action through which it could counter some of the pathogenic cellular processes occurring in HD. Foremost, it is a potent inhibitor of transglutaminase. Cystamine also increases cellular levels of glutathione, an antioxidant that can provide protection from oxidative injury and may play a role in inhibiting apoptosis. Cystamine might also affect transcriptional dysfunction in HD secondarily by reducing sequestered transcription factors in insoluble huntingtin aggregates. While it is not certain which mechanisms are most important, cystamine clearly suppresses huntingtin protein aggregation and extends survival in HD mice. A safety and tolerability trial in HD patients using cysteamine, an analog of cystamine, is currently under way.¹

Minocycline, a second-generation tetracycline antiapoptotic compound, has been used for decades as an antimicrobial agent for rheumatoid arthritis (RA), acne, and rosacea, and is indicated for the treatment of infections. It has recently been shown to inhibit caspase activity. Mutant huntingtin undergoes proteolytic processing, in part by the pro-apoptotic enzyme caspase-3, releasing an N-terminal fragment that forms macromolecular aggregates with itself and other proteins. The caspase inhibiting function of minocycline reduces proteolysis of mutant huntingtin and the formation of cytotoxic N-terminal fragments and extends survival in HD mice. Minocycline is well tolerated and safe in HD patients. A recent clinical trial using minocycline in a small cohort of HD patients for 24 months showed stabilization of motor and neuropsychological functions, amelioration of psychiatric symptoms, and improved outcomes. An open-label, placebo-controlled multi-center, phase II, clinical trial using minocycline is in progress.²

Direct interactions between mutant huntingtin and transcription factors underlies transcriptional dysfunction in HD, perturbing cellular function and compromising protective mechanisms, ultimately leading to neuronal death and is therefore an important therapeutic target. An imbalance of repressing (methylation) and activating (acetylation) transcriptional influences affects subsets of critical survival genes and chronically stresses cellular homeostasis. Experimental studies show that transcriptionally active agents, such as aureolic acid antibiotics and histone deacetylase inhibitors, significantly ameliorate the phenotype in different models of polyglutamine disorders. These compounds have been used as chemotherapeutic agents, in which the anti-tumor properties are ascribed in part by selectively modulating gene expression/transcription.

One such compound, mithramycin A, is a DNA antibiotic that modifies and enhances DNA binding. The mechanism of action involves gene silencing, inhibiting methylation of histone H3 and, as such, improves the neuropathogenic outcome in HD models by partially restoring perturbed gene transcription. Mithramycin is significantly better than any other single compound to date in extending survival in HD mice. The author is actively pursuing safety and tolerability trials using mithramycin and its analogs in HD patients.

Histones are important nuclear proteins that help to regulate transcription. Histone acetylation, a marker of gene activation, is significantly decreased in HD.