Therapeutic advances in Huntington's Disease

Abstract

Huntington's disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. The genetic mutation that causes the disease has been known for more than 20 y, and animal models have illuminated a host of intracellular derangements that occur downstream of protein translation. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification and aggregation engender new hope that a successful strategy will emerge, but there is much work ahead. Some of the clinical manifestations of the illness, particularly chorea, affective symptoms, and irritability, are amenable to palliative strategies, but physicians have a poor evidence base on which to select the best agents. Clinical trials since 2013 have dashed hopes that coenzyme Q10 or creatine might have disease-modifying properties but suggested other agents were safe or hinted at efficacy (cysteamine, selisistat, hydroxyquinoline) and could proceed into later-stage disease modification trials. The hunt for effective symptom relief suggested that pridopidine might be shown effective given the right outcome measure. This review summarizes recent progress in HD and highlights promising new strategies for slowing disease progression and relieving suffering in HD.

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

“…Results from our study are consistent with those from pre-manifest and early-stage HD patients, demonstrating increased IL-6 and TNF-α levels in plasma (Bjorkqvist, et al, 2008). In fact, innate immune hyperactivity has been identified as a potential therapeutic target for HD (Wild & Tabrizi, 2014; Shannon & Fraint, 2015). The present results suggest that HD rhesus monkeys exhibit immune hyperactivity, and could be a valuable animal model to help narrow down pharmacological treatments for HD patients.…”

“…To date, rodent models of HD have unveiled a wealth of pharmacological targets, however, no agent that has been beneficial in an HD mouse model has also proven to be beneficial in human patients (Wild & Tabrizi, 2014). Additionally, even though 15,000 Americans are affected by HD, it is still a rather rare disease, with a preclinical population that is too small to sustain the number of clinical trials needed to narrow down these pharmacological targets (Shannon & Fraint, 2015). Therefore, to facilitate the development of effective treatments an animal model that embodies the full array of HD symptoms is greatly needed.…”

“…An additional early emerging feature of HD is the appearance of inflammation prior to clinical symptom onset, such as increased cortisol, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) detected in saliva, blood, cerebrospinal fluid, and brain tissue of persons carrying the mutant HTT gene (Bjorkqvist et al, 2008; van Duijn, et al, 2010; Wang et al, 2014). This hyperactivity of the innate immune system has been identified as a potential therapeutic target for HD (Wild & Tabrizi, 2014; Shannon & Fraint, 2015). Therefore, to facilitate the development of new HD therapies, animal models of HD should exhibit these early emerging symptoms of emotional and immune dysregulation.…”

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

“…These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades.…”

Brazilian Society for Food and Nutrition position statement: nutrigenetic tests

“…Most of these tests evaluate autosomal diseases related to a single gene, in which mutations reflect high probability (100% chance) of disease development, such as in Huntington's disease [59].…”