In honor of rare disease day, I am using my Monday-Friday posts to raise awareness of some of the rare diseases as brief posts. Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease, Batten disease , Hurler Syndrome, Charcot-Marie-Tooth, Fibromuscular dysplasia today is the turn of Huntington’s disease.
Huntington’s disease is a neurodegenerative genetic disorder (worldwide prevalence is 5–10 cases per 100,000 persons) affecting muscle coordination leading to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. It is also the most common genetic cause of abnormal involuntary writhing movements called chorea, (Huntington’s chorea). The Huntingtin gene provides the genetic information for “huntingtin (Htt)” while expansion of a cytosine-adenine-guanine triplet repeat stretch within the gene leads to a mutant form of the protein that damages cells in the brain. The Htt protein interacts with over 100 other proteins, with multiple biological functions related to transcription, cell signaling and intracellular transporting. Huntington’s disease has autosomal dominant inheritance.
Symptoms include subtle problems with mood or cognition followed by general lack of coordination and an unsteady gait, uncoordinated, jerky body movements, a decline in mental abilities and behavioral and psychiatric problems. Ultimately coordinated movement becomes very difficult and dementia occurs alongside complications such as pneumonia, heart disease, and physical injury. While there is no cure full-time care is ultimately necessary although there are pharmaceutical (Tetrabenazine, neuroleptics and benzodiazepines) and non-drug treatments (physical therapy, occupational therapy, and speech therapy) which can assist with some of the symptoms.
Perhaps the most well known and largest funder of research into Huntington’s disease is the CHDI Foundation. Areas of research as therapeutic options include reducing mutant Htt production, improve cell survival and neuronal replacement using stem cells.
A recent study of the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) found Hace1 KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. A reduction of HACE1 levels in the striatum of Huntington disease patients was also observed. the authors proposed enhancing HACE1 expression may be therapeutically beneficial in HD and potentially other neurodegenerative diseases. Others have shown HACE1 (a tumor suppressor) is upregulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, Monoclonal antibody TrkB receptor agonists 29D7 and 38B8 mAbs from Pfizer induced receptor activation in a manner consistent with the activation profile of the cognate neurotrophin, BDNF which is a neuroprotective, secreted protein. Small interfering RNA delivery was used to lower huntingtin expression, reversing disease-associated alterations in cellular function in primary human cells. AAV9-RNAi given to mice by the jugular vein has positive effects on Huntington’s disease mice. the search for small molecules as potential treatments continues. Highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 was recently shown using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) which can suppress Huntington’s disease pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. Another recent study treated Huntington’s disease cells with sulforaphane which enhanced mHtt degradation but also reduced mHtt cytotoxicity. Dexamethasone treated Huntington’s Disease mice or flies significantly increased the expression and transactivation of HSF1 and induction of the heat shock response mediated through the down-regulation of HSP90. The Stimulation of GABAergic neurons with the GABAB receptor agonist, baclofen, has been shown to enhance the ubiquitin-proteasome system (UPS) function and cell survival in in vitro and in vivo models of Huntington’s Disease. Other approved dugs like fingolimod have been shown to be neuroprotective and disease modifying in disease models. The amount of research on this disease and small molecule approaches is large and while most studies propose individual therapies, it might be a case were multiple molecules are necessary in combination to impact on the disease in humans.
A recent phase II clinical trial from Prana Biotechnology while touted as successful has not impressed some analysts as it suggested a non statistically significant improvement in efficacy across early and mid stage patients. This perhaps further underlines the difficulty perhaps of extrapolating from animal models to human efficacy. Other drugs reaching the clinical stage include PDE 10 inhibitors.
Support organizations for the disease include Huntington’s Disease Society of America, Hereditary Disease Foundation, Huntington’s Disease Assistance Foundation and others .
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