The first description by Waters, of a patient with what we now call Huntington's chorea, dates from 1842. But it was not until 1872, after the lecture and description of the disease by George Huntington, that it became known as Huntington's chorea. It is a neurodegenerative disorder passing within families from generation to generation with onset in middle age and characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia [1] For many decades its name remained unchanged, until the nineteen-eighties when, fully aware of the extensive non-motor symptoms and signs, the name was changed to Huntington's disease (HD). In 1983, a linkage on chromosome 4 was established and in 1993 the gene for HD was found [2]. That period marked a tremendous increase in interest in HD and neurogenetic disorders. For the first time, actual premanifest diagnoses could be made and as more diseases involving trinucleotide repeats of CAG were found, HD served as a model for many studies in medicine. CAG (cytosine (C), adenine (A), and guanine (G)), is a trinucleotide, the building stone of DNA. CAG is the codon for the amino acid glutamic. Finding the gene opened new research lines, new models and for the first time a real rationale on the way to treat this devastating disease. Many symptomatic treatments are now available, but there is a need for better, modifying drugs.
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To date, despite several claims, no drug is available with any neuroprotective or disease-delaying effect. Disease modifying drugs are developed, but not available. Also embryonic cell implants, still under study, are not proven treatment options at the moment.
We present two cases of patients with JHD diagnosed and treated at HDCC. Although both teenagers experienced their first symptoms at a similar age and first developed difficulties with studying, the disease has affected them in different ways. This demonstrates that JDH is a unique experience for every patient and requires careful examination and targeted individual treatment.
In both cases, with the well-coordinated work of experienced professionals at HDCC, the cause of symptoms was identified in the shortest possible amount of time, allowing them to proceed with an appropriate treatment strategy. Although there is no clear evidence whether accepting the uncertainty of gradually developing symptoms without knowing their cause can result in less suffering than facing the diagnosis of an incurable and progressive disease, it seems that when adequate multidisciplinary support is available, the diagnosis provides a possibility to ensure better elaborate support of quality of life for patients and their families.
Establishment of multidisciplinary specialist centers for HD, as demonstrated by our experience, not only allows timely diagnosis and treatment plans but also ensures thorough disease management and care for the patients and support for their families, resulting in increased quality of life.
Gene therapy, such as RNAi,22,31,40,41,42,43,44 ZFN,45 and CRISPR/Cas9,19,46,47 has been investigated as a potential treatment option for HD. The inherent limitation of RNAi is partial suppression of gene expression, which might be advantageous in HD treatment because of the gain of function of mHTT and the loss of function of normal HTT potentially acting concomitantly in HD etiology.56 By knocking down the expression of HTT, which includes both mHTT and normal HTT, we showed the amelioration of the disease phenotype. Future studies on allele-specific shRNA or an inducible system to suppress mHTT, while sparing the expression of HTT, will help to improve the outcome. With ongoing clinical trials of IONIS-HTTRx and WVE-120101/2 (Phase 1/2a and Phase 1b/2a),25 RNAi technology is certainly a promising candidate in HD treatment.
The drug development approach for HD has undergone a remarkable evolution in recent years. Aside from efforts focused on symptomatic treatment, therapies that target specific aspects of HD biology are being developed and evaluated for the first time for a putative slowing of disease progression. In this review, we provide an update on the advances in the symptomatic treatment of HD and present the growing efforts in disease-modifying therapies, with a particular emphasis on interventions aimed at lowering the level of mHTT in the brain.
The field of HD therapeutics lives through promising times as novel interventions targeting proximal pathways in the HD cell pathogenesis, such as the synthesis of mHTT and its intracellular trafficking, are evaluated for a disease-modifying effect. The ability to inhibit the synthesis of mHTT is perhaps the therapeutic strategy with the highest potential for disease modification. Various mHTT-lowering approaches are at a preclinical phase, and a few clinical trials have already started in some programs (Table 2). In the following section, we provide an updated description of various therapeutic development programs aiming at identifying a disease-modifying treatment in HD, with a particular focus on approaches targeting the HTT pathway.
The advent of therapies targeting proximal pathways of HD biology is promising. Regardless of the outcome of the GENERATION-HD1 trial and potential identification (or not) of the first disease-modifying therapy in HD, it is inevitable that other human clinical trials for disease modification in HD will be conducted to find more effective treatments, with less invasive routes of administration.
Reported values of HRQoL and costs including costs for production loss may be used in modelling the cost-effectiveness of treatment for HD. Our results highlight the crucial role the informal caregivers play in the care provided to HD patients in all disease phases. Future research should focus on the estimation of productivity loss among informal caregivers.
The present study reports data that may be used in modelling the cost effectiveness of new treatments for HD patients, informing stakeholders and policy makers. In line with previous studies, we found that disease severity (HD phase) is associated with decreased HRQoL and increased costs in middle and advanced phases of HD. Moreover, the present study highlights the important contribution of the informal care provided by partners, other family members or friends to the treatment of HD patients. These costs may be considered especially high considering that Norway is a welfare state. Although we included estimations of productivity loss, further efforts should be made to estimate productivity loss for informal caregivers, given the fact that they provide substantial care to their loved-ones. Given that the present study did not include estimations of costs for medication and aids, our results are likely still to be an underestimation of the total economic burden of HD in Norway. Based on general information about disease duration and care needed, it is important to consider that the health and economic burden for society as well as for the individual patient and his/her family members of HD, is likely to be present over many years.
In HD, decision-making capacity and communication ability may become impaired or lost as the disease progresses. Therefore, patients are encouraged to engage in advance care planning (ACP) and draw up an advance directive early in the course of HD [3,4,5]. ACP is defined as the ability to enable individuals to define goals and preferences for future medical treatment and care, to discuss these with family and health-care providers, and to record and review these preferences if appropriate [6]. There is evidence that ACP positively impacts the quality of end-of-life care [7]. In general, advance directives concern treatment preferences, but in the Netherlands they may also concern a request for euthanasia or physician assisted suicide (PAS), in line with the Euthanasia act of 2002 [8].
Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.
On the other hand, it is important to be aware of the caveats in proposing PERK inhibitors as a potential therapy for neurodegenerative diseases. First, excessive repression of PERK, as a kinase involved in a generic cellular stress-response pathway, could hamper the ability of neurons to respond to cellular stress and could disrupt normal regulation of protein synthesis, thereby causing synaptic dysfunction. For example, it was shown that brain-specific knockdown of PERK in mice resulted in dramatic impairments in behavioral flexibility in multiple cognitive tasks [11]. Therefore, fine-tuning the dose and duration of treatment with any PERK inhibitor will be critical to achieve the desired outcomes: re-establishing the capability of triggering de novo protein synthesis in response to learning while retaining the cellular stress-response component of the UPR-PERK-eIF2α pathway. Second, in addition to its critical role in the brain, PERK activity is essential for skeletal system development and normal pancreatic function [12]. Indeed, Wolcott-Rallison syndrome in humans, which is characterized by early-onset diabetes mellitus, has been linked to mutations in the EIF2AK3 gene in humans [13]. In agreement, it is not surprising that Moreno and colleagues reported that GSK2606414 caused weight loss and hyperglycemia in mice. So that these undesired and harmful side effects can be avoided, it would be ideal to modify the inhibitors so that they would act predominantly in the brain without effects in peripheral tissues and organs. Third and last, the study by Moreno and colleagues also found that memory loss in prion disease model mice as evaluated by performance in the object recognition task was not restored if the PERK inhibitor treatment was started at a relatively late stage, after the onset of neuronal loss and the appearance of clinical symptoms of the disease. These findings reinforce the importance of early intervention for neurodegenerative disease therapies, which would require the development of appropriate biomarkers to detect these diseases before the manifestation of clinical symptoms [14]. 2ff7e9595c
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