Rare diseases may affect the quality of life of patients and be life-threatening. Therapeutic opportunities are often limited, in part because of the lack of understanding of the molecular mechanisms underlying these diseases. This can be ascribed to the low prevalence of rare diseases and therefore the lower sample sizes available for research. A way to overcome this is to integrate experimental rare disease data with prior knowledge using network-based methods. Taking this one step further, we hypothesized that combining and analyzing the results from multiple network-based methods could provide data-driven hypotheses of pathogenic mechanisms from multiple perspectives.We analyzed a Huntington's disease transcriptomics dataset using six network-based methods in a collaborative way. These methods either inherently reported enriched annotation terms or their results were fed into enrichment analyses. The resulting significantly enriched Reactome pathways were then summarized using the ontological hierarchy which allowed the integration and interpretation of outputs from multiple methods. Among the resulting enriched pathways, there are pathways that have been shown previously to be involved in Huntington's disease and pathways whose direct contribution to disease pathogenesis remains unclear and requires further investigation.In summary, our study shows that collaborative network analysis approaches are well-suited to study rare diseases, as they provide hypotheses for pathogenic mechanisms from multiple perspectives. Applying different methods to the same case study can uncover different disease mechanisms that would not be apparent with the application of a single method.
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions. Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates. The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15-46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study. The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation. The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production. Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.
- MeSH
- fingolimod hydrochlorid * terapeutické užití farmakologie MeSH
- Huntingtonova nemoc * farmakoterapie metabolismus MeSH
- modely nemocí na zvířatech MeSH
- modulátory receptorů sfingosin-1-fosfátu * farmakologie terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- pohybová aktivita účinky léků MeSH
- receptory sfingosin-1-fosfátu agonisté metabolismus MeSH
- testis účinky léků patologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: Dysfunction of the airway defence system in Huntington's disease (HD) is a significant but often overlooked problem. Although expiratory muscle strength training (EMST) is frequently utilized in cough effectiveness treatment, its specific impact in HD patients has not yet been explored. This study investigated the effects of EMST on voluntary peak cough flow (vPCF) in HD patients and evaluated the retention of potential gains post-intervention. METHODS: In this prospective case-controlled trial, 29 HD patients completed an 8-week wait-to-start period, which served to identify the natural development of expiratory muscle strength and vPCF. This was followed by 8 weeks of EMST training and an additional 8 weeks of follow-up. The study's outcome parameters, vPCF and maximum expiratory pressure (MEP), were measured against those of age- and sex-matched healthy controls. RESULTS: Huntington's disease patients had significantly lower MEP (p < 0.001) and vPCF (p = 0.012) compared to healthy controls at baseline. Following the EMST, significant improvements in MEP (d = 1.39, p < 0.001) and vPCF (d = 0.77, p = 0.001) were observed, with HD patients reaching the cough performance levels of healthy subjects. However, these gains diminished during the follow-up, with a significant decline in vPCF (d = -0.451, p = 0.03) and in MEP (d = -0.71; p = 0.002). CONCLUSIONS: Expiratory muscle strength training improves expiratory muscle strength and voluntary cough effectiveness in HD patients, but an ongoing maintenance programme is necessary to sustain the improvements.
- MeSH
- dechová cvičení metody MeSH
- dospělí MeSH
- dýchací svaly * patofyziologie MeSH
- Huntingtonova nemoc * patofyziologie komplikace rehabilitace MeSH
- kašel * patofyziologie etiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- odporový trénink metody MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- svalová síla * fyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by cognitive, motor, and psychiatric symptoms. Despite significant advances in understanding the underlying molecular mechanisms of HD, there is currently no cure or disease-modifying treatment available. Emerging pharmacological approaches offer promising strategies to alleviate symptoms and slow down disease progression. This comprehensive review aims to provide a critical appraisal of the latest developments in pharmacological interventions for HD. The review begins by discussing the pathogenesis of HD, focusing on the role of mutant huntingtin protein, mitochondrial dysfunction, excitotoxicity, and neuro-inflammation. It then explores emerging therapeutic targets, including the modulation of protein homeostasis, mitochondrial function, neuro-inflammation, and neurotransmitter systems. Pharmacological agents targeting these pathways are discussed, including small molecules, gene-based therapies, and neuroprotective agents. In recent years, several clinical trials have been conducted to evaluate the safety and efficiency of novel compounds for HD. This review presents an update on the outcomes of these trials, highlighting promising results and challenges encountered. Additionally, it discusses the potential of repurposing existing drugs approved for other indications as a cost-effective approach for HD treatment. The review concludes by summarizing the current state of pharmacological approaches for HD and outlining future directions in drug development. The integration of multiple therapeutic strategies, personalized medicine approaches, and combination therapies are highlighted as potential avenues to maximize treatment effectiveness.
- MeSH
- genetická terapie metody MeSH
- Huntingtonova nemoc * farmakoterapie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- neuroprotektivní látky * terapeutické užití farmakologie MeSH
- protein huntingtin genetika antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Genová terapie (GT) se postupně stává běžným způsobem léčby. Již není výsadou velkých univerzitních pracovišť, jejichž laboratoře zvládají analytické postupy zaměřené na nukleové kyseliny a jejichž klinické týmy zvládají aplikaci. Původně byla určena pro dědičné choroby, které vzhledem ke svému řídkému výskytu byly označovány jako vzácná onemocnění a GT se dosud uplatňovala jen u dětí, aby působila ještě před rozvojem onemocnění. Nové způsoby léčby začaly být používány i u chorob běžných, jakými jsou např. metabolické poruchy (diabetes), a dokonce u takových, které nás sužují stále častěji, jako nejrůznější malignity a nemoci centrální nervové soustavy (např. Alzheimerova choroba). Cílem genové terapie jsou geny, jejichž změny v podobě patogenních variant (dříve mutací) vyvolávají poruchy fenotypu. Naší snahou je buď jejich vyřazení z funkce (např. u hemoglobinopatií), nebo jejich nahrazení geny s normální funkcí. Ty lze do genomu vnést pomocí některého z vhodných přenašečů (tzv. vektorů), jakými jsou např. viry nebo lipozomy. Proces GT může probíhat přímo v těle pacienta (in vivo), nebo mimo něj na jeho izolovaných buňkách (ex vivo), kterými jsou obvykle indukované pluripotentní kmenové buňky (iPSC – induced pluripotent stem cell). Po úpravě se tyto buňky vracejí do pacientova těla, aby tak naplnily svůj „úděl“. V širším slova smyslu může být GT namířena i na produkt genové transkripce, kterým je messenger RNA (mRNA), nebo konečný produkt realizace genové funkce, jakým jsou funkční bílkoviny (např. u cystické fibrózy). U různých chorob se úspěšně používají uvedené přístupy v závislosti na jejich dostupnosti, která je mimo jiné dána i náklady s GT spojenými nebo přístupností cílové tkáně. Nejen ověřování účinnosti a bezpečnosti GT, ale i ekonomické důvody rozhodují o tom, proč se GT rozvíjí jen pozvolna a proč se jí ujímají většinou jen velké a bohaté instituce. Rozhodující je také to, že celý proces vývoje od výchozích experimentálních prací přes klinické zkoušky až ke konečnému přípravku běžně trvá i dekádu či déle.
Gene therapy is gradually becoming a mainstream treatment modality and is no longer the preserve of large university departments whose laboratories master nucleic acid analytical procedures and whose clinical teams manage its administration. It was originally designed for genetic diseases that, because of their prevalence, were a group known as rare diseases. Gene therapy has so far been applied in children to act before the disease development. These new treatments have also begun to be applied for common diseases such as metabolic disorders (e. g. diabetes) and even for those that are increasingly affecting us, such as various malignancies and diseases of the central nervous system (e. g. Alzheimer’s disease). The targets targeted by GT are genes, where pathogenic alterations in the form of pathogenic variants (formerly mutations) induce phenotypic disorders, and our aim is either to knock them out of function (e. g. haemoglobinopathies) or to replace them with genes with normal function, which we introduce into the genome using one of the appropriate vectors, such as viruses or liposomes. The process of GT can take place directly inside the patient's body (in vivo) or outside the body on isolated cells (ex vivo), which are usually stem cells (iPSCs, induced pluripotent stem cell). After treatment, these cells are returned to the patient's body to fulfil their "destiny". In a broader sense, GT can target the product of gene transcription, which is the messenger RNA, or the end product of gene function, such as functional proteins (eg. cystic fibrosis). Any of these approaches have been used successfully in various diseases, depending on their availability, which is determined, among other things, by the costs associated with GT or the accessibility of the target tissue. Ultimately, it is not only the validation of the efficacy and safety of GT, but also economic reasons that determine why GT has been slow to develop and is mostly undertaken only by large and wealthy institutions. Another decisive factor is that from initial experimental work through clinical trials, the whole process of its development normally takes up to a decade.
- MeSH
- cystická fibróza genetika terapie MeSH
- deficit alfa1-antitrypsinu genetika terapie MeSH
- Duchennova muskulární dystrofie genetika terapie MeSH
- genetická terapie * metody MeSH
- Huntingtonova nemoc genetika terapie MeSH
- krevní nemoci genetika terapie MeSH
- lidé MeSH
- myotonická dystrofie genetika terapie MeSH
- nádory genetika terapie MeSH
- retinopathia pigmentosa genetika terapie MeSH
- spinální svalová atrofie genetika terapie MeSH
- vzácné nemoci * genetika terapie MeSH
- Check Tag
- lidé MeSH
This comprehensive review explores the physiological and pathophysiological significance of VPS13A, a protein encoded by the VPS13A gene. The VPS13A gene is associated with Chorea-acanthocytosis (ChAc), a rare hereditary neurodegenerative disorder. The review covers essential aspects, beginning with the genetics of VPS13A, highlighting its role in the pathogenesis of ChAc, and addressing the spectrum of genetic variants involved. It delves into the structure and function of the VPS13A protein, emphasizing its presence in various tissues and its potential involvement in protein trafficking and lipid homeostasis. Molecular functions of VPS13A in the brain tissue and other cell types or tissues with respect to their role in cytoskeletal regulation and autophagy are explored. Finally, it explores the intriguing link between VPS13A mutations, lipid imbalances, and neurodegeneration, shedding light on future research directions. Overall, this review serves as a comprehensive resource for understanding the pivotal role of VPS13A in health and disease, particularly in the context of ChAc. Key words: Chorein , Tumor, Actin, Microfilament, Gene expression, Chorea-acanthocytosis.
- MeSH
- choreoakantocytóza * metabolismus genetika patofyziologie patologie MeSH
- lidé MeSH
- metabolismus lipidů fyziologie genetika MeSH
- mutace MeSH
- vezikulární transportní proteiny * metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
We applied Raman spectroscopy to brain and skin tissues from a minipig model of Huntington's disease. Differences were observed between measured spectra of tissues with and without Huntington's disease, for both brain tissue and skin tissue. There are linked to changes in the chemical composition between tissue types. Using machine learning we correctly classified 96% of test spectra as diseased or wild type, indicating that the test would have a similar accuracy when used as a diagnostic tool for the disease. This suggests the technique has great potential in the rapid and accurate diagnosis of Huntington's and other neurodegenerative diseases in a clinical setting.
- MeSH
- Huntingtonova nemoc * diagnóza MeSH
- lidé MeSH
- miniaturní prasata MeSH
- mozek MeSH
- neurodegenerativní nemoci * MeSH
- prasata MeSH
- Ramanova spektroskopie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antifosfolipidové protilátky farmakologie MeSH
- antifosfolipidový syndrom * patologie MeSH
- antikoagulancia farmakologie terapeutické užití MeSH
- antimalarika farmakologie terapeutické užití MeSH
- chorea * diagnóza farmakoterapie patologie MeSH
- diagnostické zobrazování metody MeSH
- diferenciální diagnóza MeSH
- glukokortikoidy farmakologie terapeutické užití MeSH
- inhibitory agregace trombocytů farmakologie terapeutické užití MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- lidé MeSH
- plazmaferéza metody MeSH
- rizikové faktory MeSH
- systémový lupus erythematodes diagnóza farmakoterapie patologie MeSH
- Check Tag
- lidé MeSH
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation in the HTT gene. To generate human-induced pluripotent stem cells (hiPSCs), we used dermal fibroblasts from 1 healthy adult control (K-Pic2), 1 HD manifest patient (M-T2), 1 healthy juvenile control (jK-N1), and 1 juvenile HD patient (jHD-V1). HD stage of patients was assessed by neurological tests and donors were without comorbidities and were non-smokers. Characterization showed that the obtained hiPSCs have the same number of CAG repeats as the parental fibroblast lines, express pluripotency markers and have the ability to differentiate into all 3 germ layers.
