Jul 2026· Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion· Vol 78 4, pp.
100047
· 0 citations· 99 references
Medicine
TL;DR
Genetic testing demonstrating an expanded HTT CAG repeat is the definitive diagnostic test and should be interpreted with genetic counseling and attention to allele categories, and therapeutic development.
Abstract
Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), resulting in mutant huntingtin (mHTT) with toxic gain-of-function and partial loss of normal huntingtin function. This narrative review summarizes recent advances in genetics, pathophysiology, clinical features, diagnostic assessment, biomarkers, and therapeutic development. Genetic testing demonstrating an expanded HTT CAG repeat is the definitive diagnostic test and should be interpreted with genetic counseling and attention to allele categories. Pathophysiologically, HD involves CAG instability, age-dependent somatic expansion in vulnerable neurons, transcriptional dysregulation, proteostasis failure, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, leading primarily to degeneration of striatal medium spiny neurons and later cortical involvement. Clinically, HD can begin from juvenile to late-adult life and manifests with motor, cognitive, psychiatric, and behavioral symptoms that evolve from premanifest biological change to functional decline. Current clinical care relies on symptom-directed treatment, whereas quantitative neuroimaging, cerebrospinal fluid biomarkers are mainly used for research and trial enrichment. Symptomatic management includes vesicular monoamine transporter type 2 inhibitors, antipsychotics, rehabilitation, nutritional support, and multidisciplinary care. Emerging disease-modifying approaches include HTT-lowering, somatic expansion inhibition, and gene-based therapies, but efficacy depends on target selectivity, timing, delivery route, dose, and patient selection.
Huntington's disease [HD] is a progressive, autosomal dominant neurodegenerative disorder caused by a pathogenic CAG repeat expansion in the HTT gene, resulting in mutant huntingtin [mHTT] protein accumulation, neuronal dysfunction, and selective neurodegeneration. Current pharmacological management remains largely symptomatic, with no approved therapies capable of modifying disease progression. In recent years, however, significant advances in molecular neuroscience and translational medicine have accelerated the development of disease-modifying strategies targeting the underlying pathogenic mechanisms of HD. This review synthesizes emerging pharmacological therapies with a particular focus on insights derived from recent and ongoing clinical trials. Key therapeutic approaches discussed include gene-silencing technologies such as antisense oligonucleotides, RNA interference, and CRISPRCas9- based strategies, as well as small-molecule modulators targeting mutant huntingtin aggregation, proteostasis, autophagy, mitochondrial dysfunction, and neuroinflammation. In addition, advances in symptomatic treatments addressing motor, cognitive, and psychiatric manifestations are reviewed. The article critically examines translational challenges encountered in clinical development, including blood-brain barrier penetration, allele selectivity, dosing paradigms, patient heterogeneity, biomarker integration, and ethical considerations associated with irreversible genetic interventions. Lessons learned from both successful and failed trials highlight the importance of precision medicine approaches, biomarker-guided trial designs, and combination therapies targeting multiple pathogenic pathways. Collectively, this review provides an updated and clinically relevant overview of the evolving HD therapeutic landscape and outlines key considerations for translating molecular advances into effective and safe pharmacological interventions.
B. Semwal, Kuldeep Singh, Ritesh Sharma et al.· Current Pharmaceutical Biote...· 0 citations
Heat shock factor 1 (HSF1) plays a pivotal role in maintaining neuronal health, and its dysfunction contributes significantly to the progression of Huntington’s disease. Rocio Gomez-Pastor tells us more. Huntington’s disease (HD) is a devastating, inherited neurodegenerative disorder marked by progressive motor dysfunction, cognitive decline, and psychiatric symptoms. At its genetic core lies a mutation in the huntingtin (HTT) gene, specifically an expansion of CAG trinucleotide repeats that encode an abnormally long polyglutamine (polyQ) tract in the huntingtin protein. (1) This mutation transforms an otherwise essential cellular protein into a toxic species prone to misfolding and aggregation. Over time, these molecular disturbances selectively damage neurons, particularly in the striatum and cortex. (2,3)
Rocio Gomez-Pastor· Open Access Government· 0 citations
MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of polyglutamine (PolyQ) diseases-a group of fatal neurodegenerative disorders caused by CAG repeat expansions, such as Huntington's disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. This review synthesizes recent advances in miRNA dysregulation across all nine PolyQ diseases, focusing on studies published since 2019. We examine how specific miRNAs modulate core pathogenic cascades-including mutant protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and apoptosis-and then link these molecular events to disease-relevant motor, cognitive, and psychiatric phenotypes. The review highlights therapeutic progress, including the preclinical efficacy of adeno-associated virus (AAV)-delivered artificial miRNAs and emerging exosome-based platforms that target mutant transcripts such as HTT, ATXN1, ATXN3, and ATXN7. AAV5-miHTT has advanced to a first-in-human trial for Huntington's disease (NCT04120493)-a key milestone in clinical translation. Circulating miRNAs in plasma and cerebrospinal fluid show diagnostic potential as minimally invasive, stage-specific biomarkers, but challenges persist in normalization, cross-biofluid concordance, and clinical validation. Despite substantial progress, translational barriers remain-including off-target effects, delivery optimization, immunogenicity, and patient heterogeneity. Overcoming these barriers will require integrative approaches that combine single-cell transcriptomics, engineered delivery systems, machine learning, and longitudinally phenotyped clinical cohorts. This review integrates mechanistic insights, biomarker discovery, and therapeutic development to move miRNA-based strategies toward disease-modifying interventions for PolyQ disorders.
Unknown authors· Neurobiology of Disease· 0 citations
Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene. Given their therapeutic potential, small-molecule strategies have gained significant traction, leading to the design of numerous lead candidates aimed at diverse pathological hallmarks of HD. These developmental efforts target various facets of the disease, including the inhibition and degradation of mutant huntingtin (mHTT) proteins, alleviation of motor dysfunction, and the provision of neuroprotective effects. For instance, gossypol acetate has been identified to induce the autophagic degradation of mHTT. Furthermore, these small molecules modulate critical signaling pathways within HD neurons, such as the store-operated calcium (SOC) channels, dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32), ataxia-telangiectasia mutated (ATM)/ataxia-telangiectasia and rad3-related (ATR)-p53 pathway, and the kynurenine (KYN) metabolic pathway. While currently explored small-molecule therapies have demonstrated preclinical efficacy, further clinical investigation is imperative to expand the chemical space of viable HD therapeutics. This review critically summarizes the design, synthesis, and structural motifs of small-molecule candidates, clinically used agents, and antioxidant natural products, providing a structural framework to guide the rational design and development of next-generation anti-HD compounds.
Yi-Tian Jiang, Xin-Yi Chen, Zhaoxin Xu et al.· European journal of medicina...· 0 citations
The urgent need for reliable biomarkers, early diagnosis, and multidisciplinary disease-modifying strategies for future therapeutic interventions is highlighted, with particular emphasis on challenges associated with bench-to-bedside translation.
Jeewanjot Singh, Subhi Sharma, Prabhjot Singh et al.· Advances in Modern Biomedici...· 0 citations
Physical sign, behavioral, as well as increasing cognition are hallmarks of Huntington Disease (HD), a monogenic neurodegenerative illness that causes early impairment and death. In 1993, the genetic effect was identified as an enlarged Cytosine, Adenine, Guanine repeat on chromosome 4's exon 1 of the Huntington gene. The assessment of individuals who are clinically afflicted by Huntington's disease depends on the differential diagnosis. A variety of treatments are accessible to lessen the symptoms of Hunti ngton's disorder, and efficient solutions for its chorea. Additionally, RNA interference medicines are being developed for clinical use, antibody treatments, stem cell treatments, etc. Discussing the effectiveness of the recent therapy for Huntington's illness is the main ambition in this regard comprehen sive analysis.
Unknown authors· Future Journal of Pharmaceut...· 0 citations
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