Bệnh Huntington là liên quan đến gen, phổ biến chủ yếu ở người da trắng. Biểu hiện bệnh gần giống với tâm thần phân liệt, parkinson,... Vì thế cần hiểu rõ để các triệu chứng để chẩn đoán. Ngoài ra, hiện nay một số phương pháp chữa bệnh này đang được nghiên cứu.
Huntington disease LE THI HUNG, JEONBUK NATIONAL UNIVERSITY Biometris Quantitative Methods brought to Life Outline I Huntington disease II Pathogenesis III Symptoms IV Diagnosis V Treatment VI Emerging therapies Biometris Quantitative Methods brought to Life I Huntington disease Definition: an autosomal dominant, neurodegenerative condition Causes: pathogenic repeat expansion of CAG trinucleotide in exon of the hunting gene (HTT) on chromosome I Huntington disease The average age at diagnosis Meta-analyses show a worldwide prevalence of 2.7 per 100,000 with the highest is rates in Western 49 years old populations and lowest among Asians Both male and female, have a 50% risk of inheriting the faulty gene II Pathogenesis III Symptoms Table Motor symptoms of HD III Symptoms Table Motor symptoms of HD III Symptoms Cognitive symptoms: Memory deficits Psychomotor slowing Impairment in executive, perceptual and spatial skills The ability to communicate diminishes Common speech difficulties include dysarthria, with poor articulation and slurring of words, slow production of words, poor speech initiation and difficulty organising thoughts III Symptoms III Symptoms 10 III Symptoms 11 III Symptoms 12 IV Diagnosis CAG repeats ≥ 40 to determine a positive test Diagnostic testing can determine the nature of clinical presentation and guide treatment decisions MRI brain comparison and measurements in control person and Person with Huntington’s Disease Predictive testing those at risk for HD, usually a family history 13 V Treatment There are no treatment to stop or reverse Huntington’s disease However, some medications can help keep symptoms under control: - Tetrabenazine - Antipsychotic drugs - Antidepressants - Tranquilizers Better to exercise 14 [REF: Tasuku Matsuoka and Masakazu Yashiro, 2018] VI Emerging therapies HTT lowering HTT modulation Immunomodulation Immunomodulation Cell replacement Deep Deep brain brain stimulation stimulation Synaptic modulation Other medical therapies 15 VI Emerging therapies HTT lowering -RNA- based approaches One of the most intriguing and promising emerging therapy Only the use of ASOs has reached clinical stages of development -DNA- based approaches: ZFPs were able to reduce mHTT levels and an HD-like behavioral phenotype These models has high CAPrepeat numbers (115-160 repeats) (no clinical studies of ZFPs in HD) CRISPR – Cas9: reduce DNA breaks at sequence- specific sites 16 VI Emerging therapies HTT modulation Selisistat - A SirT1 (silent information regulator T1) inhibitor - A selective decrease of mHTT levels (Drosophia and mouse models) may specially increase the rate of clearance of mHTT PBT2: - An 8-hydroxyquinolin - PBT2 treatment in an HD nematode and mouse model improved motor ability and ameliorated the toxic effects of polyglutamine aggregation 17 VI Emerging therapies Immunomodulation -Laquinimod An immunomodulatory drug originally studied for the treatment of relapsing-remitting multiple sclerosis A significant reduction of caudate atrophy and whole brain atrophy that was most evident in early HD -Semaphorin 4AD (SEMA4D): A transmembrane signaling protein that modulates pathways of neuroinflammation The blockage of SEMA4D using a monoclonal antibody (mAb67-2) reduced striatal, corpus, callosal and cortical atrophy, improved behavioral measures (in an HD mouse model study) 18 VI Emerging therapies Synaptic modulation Pridopidine - Have low D2 affinity and much higher affinity for the sigma-1 receptor (SIG1R) - SIG1R agonist (PRE084) used in neuronal cells expressing mHTT improved survival Phosphodiesterase 10A inhibitors - A member of the PDE enzyme family to hydrolyze cAMP, cGMP vital for modulating cyclic signaling pathways impairment of several transcription factors including the cAMP response element-binding protein (CREB) BN82451 Reduce neuronal death, improve mitochondrial dysfunction and reduce neuroinflammation 19 VI Emerging therapies Other medical therapies SRX246 - SRX246 is a novel vasopressin 1a (V1a) receptor antagonist being evaluated for the treatment of specific mood disorders Cysteamine -Transglutaminase (TGA) inhibitor TGA promotes aggregation by crosslinking the expanded polyglutamine tract of mHTT Deep brain stimulation - Significant reduction of chorea Cell replacement therapy - Replace lost cellsreversing disease or modifying progression Replace the degenerated striatal MSNs and reconstruct neural circuity 20 Key references • [1] Hassaan (2019) Emerging therapies in Huntington’s disease, Expert Review of Neurotherapeurics, Vol 19(10), 983-995 • [2] Pierre, Samentha, Mark et.al (2018) Huntington’s disease: Neuropsychiatric manifestations of Huntington’s disease, Australasian Psychiatry, Vol 26(1), 366-375 • [3] Anthony J Hannan (2018 Synaptopathy, circuitopathy and the computational biology of Huntington’s disease, BMC biology, 16, 71-73 21 Thank you very much! ... Pierre, Samentha, Mark et.al (2018) Huntington’s disease: Neuropsychiatric manifestations of Huntington’s disease, Australasian Psychiatry, Vol 2 6(1), 366-375 • [3] Anthony J Hannan (2018 Synaptopathy,... Person with Huntington’s Disease Predictive testing those at risk for HD, usually a family history 13 V Treatment There are no treatment to stop or reverse Huntington’s disease However, some... cellsreversing disease or modifying progression Replace the degenerated striatal MSNs and reconstruct neural circuity 20 Key references • [1] Hassaan (2019) Emerging therapies in Huntington’s disease,