2013-04-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/679685摘要：Dravet Syndrome是小兒肌張力型癲癇症候群(severe myotonic epilepsy of infant type, SMEI)，發生率約2萬分之1，病患通常在新生兒時期已經發病，表現在幼童為熱痙攣 (成人為非熱痙攣)，新生兒期會產生肌僵直性癲癇(SMEI)，而後出現非特定型態的全身性或局部痙攣(包括肌肉僵直)，稍後也會表現心理運動能力的延遲。Dravet病人因對藥物治療有抗藥性故預後極差。文獻顯示此疾病與SCN1A基因所轉錄之第一型鈉離子通道(Nav1.1 channel)突變有關，目前約有三百多種異型合子突變被發現，在台灣也有相關病例。為了尋找更適合的治療策略，本計畫針對東方人疾病模型製備基因替換小鼠(E1099X)，成為有潛力的藥物篩選平台，期能對此型癲癇提出有效之治療方式。在前期計畫中初步針對concordant antisense oligonucleotides CUR-1901 (許照惠博士提供) 新型藥物對於此SCN1A突變小鼠之治療成效及其藥理作用，包含劑量的選擇、藥效(efficacy)試驗、增加SCN1A在腦部各區域表現量、行為表現的評估 (behavioral assessments)等已有初步實驗結果。 本期計畫提出4個目標繼續分析反意核&#33527;酸的療效及達成找到治療Dravet 的目標: (1)利用Scn1aE1099X小鼠的熱痙攣特性，以熱誘發癲癇探討Oligo的療效；(2)研究本計畫專屬(proprietary) Oligo藥物治療Scn1aE1099X小鼠的藥效與期程；(3)測試脊椎注射或鼻腔噴霧給予Oligo治療後熱痙攣症狀的緩解； (4)配種本計畫所需所有Dravet小鼠品系。 <br> Abstract: Dravet Syndrome (severe myotonic epilepsy of infant, SMEI) is a rare disease in clinic, occurring at a frequecy of 1 per 2 twenty thousand. Patients usually have early onset as febrile seizures during neonatal period and the onset of the disease typically occurs within the first year, with prolonged, generalized, or unilateral clonic seizures triggered by fever. Patients suffer from poor outcome due to refractory to classical antiepileptic medical therapy. Literature search results indicate that most of the patients with Dravet syndrome are resulted from de novo point mutations in the SCN1A gene coding for the voltage-gated sodium channel type I alpha (Nav1.1 channel). There are more than 300 different heterozygous SCN1A mutants identified worldwide, including cases from Taiwan. To optimize the therapeutic formulation, we built a drug testing platform using a mutant mouse model carrying an Asian-specific point mutation allele which leads to a premature translation termination (E1099X). Our previous project has screened the efficacies of one concordant antisense oligonucleotide CUR-1901 (owned by Dr. Jane Hsiao, 許照惠博士) for effectiveness in reducing epileptogenesis. We had generated some preliminary results of the Oligo CUR-1901 on the pharmacological properties and therapeutic efficacy, including determination of the suitable dosages (determination of the the dose-dependent curve), the effects of increases in the SCN1A expression in several brain structures, and the assessments of animal behaviors before and after treatment. This project proposes 4 specific aims to continue studying the efficacy of antisense oligos and to achieve above goals of treating Dravet: (1) to compare the `protection` from the susceptibility to hyperthermia-induced seizure in heterozygous Scn1aE1099X mice by administration of oligo; (2) to study the duration of drug effect by proprietary oligo; (3) to compare relative efficacy of oligo by IT or intra-nasal routes using hyperthemia-induced seizure model ; (4) to continue breeding of Scn1aE1099X mice for the studies of aims 1-3.Dravet SyndromeSCN1aconcordant antisense oligonucleotidehyperthermia-induced seizureDravet SyndromeSCN1aconcordant antisense oligonucleotidehyperthermia-induced seizure