TWI666325B - 以小分子治療與電壓門控鈉離子通道α次單元(SCNxA)相關之疾病 - Google Patents
以小分子治療與電壓門控鈉離子通道α次單元(SCNxA)相關之疾病 Download PDFInfo
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- TWI666325B TWI666325B TW101132597A TW101132597A TWI666325B TW I666325 B TWI666325 B TW I666325B TW 101132597 A TW101132597 A TW 101132597A TW 101132597 A TW101132597 A TW 101132597A TW I666325 B TWI666325 B TW I666325B
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Abstract
本發明係關於調節電壓門控鈉離子通道α次單元(SCNxA)之表現及/或功能之小化合物。本發明亦係關於含有該等小分子之醫藥組合物及其在治療與SCNxA表現相關之疾病及病症中的用途。
Description
本發明之實施例包含調節電壓門控鈉離子通道α次單元之表現及/或功能之小分子及相關分子。
本申請案主張2011年9月6日申請之美國臨時專利申請案第61/531,361號之優先權,該臨時專利申請案係以全文引用的方式併入本文中。
蛋白質在使用醫藥藥劑之生物系統中表現偏低提供了一種有前景的治療或潛在治療許多疾病病況之方法。醫學及藥學團體已藉由多種機構及途徑實現對此類型疾病形態之治療。在一種方法中,已選擇對應於特定標靶蛋白質之mRNA之天然反義轉錄物(NAT)作為標靶。已設計寡核苷酸及/或經修飾之寡核苷酸靶向NAT且「上調」標靶mRNA及蛋白質之表現。由於需求或需要新型及/或第一線醫藥治療之疾病病況及病狀的數目巨大,因此顯著需要新的方法及藥物來調節蛋白質表現或表現偏低。
先前技術一般包括基因療法、反義技術、siRNA技術以及使用小分子調節蛋白質表現。大部分反義技術及siRNA技術及相關專利或專利申請案係關於使用該等「藥物」來減輕(下調)蛋白質表現。治療標靶通常為編碼特定蛋白質或編碼可轉譯成相關蛋白質之RNA的mRNA或DNA。下文提供來自專利文獻之各種揭示內容之實例。
美國專利第5739119號主張對蕈毒鹼2型乙醯膽鹼受體
mRNA具有特異性之反義寡核苷酸。投藥引起記憶及學習能力增加。
美國專利第5985663號主張對介白素-15表現之反義抑制。
美國專利第6165712號主張轉錄調節基因表現且增加重組蛋白質產生之分子。此參考文獻揭示蛋白質上調。該調節分子可包含反義核酸。該調節分子可結合於編碼致癌基因或腫瘤抑制基因之編碼序列上游的啟動子區域。
美國專利第6165990號主張使用編碼靶向與結腸癌相關之mRNA-胃泌素基因之反義核苷酸的表現載體。
美國專利第6303374號主張對卡斯蛋白酶3表現之反義調節。該等反義核苷酸靶向編碼卡斯蛋白酶3之核酸以供治療阿茲海默氏病(Alzheimer's)、帕金森氏病(Parkinson's)、ALS等。
美國專利第6376541號主張一種藉由用可引起***素上調之藥劑治療患者而「上調」***素產生來治療青光眼之方法,該等藥劑包括介白素-1、轉型生長因子-β1、轉型生長因子-β2、血小板衍生生長因子、左旋咪唑等。此專利揭示使用藥物上調小分子而非蛋白質之表現的一個實例。
美國專利第6444464號揭示靶向編碼轉錄因子E2F之核酸的反義核苷酸。
美國專利第6617122號主張多肽、表現該等多肽之核酸分子及治療具有低HDL之人類的方法,該方法包含向該人
類投與ABC1多肽或其膽固醇調節片段。該ABC-1多肽為野生型ABC-1或具有增加其穩定性或其生物活性之突變。該專利亦揭示調節(增加)該蛋白質之表現量的候選化合物。揭示針對ABC-1蛋白之cDNA的反義核苷酸。該參考文獻揭示預期使用化合物來抑制可壓抑ABC1之轉錄因子將引起ABC1上調,且因此升高HDL含量。該轉錄因子為蛋白質。
美國專利第6710174號揭示血管內皮生長因子之反義抑制。
美國專利第7144999號揭示靶向低氧誘導性因子1α(aHIF)表現之寡核苷酸及用於治療與此種蛋白質之表現相關之疾病的方法。此專利揭示與HIF-1α之3'未轉譯區域互補且與人類疾病(非乳突狀透明細胞腎癌)相關之aHIF之天然反義轉錄物的過表現。
美國專利第7148204號揭示BCL-X表現之反義調節劑。調節誘導細胞凋亡。
美國專利第7199107號揭示類運動素1表現之反義調節劑。
美國專利第7202357號揭示用於調節醯基CoA膽固醇醯基轉移酶-2之表現的反義化合物、組合物及方法。該等化合物為靶向編碼醯基CoA膽固醇醯基轉移酶-2之核酸的反義寡核苷酸。
美國專利第7229976號揭示靶向編碼叉頭盒O1A之核酸以調節其表現的反義寡聚物。
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美國專利第7662948號揭示用於治療疼痛之針對VR1(辣椒鹼受體)之反義寡核苷酸。
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美國專利第7687617號揭示具有鎖核苷酸及非鎖核苷酸之交替區段的寡核苷酸。
美國專利第7691995號揭示小干擾RNA之活體內產生。
美國專利第7709546號揭示藉由靶向染色體DNA之寡聚物調節基因表現。
美國專利第7709630號揭示結締組織生長因子表現之反義調節。
美國專利第7723508號揭示脂蛋白元(A)表現之調節。
美國專利第7732422號揭示用於治療癌症之TRPM-2反義療法。
美國專利第7732590號揭示二醯基甘油醯基轉移酶2表現之調節。
美國專利第7737265號揭示HIF-1之RNAi調節及其治療性用途。
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US2003/0191075揭示使用經修飾之寡核苷酸-親脂性寡核苷酸結合物對特定器官進行靶向基因療法(反義核苷酸)之方法。
US2004/0033480揭示使用白藜蘆醇(3,5,4'-三羥基-反芪)上調脂蛋白元A1之表現。
US2004/0137423揭示用於鑑別可藉由增加ABCA1-基因表現來調節動物體內HDL含量之藥劑的組合物及方法。
US2004/0175803揭示一種干擾素-α誘導(上調)基因。
本發明人已發現已知小分子之新用途,即調節SCNA基
因家族及其變異體之表現。
提供本發明內容以簡要指示本發明之本質及物質。其呈遞如下理解:其將不會用於解釋或限制申請專利範圍之範疇或意義。
在一個實施例中,本發明包含一種調節編碼電壓門控鈉離子通道α次單元(SCNxA)之基因之表現的方法,該方法包含向有需要之患者投與至少一種選自由以下組成之群的用於治療SCNxA相關病症或疾病之活性成份:利尿劑、非典型抗精神病藥、鉀通道開放劑、鈣通道阻斷劑、抗真菌劑、抗氧化劑、PDE5抑制劑、***促效劑(類固醇或非類固醇)、抗抑鬱劑、質子泵抑制劑、5HT1D受體促效劑、催眠藥、抗潰瘍藥、5HT4促效劑、GABA促效劑、抗組織胺或同化類固醇。
在另一實施例中,本發明包含一種調節SCNxA基因表現之方法,該方法包含投與至少一種選自由以下組成之群的小分子:米那普侖(milnacipran)、托西邁(torsemide)、利培酮(risperidone)、吡那地爾(pinacidil)、貝尼地平(benidipine)、酮康唑(ketoconazole)、依布硒(ebselen)、他達那非(tadalafil)、折侖諾(zeranol)、萘法唑酮(nefazadone)、洛美利嗪(lomerizine)、淫羊藿苷(icariin)、奧美拉唑(omeprazole)、L-694,247、尼群地平(nitrendipine)、尼美西泮(nimetazepam)、胺來呫諾(amlexanox)、莫沙必利(mosapride)、舍曲林(sertraline)或司坦唑醇(stanozolol)或
其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥。
在一個實施例中,該方法包含針對具有SCNxA基因表現系統之生物系統篩選小分子化合物庫,其中該篩選產生可上調SCNxA表現產物及/或基因產物之表現的假定目標(putative hit)。較佳表現產物標靶為SCN1A。
在另一實施例中,本發明包含一種干擾SCNxA RNA功能之方法,其中該干擾引起SCNxA基因產物上調,該方法包含投與選自由以下組成之群的小分子:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,其中欲干擾之RNA功能包括至少一種生命機能,諸如該RNA之轉錄、RNA移位至蛋白質轉譯位點、自RNA轉譯成蛋白質、剪接RNA以產生一或多種mRNA物質及可由酶促RNA參與或促進之催化活性。
一個實施例提供一種調節SCNxA聚核苷酸於生物系統中之功能及/或表現之方法,該方法包含使該系統與選自由以下組成之群的小分子接觸:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、
舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,藉此調節SCNxA聚核苷酸於生物系統中之功能及/或表現。
一個實施例提供一種活體內或活體外調節患者細胞或組織中SCNxA聚核苷酸之功能及/或表現的方法,該方法包含使該等細胞或組織與選自由以下組成之群的小分子接觸:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,藉此活體內或活體外調節患者細胞或組織中SCNxA聚核苷酸之功能及/或表現。
在另一實施例中,選自由以下組成之群的小分子:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,調節SCNxA聚核苷酸之表現,例如SEQ ID NO:1中所述之核苷酸及其任何變異體、等位基因、同源物、突變體、衍生物、片段及互補序列。
另一實施例提供一種活體內或活體外調節患者細胞或組織中SCN1A聚核苷酸之功能及/或表現的方法,該方法包含使該等細胞或組織與選自由以下組成之群的小分子接觸:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,藉此活體內或活體外調節患者細胞或組織中SCN1A聚核苷酸之功能及/或表現。
在一個實施例中,本發明包含一種醫藥組合物,其包含選自由以下組成之群的小分子:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,以及醫藥學上可接受之賦形劑,其中該組合物調節SCNxA聚核苷酸之表現。
在另一實施例中,該等小分子係經口、皮下、肌肉內、靜脈內或腹膜內投與患者。
治療方案包含至少一次向患者投與小分子;然而,此治療可經改進而包括經一段時期之多個劑量。該治療可與一
或多種其他類型之療法組合。
在另一實施例中,該等小分子係囊封於脂質體中或附著於載劑分子(例如膽固醇、TAT肽)或所靶向之奈米粒子及/或塗有抗體之囊胞,視特定選擇之小分子的物理及/或化學性質而定。
在一個實施例中,本發明包含調節SCNxA家族成員之同功異型物及其變異體中之任一者的表現,該調節包含向有需要之患者投與醫藥學上有效量之至少一種本文所述化合物,其中該調節可治療與SCNxA基因或由其產生之表現產物中之至少一者相關的疾病。
下文描述其他態樣。
SEQ ID NO:1:智人I型電壓門控鈉離子通道α次單元(SCN1A)轉錄變異體1 mRNA(NCBI寄存編號:NM_001165963)。
SEQ ID NO:2:智人II型電壓門控鈉離子通道α次單元(SCN2A)轉錄變異體1 mRNA(NCBI寄存編號:NM_021007.2)。
SEQ ID NO:3:智人III型電壓門控鈉離子通道α次單元(SCN3A)轉錄變異體1 mRNA(NCBI寄存編號:NM_006922.3)。
SEQ ID NO:4:智人IV型電壓門控鈉離子通道α次單元(SCN4A)mRNA(NCBI寄存編號:NM_000334.4)。
SEQ ID NO:5:智人V型電壓門控鈉離子通道α次單元(SCN5A)轉錄變異體1 mRNA(NCBI寄存編號:NM_198056.2)。
SEQ ID NO:6:智人VII型電壓門控鈉離子通道α次單元(SCN7A)mRNA(NCBI寄存編號:NM_002976.3)。
SEQ ID NO:7:智人VIII型電壓門控鈉離子通道α次單元(SCN8A)轉錄變異體1 mRNA(NCBI寄存編號:NM_014191.2)。
SEQ ID NO:8:智人IX型電壓門控鈉離子通道α次單元(SCN9A)mRNA(NCBI寄存編號:NM_002977.3)。
SEQ ID NO:9:智人X型電壓門控鈉離子通道α次單元(SCN10A)mRNA(NCBI寄存編號:NM_006514.2)。
SEQ ID NO:10:智人XI型電壓門控鈉離子通道α次單元(SCN11A)mRNA(NCBI寄存編號:NM_014139.2)。
SEQ ID NO:11:智人電壓門控鈉離子通道α次單元SCN12A(SCN12A)mRNA(NCBI寄存編號:AF109737.1)。在所有情況下提供之序列表實際上為RNS轉錄物之cDNA型式。
以下參考用於說明之實例應用來描述本發明之若干態樣。應瞭解闡述許多特定細節、關係及方法以便全面瞭解本發明。然而,一般熟習相關技術者將容易認識到本發明可在無一或多個特定細節之情況下或用其他方法來實施。本發明不受動作或事件之順序限制,因為有些動作可能以不同順序發生及/或與其他動作或事件同時發生。此外,
並非所說明之所有動作或事件均為實施根據本發明之方法所需。
本文揭示之所有基因、基因名稱及基因產物均意欲對應於來自本文揭示之組合物及方法所適用之任何物種的同源物。因此,該等術語包括(但不限於)來自人類及小鼠之基因及基因產物。應瞭解當揭示來自特定物種之基因或基因產物時,除非其所出現之上下文清楚指明,否則此揭示內容僅欲為例示性的,且不應解釋為限制。因此,舉例而言,對於本文揭示之在一些實施例中與哺乳動物核酸及胺基酸序列相關之基因,其意欲涵蓋來自其他動物(包括(但不限於)其他哺乳動物、魚類、兩棲動物、爬行動物及鳥類)之同源及/或直系同源基因及基因產物。在一個實施例中,基因或核酸序列為人類基因或核酸序列。
定義
本文中使用之術語僅係用於描述特定實施例之目的,且不欲限制本發明。如本文中所使用,除非上下文另外清楚指明,否則單數形式「一(a)」、「一(an)」及「該」意欲亦包括複數形式。此外,就術語「包括(including)」、「包括(includs)」、「具有(having)」、「具有(has)」、「具有(with)」或其變化形式用於[實施方式]及/或申請專利範圍中而言,該等術語意欲以與術語「包含」相似之方式具有包括性。
術語「約(about)」或「約(approximately)」意謂在如由一般技術者確定之特定值的可接受誤差範圍內,該誤差範圍將部分視如何量測或測定該值,亦即量測系統之限制而
定。舉例而言,「約」可意謂根據此項技術中之實踐,在1或大於1之標準差內。或者,「約」可意謂既定值之至多20%、較佳至多10%、更佳至多5%且甚至更佳至多1%之範圍。或者,特別就生物系統或過程而言,術語可意謂在某一值之一定數量級內,較佳在5倍內,且更佳在2倍內。當本申請案及申請專利範圍中描述特定值時,除非另外陳述,否則術語「約」意謂應假定在特定值之可接受誤差範圍內。
如本文中所使用,術語「mRNA」意謂所靶向基因之目前已知mRNA轉錄物及可闡明之任何其他轉錄物。
如本文中所使用,「SCNxA」及「電壓門控鈉離子通道α次單元」包括所有家族成員、突變體、等位基因、同功異型物、片段、物質、編碼及非編碼序列、有義及反義聚核苷酸股等。SCNxA基因家族由11個已知成員(SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、SCN7A(亦稱為SCN6A)、SCN8A、SCN9A、SCN10A、SCN11A及SCN12A)組成。
如本文中所使用,詞語『I型電壓門控鈉離子通道α次單元』、SCN1A、FEB3、FEB3A、GEFSP2、HBSCI、NAC1、Nav1.1、SCN1、SMEI、腦鈉離子通道蛋白I次單元α、1型鈉離子通道蛋白質次單元α及電壓門控鈉離子通道次單元αNav1.1在文獻中被視為相同且在本申請案中可互換使用。
術語「核苷酸」涵蓋天然存在之核苷酸以及非天然存在
之核苷酸。熟習此項技術者應清楚先前已視為「非天然存在」之各種核苷酸隨後已在自然界中發現。因此,「核苷酸」不僅包括已知含嘌呤及嘧啶雜環之分子,而且亦包括其雜環類似物及互變異構體。其他類型核苷酸之說明性實例為含有以下之分子:腺嘌呤、鳥嘌呤、胸嘧啶、胞嘧啶、尿嘧啶、嘌呤、黃嘌呤、二胺基嘌呤、8-側氧基-N6-甲基腺嘌呤、7-去氮黃嘌呤、7-去氮鳥嘌呤、N4,N4-乙橋胞嘧啶、N6,N6-乙橋-2,6-二胺基嘌呤、5-甲基胞嘧啶、5-(C3-C6)-炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、假異胞嘧啶、2-羥基-5-甲基-4-***并吡啶、異胞嘧啶、異鳥嘌呤、肌苷,及Benner等人,美國專利第5,432,272號中所述之「非天然存在」之核苷酸。術語「核苷酸」意欲涵蓋每一及所有此等實例以及其類似物及互變異構體。尤其關注之核苷酸為含有腺嘌呤、鳥嘌呤、胸嘧啶、胞嘧啶及尿嘧啶之核苷酸,其被視為與人類中之治療及診斷應用相關之天然存在之核苷酸。核苷酸包括例如Kornberg及Baker,DNA Replication,第2版(Freeman,San Francisco,1992)中所述之天然2'-去氧糖及2'-羥基糖以及其類似物。
如本文中所使用,「調節」意謂增加(刺激)或減少(抑制)基因表現。術語「調節表現」進一步意謂藉由干擾RNA表現或轉譯來增加或減少既定蛋白質之表現。在增加蛋白質表現之情況下,藥物可阻斷抑制基因(例如腫瘤抑制基因)或引起蛋白質產物下調或表現偏低之任何其他基因產物或突變基因之表現。在減少蛋白質表現之情況下,藥物可直
接阻斷既定基因之表現或有助於自該基因轉錄之RNA加速分解。
術語「變異體」在用於聚核苷酸序列之情形時可涵蓋與野生型基因相關之聚核苷酸序列。此定義亦可包括例如「對偶基因」、「剪接」、「物種」或「多形性」變異體。剪接變異體可與參考分子具有顯著一致性,但由於mRNA加工期間外顯子之交替剪接,一般將具有較大或較小數目之聚核苷酸。相應多肽可具有其他功能域或不存在功能域。物種變異體為自一個物種變成另一物種之聚核苷酸序列。在本發明中,野生型基因產物之變異體具有特定效用。變異體可由核酸序列中之至少一個突變產生且可產生經改變之mRNA或結構或功能可能得以改變或可能未改變之多肽。任何既定天然或重組基因可不具有、具有1個或許多個對偶基因形式。產生變異體之常見突變變化一般歸因於核苷酸之天然缺失、添加或取代。此等類型變化中之每一者可單獨或與其他變化組合在既定序列中發生一或多次。
所得多肽相對於彼此一般將具有顯著胺基酸一致性。多形性變異體為既定物種之個體間的特定基因之聚核苷酸序列中的變化。多形性變異體亦可涵蓋「單核苷酸多形現象」(SNP)或聚核苷酸序列有1個鹼基發生變化之單鹼基突變。SNP之存在可指示例如某一群體具有疾病病況傾向,亦即對抗性之敏感性。
「衍生」多肽或肽為例如藉由糖基化、聚乙二醇化、磷酸化、硫酸化、還原/烷基化、醯化、化學偶合或適度福
馬林(formalin)處理加以修飾之多肽或肽。衍生物亦可直接或間接經修飾以含有可偵測標記,包括(但不限於)放射性同位素、螢光標記及酶標記。
如本文中所使用,術語「動物」或「患者」意欲包括例如人類、綿羊、麋鹿、鹿、黑尾鹿(mule deer)、貂、哺乳動物、猴、馬、牛、豬、山羊、狗、貓、大鼠、小鼠、鳥類、雞、爬行動物、魚、昆蟲及蛛形綱動物。
「哺乳動物」涵蓋通常正在接受醫療護理之溫血哺乳動物(例如人類及馴化動物)。實例包括貓科動物、犬科動物、馬科動物、牛科動物及人類,以及僅人類。
「治療(treating)」或「治療(treatment)」涵蓋治療哺乳動物之疾病病況,且包括:(a)預防該疾病病況在哺乳動物中發生,尤其當該哺乳動物易患該疾病病況但尚未診斷為患有該疾病病況時;(b)抑制該疾病病況,例如遏止其發展;及/或(c)減輕該疾病病況,例如使得該疾病病況消退直至達到所要終點。治療亦包括改善疾病之症狀(例如減輕疼痛或不適),其中該改善可能或可能不直接影響該疾病(例如病因、傳播、表現等)。
「神經疾病或病症」係指神經系統及/或視覺系統之任何疾病或病症。「神經疾病或病症」包括涉及中樞神經系統(腦、腦幹及小腦)、周邊神經系統(包括腦神經)及自主神經系統(其部分位於中樞神經系統與周邊神經系統兩者中)之疾病或病症。神經病症之實例包括(但不限於)頭痛、木僵及昏迷、癡呆症、癲癇發作、睡眠障礙、外傷、感
染、贅瘤、神經眼科疾病、運動障礙、脫髓鞘疾病、脊髓病症以及周圍神經、肌肉及肌神經接點之病症。成癮及精神病包括(但不限於)躁鬱症及精神***症,該等病症亦包括於神經病症之定義中。以下為可使用本發明之小分子、醫藥組合物及方法加以治療之若干種神經病症、症狀、病徵及症候群的清單:後天性癲癇狀失語症(acquired epileptiform aphasia);急性播散性腦脊髓炎(acute disseminated encephalomyelitis);腎上腺腦白質營養不良(adrenoleukodystrophy);年齡相關之黃斑部變性(age-related macular degeneration);胼胝體發育不全(agenesis of the corpus callosum);認知障礙症(agnosia);艾卡迪症候群(Aicardi syndrome);亞歷山大病(Alexander disease);阿爾珀斯病(Alpers' disease);交替性偏癱(alternating hemiplegia);血管性癡呆(Vascular dementia);肌萎縮性側索硬化(amyotrophic lateral sclerosis);無腦(anencephaly);安琪曼症候群(Angelman syndrome);血管瘤病(angiomatosis);缺氧症(anoxia);失語症(aphasia);精神性運動不能(apraxia);蛛網膜囊腫(arachnoid cysts);蛛網膜炎(arachnoiditis);阿諾尼-加里畸形(Anronl-Chiari malformation);動靜脈畸形(arteriovenous malformation);亞斯伯格症候群(Asperger syndrome);共濟失調毛細管擴張症(ataxia telegiectasia);注意力不足過動症(attention deficit hyperactivity disorder);自閉症(autism);自主功能障礙(autonomic dysfunction);背痛;巴登病(Batten
disease);***(Behcet's disease);貝爾氏麻痺(Bell's palsy);良性原發性瞼痙攣(benign essential blepharospasm);良性病灶(benign focal);肌萎縮(amyotrophy);良性顱內高壓;賓斯萬格氏病(Binswanger's disease);瞼痙攣(blepharospasm);布洛克-蘇茲貝格症候群(Bloch Sulzberger syndrome);臂叢損傷(brachial plexus injury);腦膿腫(brain abscess);腦損傷;腦腫瘤(包括多形性膠質母細胞瘤(glioblastoma multiforme));脊椎腫瘤;布朗-塞卡爾症候群(Brown-Sequard syndrome);卡納文病(Canavan disease);腕隧道症候群(carpal tunnel syndrome);灼性神經痛(causalgia);中樞性疼痛症候群;中央腦橋脊髓溶解(central pontine myelinolysis);頭部病症;腦動脈瘤(cerebral aneurysm);腦動脈硬化(cerebral arteriosclerosis);腦萎縮(cerebral atrophy);大腦性巨人症(cerebral gigantism);大腦性麻痺(cerebral palsy);夏科-馬里-圖斯病(Charcot-Marie-Tooth disease);化學療法誘發之神經病及神經痛;加里畸形(Chiari malformation);舞蹈病(chorea);慢性發炎性脫髓鞘多發性神經病(chronic inflammatory demyelinating polyneuropathy);慢性疼痛;慢性區域疼痛症候群;科芬-勞里症候群(Coffin Lowry syndrome);昏迷(coma),包括持續性植物狀態;先天性兩側面癱(congenital facial diplegia);皮質基底核退化症(corticobasal degeneration);顱動脈炎(cranial arteritis);顱縫早閉(craniosynostosis);庫賈氏病(Creutzfeldt-Jakob
disease);累積性損傷病症;庫欣氏症候群(Cushing's syndrome);巨大細胞包涵體病(cytomegalic inclusion body disease);細胞巨大病毒感染;舞蹈眼-舞蹈足症候群(dancing eyes-dancing feet syndrome);丹尼沃克症候群(DandyWalker syndrome);道森病(Dawson disease);德莫斯特氏症候群(De Morsier's syndrome);代哲因-科魯姆克麻痺(Dejerine-Klumke palsy);癡呆;皮肌炎(dermatomyositis);糖尿病性神經病變;彌漫性硬化症(diffuse sclerosis);德拉韋特氏病(Dravetts);自主神經障礙(dysautonomia);書寫困難(dysgraphia);閱讀困難(dyslexia);肌張力障礙(dystonias);早期嬰兒癲癇腦病(early infantile epileptic encephalopathy);空蝶鞍症候群(empty sella syndrome);腦炎(encephalitis);腦膨出(encephaloceles);腦三叉血管瘤病(encephalotrigeminal angiomatosis);癲癇症(epilepsy);厄博氏麻痺(Erb's palsy);原發性震顫(essential tremor);法布瑞氏病(Fabry's disease);華氏症候群(Fahr's syndrome);暈厥(fainting);家族性痙攣性麻痺(familial spastic paralysis);熱性癲癇發作(febrile seizures);費雪症候群(Fisher syndrome);弗里德棘希氏共濟失調(Friedreich's ataxia);額顳葉型癡呆(fronto-temporal dementia)及其他「τ病變(tauopathies)」;高雪氏病(Gaucher's disease);格斯特曼氏症候群(Gerstmann's syndrome);巨細胞動脈炎(giant cell arteritis);巨細胞性包涵體病(giant cell inclusion
disease);球狀細胞白血質障礙(globoid cell leukodystrophy);古立安-白瑞症候群(Guillain-Barre syndrome);HTLV-1相關之脊髓病(HTLV-1-associated myelopathy);哈勒沃登-施帕茨病(Hallervorden-Spatz disease);頭部損傷;頭痛;半面痙攣(hemifacial spasm);遺傳性痙孿性截癱(hereditary spastic paraplegia);多神經炎型遺傳性共濟失調(heredopathia atactic a polyneuritiformis);耳部帶狀疱疹(herpes zoster oticus);帶狀疱疹(herpes zoster);平山症候群(Hirayama syndrome);HIV相關之癡呆及神經病(亦為AIDS之神經學表現);前腦無裂畸形(holoprosencephaly);亨廷頓氏病(Huntington's disease)及其他聚麩醯胺酸重複疾病;腦內積水(hydranencephaly);腦積水(hydrocephalus);高皮質醇症(hypercortisolism);低氧(hypoxia);免疫介導之腦脊髓炎;包涵體肌炎;色素失調症(incontinentia pigmenti);嬰兒植烷酸儲積病(infantile phytanic acid storage disease);嬰兒雷夫蘇姆病(infantile refsum disease);嬰兒痙攣症(infantile spasms);發炎性肌病;顱內囊腫;顱內高壓;喬伯特症候群(Joubert syndrome);卡恩斯-塞爾症候群(Keams-Sayre syndrome);肯尼迪病(Kennedy disease)金斯布恩症候群(Kinsboume syndrome);克利佩爾-費爾症候群(Klippel Feil syndrome);克拉培病(Krabbe disease);庫格爾貝格-韋蘭德病(Kugelberg-Welander disease);庫魯症(kuru);拉弗拉病(Lafora disease);蘭伯特-伊頓重肌無
力症候群(Lambert-Eaton myasthenic syndrome);蘭道-科萊弗勒症候群(Landau-Kleffner syndrome);側髓(瓦倫伯格)症候群(lateral medullary(Wallenberg)syndrome);學習困難(learning disabilities);雷氏病(Leigh's disease);勒諾克斯-古斯托特症候群(Lennox-Gustaut syndrome);萊施-奈恩症候群(Lesch-Nyhan syndrome);腦白質營養不良(leukodystrophy);路易體性癡呆(Lewy body dementia);無腦回症(Lissencephaly);閉鎖症候群(locked-in syndrome);盧.賈里格氏病(Lou Gehrig's disease)(亦即運動神經元病或肌萎縮性側索硬化);腰椎盤疾病;萊姆病(lyme disease)-神經後遺症;馬查多-約瑟夫病(Machado-Joseph disease);巨腦畸形(macrencephaly);巨腦畸形(megalencephaly);梅爾克遜-羅森塔爾症候群(Melkersson-Rosenthal syndrome);梅尼爾氏病(Menieres disease);腦膜炎;緬克斯病(Menkes disease);異染性腦白質營養不良(metachromatic leukodystrophy);小頭畸形(microcephaly);偏頭痛;米勒費雪症候群(Miller Fisher syndrome);小中風(mini-strokes);粒線體肌病(mitochondrial myopathies);默比厄斯症候群(Mobius syndrome);單肢肌萎縮;運動神經元病;煙霧病(Moyamoya disease);黏多醣病(mucopolysaccharidoses);多梗塞性癡呆(milti-infarct dementia);多病灶運動神經病(multifocal motor neuropathy);多發性硬化症及其他脫髓鞘病症;伴有體位性低血壓之多發性系統萎縮症(multiple system atrophy
with postural hypotension);肌肉萎縮症;重症肌無力;脫髓鞘彌漫性硬化症(myelinoclastic diffuse sclerosis);嬰兒肌陣攣性腦病(myoclonic encephalopathy of infants);肌陣攣(myoclonus);肌病(myopathy);先天性肌強直(myotonia congenital);發作性睡病(narcolepsy);神經纖維瘤;精神抑制劑性惡性症候群(neuroleptic malignant syndrome);AIDS之神經表現;狼瘡之神經後遺症(neurological sequelae of lupus);神經性肌強直(neuromyotonia);神經性類蠟質褐質病(neuronal ceroid lipofuscinosis);神經元遷移病症(neuronal migration disorders);尼曼-匹克病(Niemann-Pick disease);奧沙利文-麥克里德症候群(O'Sullivan-McLeod syndrome);枕神經痛(occipital neuralgia);潛隱性脊髓神經管縫合不全序列征(occult spinal dysraphism sequence);大田原症候群(Ohtahara syndrome);橄欖體腦橋小腦萎縮(olivopontocerebellar atrophy);斜視眼陣攣肌陣攣(opsoclonus myoclonus);視神經炎(optic neuritis);起立性低血壓(orthostatic hypotension);過度使用症候群(overuse syndrome);感覺異常;神經退化性疾病或病症(帕金森氏病、亨廷頓氏病、阿茲海默氏病、肌萎縮性側索硬化(ALS)、癡呆、多發性硬化症及與神經元細胞死亡相關之其他疾病及病症);先天性肌強直病(paramyotonia congenital);副腫瘤疾病(paraneoplastic diseases);陣發性發作;帕里-羅格症候群(Parry Romberg syndrome);佩利措伊斯-梅茨巴赫病
(Pelizaeus-Merzbacher disease);週期性麻痺(periodic paralyses);周邊神經病(peripheral neuropathy);疼痛性神經病及神經痛;持續性增長狀態;滲透性發育病症(pervasive developmental disorders);感光性噴嚏反射(photic sneeze reflex);植烷酸儲積病;皮克氏病(Pick's disease);神經挫傷;垂體瘤;多發性肌炎;腦穿通畸形(porencephaly);小兒麻痺症後症候群(post-polio syndrome);帶狀疱疹後神經痛(postherpetic neuralgia);感染後腦脊髓炎(postinfectious encephalomyelitis);體位性低血壓;普威二氏症候群(Prader-Willi syndrome);原發性側索硬化(primary lateral sclerosis);朊病毒疾病(prion diseases);進行性面部單側萎縮(progressive hemifacial atrophy);進行性多病灶腦白質病(progressive multifocalleukoencephalopathy);進行性硬化性灰質萎縮(progressive sclerosing poliodystrophy);進行性核上眼神經麻痺症(progressive supranuclear palsy);腦假瘤(pseudotumor cerebri);拉姆西-亨特症候群(Ramsay-Hunt syndrome)(第I型及第II型);拉斯木森氏腦炎(Rasmussen's encephalitis);反射交感性營養不良症候群(reflex sympathetic dystrophy syndrome);雷夫蘇姆病;重複運動病症(repetitive motion disorders);重複應力損傷;腿不寧症候群(restless legs syndrome);反轉錄病毒相關之脊髓病;瑞特症候群(Rett syndrome);雷依氏症候群(Reye's syndrome);聖維特斯舞蹈病(Saint Vitus dance);山多夫
病(Sandhoff disease);希爾逗氏病(Schilder's disease);腦裂(schizencephaly);中隔-眼發育不良(septo-optic dysplasia);嬰兒期嚴重肌陣攣性癲癇(severe myoclonic epilepsy of infancy);搖晃嬰兒症候群(shaken baby syndrome);帶狀疱疹(shingles);夏-德里格症候群(Shy-Drager syndrome);休格連氏症候群(Sjogren's syndrome);睡眠呼吸暫停(sleep apnea);索特氏症候群(Soto's syndrome);痙攣(spasticity);脊椎裂;脊髓損傷;脊髓腫瘤;脊髓性肌萎縮;僵人症候群(Stiff-Person syndrome);中風;斯德奇-韋伯症候群(Sturge-Weber syndrome);亞急性硬化性全腦炎(subacute sclerosing panencephalitis);皮質下動脈硬化腦病(subcortical arteriosclerotic encephalopathy);西登哈姆舞蹈病(Sydenham chorea);昏厥(syncope);脊髓空洞症(syringomyelia);遲發性運動不能(tardive dyskinesia);泰-薩二氏病(Tay-Sachs disease);顳動脈炎(temporal arteritis);脊髓栓繫症候群(tethered spinal cord syndrome);托馬森病(Thomsen disease);胸部出口症候群(thoracic outlet syndrome);三叉神經痛(Tic Douloureux);托德氏麻痺(Todd's paralysis);妥瑞症候群(Tourette syndrome);短暫性缺血發作;傳染性海綿狀腦病(transmissible spongiform encephalopathies);橫貫性脊髓炎(transverse myelitis);創傷性腦損傷;震顫;三叉神經痛(trigeminal neuralgia);熱帶痙攣性輕癱(tropical
spastic paraparesis);結節性硬化症(tuberous sclerosis);血管性癡呆(多梗塞性癡呆);血管炎,包括顳動脈炎;逢希伯-林道病(Von Hippel-Lindau disease);瓦倫伯格氏症候群(Wallenberg's syndrome);偉-霍二氏病(Werdnig-Hoffman disease);韋斯特症候群(West syndrome);鞭抽式損傷(whiplash);威廉氏症候群(Williams syndrome);威爾頓氏病(Wildon's disease);及澤爾維格症候群(Zellweger syndrome)。
心血管疾病或病症包括可引起局部缺血或由心臟再灌注引起之病症。實例包括(但不限於)動脈粥樣硬化、冠狀動脈病、巨細胞性心肌炎、慢性心肌炎(非肉芽腫型)、原發性肥厚型心肌病、周邊動脈疾病(PAD)、周邊血管疾病、靜脈血栓栓塞、肺栓塞、中風、心絞痛、心肌梗塞、由心跳驟停所致之心血管組織損傷、由心臟分流所致之心血管組織損傷、心原性休克及一般技術者已知或涉及心臟或血管結構之功能障礙或組織損傷的相關病症,尤其為(但不限於)與SCN1A活化相關之組織損傷。CVS病包括(但不限於)動脈粥樣硬化、巨細胞性心肌炎、心肌梗塞、心臟瓣膜病之繼發性心肌纖維化、不伴有梗塞之心肌纖維化、原發性肥厚型心肌病及慢性心肌炎(非肉芽腫型)。
與鈉離子通道功能障礙相關之疾病或病症之實例包括(但不侷限於)惡性高熱、肌無力、陣發性運動失調、神經性及發炎性疼痛、阿茲海默氏病、帕金森氏病、精神***症、肌張力過度、SMEI、FEB3、家族性偏癱性偏頭痛3
型、肌強直(諸如低血鉀性週期性麻痺及高血鉀性週期性麻痺)、先天性肌強直病及鉀加重性肌強直,以及心律不整(諸如長QT症候群)。
標靶:在一個實施例中,調節之標靶包括電壓門控鈉離子通道α次單元家族成員(SCNxA)之核酸序列,包括而不限於與SCNxA轉錄及/或轉譯及/或調節相關之有義及/或反義非編碼及/或編碼以及蛋白質序列。較佳標靶為SCN1A通道。
電壓敏感性離子通道為一類跨膜蛋白質,其為細胞興奮性之基礎,且能夠經由離子產生之膜電位傳輸資訊。電壓門控鈉離子通道負責在大部分電興奮性細胞(包括神經元、心臟細胞及肌肉)中產生並傳播作用電位。由細胞膜去極化觸發電活性,由此開放對鈉離子具有高度選擇性之跨膜通道。接著藉由電化學梯度驅動離子在細胞內通過開放之通道。雖然不同組織中基於鈉之作用電位相似,但電生理學研究已顯示,有許多種結構上及功能上互異之鈉離子通道,且已選殖許多編碼鈉離子通道之基因。SCN1A基因屬於電壓門控鈉離子通道基因家族(SCNxA家族)。
電壓門控鈉離子通道在神經細胞及肌肉中之作用電位產生中扮演重要作用。α次單元(SCNxA)為該等通道之主要組份,且應足以在活體外表現於細胞中時產生離子電流。然而,在自然界中,電壓門控鈉離子通道包括兩個其他調節性β次單元。此等次單元之作用應在於主要藉由影響鈉電流之不活化來改變鈉離子通道定位及密度以及動力學性
質。SCN1B基因中之突變與GEFS+、布魯格達氏症候群(Brugada syndrome)及非特異性心臟傳導缺陷相關。SCN3B中之突變亦與布魯格達氏症候群相關,SCN4B中之突變導致長QT症候群-10。
在一個實施例中,該等小分子係選自由以下組成之群:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥,其係用於預防或治療與SCNxA家族成員相關之疾病或病症。可使用藥物及/或自使用化合物獲得之幹細胞再生之細胞/組織治療的例示性I型電壓門控鈉離子通道α次單元(SCN1A)介導之疾病及病症包括:神經疾病或病症、痙攣、疼痛(包括慢性疼痛)、涉及鈉離子通道功能障礙之電興奮性受損、與鈉離子通道功能障礙相關之疾病或病症、與電壓門控鈉離子通道α次單元活性之失調相關的疾病或病症(例如麻痺、高血鉀性週期性麻痺、先天性肌強直病、鉀加重性肌強直、長Q-T症候群3、運動終板病、運動失調等)、由於腸神經系統功能障礙所致之胃腸道疾病(例如結腸炎、迴腸炎、發炎性腸症候群等)、心血管疾病或病症(例如高血壓、充血性心臟衰竭等);涉及交感神經及副交感神經分佈之生殖泌尿道疾病或病症(例如良性***增生、無力);與神經肌肉
系統相關之疾病或病症(例如肌肉萎縮症、多發性硬化症、癲癇症、自閉症、偏頭痛(例如偶發性及家族性偏癱性偏頭痛等)、嬰兒期嚴重肌陣攣性癲癇(SMEI)或德拉韋特症候群(Dravet syndrome)、全身性癲癇伴熱性痙攣附加症(generalized epilepsy with febrile seizure plus;GEFS+)等)及SCN1A相關之癲癇發作病症。
在一個實施例中,小分子上調SCN1A之聚核苷酸。SCN1A標靶包含SCN1A變異體;SCN1A突變體,包括SNP;SCN1A之非編碼序列;等位基因、同功異型物、片段及其類似物。該等小分子較佳選自由以下組成之群:米那普侖、托拉塞米(torasemide)、利培酮(resperidone)、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥。
根據本發明之實施例,標靶核酸分子不限於單獨SCN1A聚核苷酸,而是擴展至SCN1A之同功異型物、受體、同源物、非編碼區及其類似物中之任一者,例如SCNxA家族。
在另一實施例中,小分子調節SCN1A標靶,包括而不限於其變異體、等位基因、同源物、突變體、衍生物、片段及互補序列。
在一個實施例中,小分子調節I型電壓門控鈉離子通道α
次單元(SCN1A)之表現,且調節I型電壓門控鈉離子通道α次單元(SCN1A)(SEQ ID NO:1)之表現及/或功能。
替代性RNA轉錄物可由DNA之同一基因組區域產生。此等替代性轉錄物一般稱為「剪接變異體」。更特定言之,「前mRNA變異體」為由含有內含子序列與外顯子序列兩者之基因組DNA產生的轉錄物。
在剪接期間切除一或多個外顯子或內含子區域或其部分時,前mRNA變異體產生較小「mRNA變異體」。此等mRNA變異體亦稱為「替代性剪接變異體」。若不發生前mRNA變異體之剪接,則前mRNA變異體與mRNA變異體相同。
變異體可經由使用替代性信號起始或終止轉錄來產生。前mRNA及mRNA可具有一個以上起始密碼子或終止密碼子。源於前mRNA或mRNA之使用替代性起始密碼子之變異體稱為該前mRNA或mRNA之「替代性起始變異體」。使用替代性終止密碼子之該等轉錄物稱為該前mRNA或mRNA之「替代性終止變異體」。一種特定類型之替代性終止變異體為「polyA變異體」,其中所產生之多種轉錄物由藉由轉錄機構替代性選擇一個「polyA終止信號」,藉此產生在獨特polyA位點處終止之轉錄物來產生。在本發明內容中,本文所述之變異體類型亦為標靶核酸之實施例。
雖然本文中闡述某些例示性標靶區段之特定序列,但熟習此項技術者應認識到此等序列用於說明及描述本發明之範疇內之特定實施例。一般技術者鑒於本發明可容易地鑑
別其他標靶區段。
在另一實施例中,本文所鑑別之「較佳標靶區段」可用於篩選調節I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸之表現的其他化合物。「調節劑」為減少或增加編碼I型電壓門控鈉離子通道α次單元(SCN1A)或其相應蛋白質之核酸分子之表現的化合物。篩選方法包含以下步驟:使編碼I型電壓門控鈉離子通道α次單元(SCN1A)或其相應蛋白質之有義或天然反義聚核苷酸之核酸分子的較佳標靶區段與一或多種候選調節劑接觸;及選擇一或多種減少或增加編碼I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸或其相應蛋白質之核酸分子之表現的候選調節劑。一旦顯示候選調節劑能夠調節(例如減少或增加)編碼電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸之核酸分子之表現,則可將調節劑用於進一步調查研究電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸之功能或用作本發明之研究劑、診斷劑或治療劑。
根據本發明所用之小分子宜且通常藉由熟知合成方法來製造。亦可採用用於該合成之任何其他方法;小分子之實際合成完全在一般技術者之能力範圍內,或該等分子可獲自商業供應商或供應商。本發明方法中所用之各較佳分子為已知醫藥學藥品,且可購自或獲自有效藥劑成份製造商。另外,該等藥物具有公開之合成方法,且一般熟習合成化學技術者可經由已知途徑合成該等藥物,或一般技術者可設計新的合成方法。此等藥物及其物理性質及鹽形式
可藉由標準化學方法加以改質,從而製造前藥。該等前藥包括酯及/或其他化學衍生物及/或修飾,其中在投藥時,前藥裂解成劑型(藥品)中之已知有效藥劑成份。就此而言,此等藥物可代謝成已知活性代謝物,且該等代謝物包括在本發明之範疇內。本發明進一步包括藥品之對映異構體及/或非對映異構體、該等產物之各種鹽形式(包括鈉鹽及鉀鹽)以及水合物及溶劑合物。本發明進一步包括呈任何適合劑型之各藥品或其鹽之非晶形式的用途。若特定藥品含有胺部分,則本發明進一步包括該等產物之酸式鹽,其中相對離子係選自鹵化物鹽,諸如氯化物或溴化物及其類似物。可利用再結晶方法及其他已知純化方法來製備該等有效藥劑成份之晶體形式。
可藉由此項技術中熟知之若干方法來評定小分子向宿主細胞或生物體中之轉移及其對RNA或蛋白質上調或下調之作用之測定。舉例而言,需要時選擇SCN1A纖維母細胞及/或角質細胞或其他細胞類型且使其生長以供本文中之特定分析。在實驗前一天將細胞以每孔約4×104個之密度接種於24孔盤中之生長培養基中,且在37℃及5% CO2下培育隔夜。第二天,將24孔盤中之培養基換成新鮮生長培養基(1毫升/孔)且給予細胞小化合物。用DMSO製備1 mM濃度之化合物儲備液。在實驗時,用生長培養基將1 mM儲備溶液稀釋至1 μM之濃度。對於對照孔,使用1/1000之DMSO稀釋液。在37℃及5% CO2下培育24小時至48小時之後,移出培養基且使用得自Promega之SV總RNA分離系統(目錄號
Z3105),按照製造商說明書自細胞中萃取RNA。將600奈克經純化之總RNA添加至使用得自Invitrogen之SuperScript VILO cDNA合成套組(目錄號11754-250)如製造商方案中所述進行之反轉錄反應中。使用得自此反轉錄反應之cDNA,藉由即時PCR,使用ABI Taqman基因表現混合物(目錄號4369510)及由ABI設計之引子/探針(針對人類SCN1A之分析Hs00374696_m1、Hs00897350_m1或Hs00897341_m1)來監測基因表現。使用以下PCR循環:50℃,2分鐘;95℃,10分鐘;40個循環(95℃,15秒;60℃,1分鐘);使用StepOne Plus即時PCR系統(Applied Biosystems)。針對18S之分析由ABI製造(目錄號4319413E)。用化合物處理後之基因表現倍數變化係基於經化合物處理之樣品與經媒劑處理之樣品之間的經18S校正之dCt值之差來計算。
亦可藉由量測酶活性或報導體蛋白質活性來偵測添加小分子後之RNA表現。舉例而言,來自基因之編碼區可用於藉由將基因與其poly(A)信號之間的報導體編碼區***自我複製質體中以使得基因及報導體將始終以相同水準表現來建造模型對照基因。將藉由觀察報導體基因之調節來分析個別小分子之有效性。適用於本發明方法中之報導體基因包括乙醯羥基酸合成酶(AHAS)、鹼性磷酸酶(AP)、β半乳糖苷酶(LacZ)、β葡糖醛酸酶(GUS)、氯黴素乙醯轉移酶(chloramphenicol acetyltransferase;CAT)、綠色螢光蛋白(GFP)、紅色螢光蛋白(RFP)、黃色螢光蛋白(YFP)、藍螢
光蛋白(cyan fluorescent protein;CFP)、辣根過氧化酶(horseradish peroxidase;HRP)、螢光素酶(luciferase;Luc)、胭脂鹼合成酶(nopaline synthase;NOS)、章魚鹼合成酶(octopine synthase;OCS)及其衍生物。可利用賦予安比西林(ampicillin)、博來黴素(bleomycin)、氯黴素、健大黴素(gentamycin)、潮黴素(hygromycin)、康黴素(kanamycin)、林可黴素(lincomycin)、甲胺喋呤(methotrexate)、草胺膦(phosphinothricin)、嘌呤黴素(puromycin)及四環素(tetracycline)抗性之多種可選擇標記。用於確定報導體基因之調節的方法在此項技術中為熟知的,且包括(但不限於)螢光分析法(例如螢光光譜法、螢光活化之細胞淘選(FACS)、螢光顯微術)、抗生素抗性測定。
可使用熟習此項技術者已知及本文其他部分所述之方法來分析SCNxA蛋白質及mRNA表現。舉例而言,諸如免疫組織化學之分析法可用於評估蛋白質含量。為達成此目的,將使用適當生長條件使細胞在24孔盤中生長。在添加小化合物後48小時,移出培養基且用無鈣及鎂之杜爾貝科氏(Dulbecco's)磷酸鹽緩衝生理鹽水(PBS)(Mediatech目錄號21-031-CV)將細胞洗滌3次。接著丟棄PBS,且在-20℃下使用300 μl 100%甲醇將細胞固定於24孔盤中15分鐘。移除甲醇且用PBS洗滌後,在21℃下將細胞與3%過氧化氫(Fisher Chemical目錄號H325-100)一起培育5分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl含
0.1%牛血清白蛋白(BSA)(Sigma目錄號A-9647)之PBS一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl抗生物素蛋白溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞簡單沖洗3次,接著在21℃下與生物素溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞洗滌3次,接著在4℃下與300微升/孔以1:250用PBS/BSA 0.1%稀釋之針對對應於大鼠Scn1a之C端胺基酸1491-1508的合成肽(EEQKKYYNAMKKLGSKKP)而產生之兔抗體(Abcam目錄號ab24820;已知可識別大鼠Scn1a、人類SCN1A及小鼠Scn1a)一起培育隔夜。在21℃下使培養盤平衡5分鐘後,用PBS將細胞洗滌三次,每次5分鐘,接著在21℃下與以1:200用PBS/BSA 0.1%稀釋之山羊抗兔抗體一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著與300 μl Vectastain Elite ABC試劑A+B溶液(Vector Laboratories目錄號PK-6101)一起培育30分鐘;該Vectastain Elite ABC試劑A+B溶液將在與細胞一起培育前30分鐘,在21℃下,藉由依序將2滴試劑A添加至5 ml PBS中並混合,接著添加2滴試劑B並混合來製備。在21℃下用PBS將細胞洗滌3次,每次5分鐘,接著與二胺基聯苯胺(DAB)過氧化酶受質溶液(Vector Laboratories目錄號SK-4105)一起培育直至細胞被染色;在添加至細胞中之前,藉由混合1 ml ImmPACTTM DAB稀釋劑與30 μl ImmPACTTM DAB色原體濃縮物使DAB過氧化酶受質溶液復原。此時,用PBS將細胞簡單洗滌3次
且各孔中將留有300 μl PBS。使用配備有與Nikon數位觀測設備耦聯之Nikon DS-Ril攝影機的反向Nikon Eclipse TS100顯微鏡,在Dell Latitude D630膝上型電腦之螢幕上直接分析24孔盤之各孔內的細胞染色。個別孔之相片將使用與Nikon攝影機一起提供之軟體NIS-Elements D 3.0來拍攝。
此外,可藉由酶聯免疫吸附分析法(ELISA)對SCN1A蛋白質進行定量。為達成此目的,將使用適當生長條件使細胞在24孔盤中生長。在添加小化合物後48小時,移出培養基且用無鈣及鎂之杜爾貝科氏磷酸鹽緩衝生理鹽水(PBS)(Mediatech目錄號21-031-CV)將細胞洗滌3次。接著丟棄PBS,且在-20℃下使用100 μl 100%甲醇將細胞固定於24孔盤中15分鐘。移除甲醇且用PBS洗滌後,在21℃下將細胞與3%過氧化氫(Fisher Chemical目錄號H325-100)一起培育5分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與100 μl含0.1%牛血清白蛋白(BSA)(Sigma目錄號A-9647)之PBS一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl抗生物素蛋白溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞簡單沖洗3次,接著在21℃下與生物素溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞洗滌3次,接著在4℃下與100微升/孔以1:250用PBS/BSA 0.1%稀釋之針對對應於大鼠Scn1a之C端胺基酸1491-1508的合成肽(EEQKKYYNAMKKLGSKKP)而產生之
兔抗體(Abcam目錄號ab24820;已知至少可識別大鼠Scn1a、人類SCN1A以及小鼠Scn1a)一起培育隔夜。在21℃下使培養盤平衡5分鐘後,用PBS將細胞洗滌三次,每次5分鐘,接著在21℃下與以1:200用PBS/BSA 0.1%稀釋之山羊抗兔抗體一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著與300 μl Vectastain Elite ABC試劑A+B溶液(Vector Laboratories目錄號PK-6101)一起培育30分鐘;該Vectastain Elite ABC試劑A+B溶液將在與細胞一起培育前30分鐘,在21℃下,藉由依序將2滴試劑A添加至5 ml PBS中並混合,接著添加2滴試劑B並混合來製備。在21℃下用PBS將細胞洗滌3次,持續5分鐘,接著與四甲基聯苯胺(TMB)過氧化酶受質溶液(Thermo Scientific目錄號N301)一起培育。在上清液變藍後,將其轉移至新的96孔ELISA盤(Greiner bio one目錄號65121)中且添加1 M硫酸。使用Multiskan Spectrum光譜儀(Thermo Scientific)在450 nm下讀取吸光度。將用作為初級抗體之兔抗小鼠IgG(Abcam目錄號ab6709)染色之孔中讀取的背景信號自所有SCN1A及肌動蛋白讀數中減去。使用得自Abcam之兔抗肌動蛋白抗體(目錄號ab1801)。針對肌動蛋白信號校正各條件之SCN1A信號且比較各實驗變異體之校正值。
在實施例中,藉由與對照樣品中之SCN1A表現進行比較來評估使用本發明小分子處理之樣品(例如活體內或活體外細胞或組織)中之SCN1A表現(例如mRNA或蛋白質)。舉例而言,可使用熟習此項技術者已知之方法來比較蛋白質
或核酸之表現與經假處理或未經處理樣品中之蛋白質或核酸之表現。或者,可視所要資訊而定,與經對照非活性分子處理之樣品進行比較。在另一實施例中,經處理與未經處理樣品中SCN1A蛋白質或核酸之表現差異可與經處理與未經處理樣品中不同核酸(包括研究者認為適當之任何標準物,例如管家基因)之表現差異進行比較。
所觀察到之差異可根據需要來表示,例如以比率或分數形式表示,以用於與對照組進行比較。在實施例中,相對於未經處理之樣品或經對照核酸處理之樣品,經本發明之反義寡核苷酸處理之樣品中SCN1A mRNA或蛋白質之含量增加或降低約1.25倍至約10倍或10倍以上。在實施例中,SCN1A mRNA或蛋白質之含量增加或降低至少約1.25倍、至少約1.3倍、至少約1.4倍、至少約1.5倍、至少約1.6倍、至少約1.7倍、至少約1.8倍、至少約2倍、至少約2.5倍、至少約3倍、至少約3.5倍、至少約4倍、至少約4.5倍、至少約5倍、至少約5.5倍、至少約6倍、至少約6.5倍、至少約7倍、至少約7.5倍、至少約8倍、至少約8.5倍、至少約9倍、至少約9.5倍或至少約10倍或10倍以上。
除SCN1A蛋白質或mRNA表現之變化外,可定量Nav1.1通道功能之變化。舉例而言,可在離散之海馬中間神經元中量測小化合物所致之SCN1A上調所誘導之鈉電流幅度變化。為達成此目的,藉由在以95% O2及5% CO2連續氧化之緩衝液中依序用鏈黴蛋白酶及嗜熱菌蛋白酶消化而自11至16天齡大鼠中離散出海馬GAD陽性雙極性細胞(GABA激
導性中間神經元)。將離散細胞接種於組織培養盤中且用所選小化合物處理24小時,此後進行電生理學記錄。使用全細胞膜片鉗技術用EPC-9膜片鉗放大器(HEKA)記錄電流。使用P-97型Flaming-Brown微電極拉製儀(Sutter Instrument)製造膜片吸移管。使用PULSE程式(7.5版;HEKA Elektronik)進行刺激及資料獲取。對於電壓鉗實驗,使用蠕動泵將含有19.1 mM NaCl、19.1 mM氯化四乙銨、0.95 mM BaCl2、1.90 mM MgCl2、52.4 mM CsCl、0.1 mM CdCl2、0.95 mM CaCl2、9.52 mM HEPES、117 mM葡萄糖之灌注緩衝液(pH 7.35)持續灌注於細胞上。膜片吸移管將含有157 mM N-甲基-d-葡糖胺、126 mM HCl、0.90 mM NaCl、3.60 mM MgCl2、9.01 mM EGTA、1.80 mM ATP-Na2、9.01 mM HEPES、4.50 mM肌酸-磷酸鹽,pH 7.2。將細胞保持在-100 mV下,且自-60 mV至-15 mV以5 mV增量施加去極化步驟。測定且比較經處理與未經處理之神經元的最大電流密度。
另外,可評定海馬中間神經元中SCN1A上調所誘導之鈉電流特徵變化。藉由在以95% O2及5% CO2連續氧化之緩衝液中依序用鏈黴蛋白酶及嗜熱菌蛋白酶消化而自11至16天齡大鼠中離散出海馬GAD陽性雙極性細胞(GABA激導性中間神經元)。將離散細胞接種於組織培養盤中且用所選小化合物處理24小時,此後進行電生理學記錄。使用全細胞膜片鉗技術用EPC-9膜片鉗放大器(HEKA)記錄電流。使用P-97型Flaming-Brown微電極拉製儀(Sutter Instrument)
製造膜片吸移管。使用PULSE程式(7.5版;HEKA Elektronik)進行刺激及資料獲取。對於電壓鉗實驗,使用蠕動泵將含有19.1 mM NaCl、19.1 mM氯化四乙銨、0.95 mM BaCl2、1.90 mM MgCl2、52.4 mM CsCl、0.1 mM CdCl2、0.95 mM CaCl2、9.52 mM HEPES、117 mM葡萄糖之灌注緩衝液(pH 7.35)持續灌注於細胞上。膜片吸移管將含有157 mM N-甲基-d-葡糖胺、126 mM HCl、0.90 mM NaCl、3.60 mM MgCl2、9.01 mM EGTA、1.80 mM ATP-Na2、9.01 mM HEPES、4.50 mM肌酸-磷酸鹽,pH 7.2。將細胞保持在-100 mV下且自-60 mV至-15 mV以5 mV增量施加去極化步驟。活化曲線(電導/電壓關係)將根據g=INa/(V-ENa)由電流/電壓關係計算,其中INa表示在電位V下所量測之峰值鈉電流,且ENa表示平衡電位。將擬合波耳茲曼函數(Boltzmann function)以校正活化及不活化曲線,且確定曲線特徵。將藉由使電流衰減擬合單指數函數來評估不活化時間常數。將比較經處理與未經處理之細胞的活化及不活化概況以確定治療是否改變電流特徵。對於電流鉗實驗,將細胞保持在-80 mV下,且在以10 pA之增量施加800 ms脈衝後記錄其放電模式。電極緩衝液將含有135 mM葡萄糖酸鉀、20 mM KCl、2 mM MgCl2、2 mM ATPNa2、0.3 mM GTP-Na及10 mM HEPES、0.2 mM EGTA,pH 7.3。灌注緩衝液將含有140 mM NaCl、5 mM KCl、2 mM CaCl2、1 mM MgCl2、10 mM HEPES及10 mM葡萄糖,pH值用NaOH調節至7.4。將量測並比較經處理與
未經處理之海馬抑制性中間神經元的輸入-輸出關係(作用電位/注入pA之數值)、作用電位半寬度、尖峰幅度及尖峰衰減。單通道電流記錄將在外部/外膜片組態下使用與上文關於全細胞膜片記錄所述相同之溶液及方案來進行。
用小化合物處理所誘導之SCN1A上調亦可影響細胞內鈉含量。可在以下實驗中評定該等變化。使細胞在96孔盤中生長且給予不同濃度之小化合物。48小時後,用洛克緩衝液(Locke's buffer)(8.6 mM HEPES、5.6 mM KCl、154 mM NaCl、5.6 mM葡萄糖、1.0 mM MgCl2、2.3 mM CaCl2、0.0001 mM甘胺酸,pH 7.4)洗滌細胞。在將染料加載於細胞內之前量測螢光背景。藉由在37℃下將細胞與染料以及含10 μM SBFI-AM(結合Na+之染料)、0.04% Pluronic F-127(Molecular Probes,OR,USA)及2.5 mM丙磺舒(probenecid)之洛克緩衝液(50微升/孔)一起培育1小時而將染料加載於細胞內。此時,用含2.5 mM丙磺舒之洛克緩衝液(150微升/孔)將細胞洗滌兩次。將含有經加載之細胞的培養盤置於諸如FLEXstationTM II(Molecular Devices,Sunnyvale,CA,USA)之讀數器內。在340 nm及380 nm下激發加載有染料之細胞;在505 nm下記錄發射信號。此時量測信號基線。量測信號基線後,將莫能菌素(monensin)(EMD,Gibbstown,NJ,USA,目錄號475895)或短桿菌肽(EMD,Gibbstown,NJ,USA,目錄號368020-25MG)添加至含細胞之個別孔中作為陽性對照組。將使用TTX(1 μM)處理作為陰性對照組。接著將確定經活性化合
物預處理之細胞中活性SCN1A於質膜處之相對表現(與媒劑對照組相比)。將使用Excel軟體以505 nm下之發射與340 nm/380 nm之比率來計算信號。
亦可評定單細胞中SCN1A上調對鈉含量之作用。使細胞在蓋玻片上或在96孔盤中生長且給予不同濃度之小化合物。48小時後,用洛克緩衝液(8.6 mM HEPES、5.6 mM KCl、154 mM NaCl、5.6 mM葡萄糖、1.0 mM MgCl2、2.3 mM CaCl2、0.0001 mM甘胺酸,pH 7.4)洗滌細胞。在將染料加載於細胞內之前量測螢光背景。藉由在37℃下將細胞與染料以及含10 μM SBFI-AM(結合Na+之染料)、0.04%普洛尼克酸(pluronic acid)F-127及2.5 mM丙磺舒之洛克緩衝液(50微升/孔)一起培育1小時而將染料加載於細胞內。此時用含2.5 mM丙磺舒之洛克緩衝液將細胞洗滌兩次(150微升/孔)。將96孔盤中或蓋玻片上之細胞置於裝備有用於激發及發射之汞燈及適當濾光片的落射螢光顯微鏡(epi-fluorescent microscope)(得自Omega Optical Inc,Brattleboro,VT,USA,目錄號:套件X-F04-2;或得自Chroma Technology Corp,Falls,VT,USA,目錄號79001)下。在340 nm及380 nm下激發加載有染料之細胞;在505 nm下記錄發射信號。量測信號基線後,將莫能菌素(EMD,Gibbstown,NJ,USA,目錄號475895)或短桿菌肽(EMD,Gibbstown,NJ,USA,目錄號368020-25MG)添加至含細胞之個別孔中作為陽性對照組。為確定活性SCN1A於質膜處之相對上調,將經活性化合物預處理之細胞與媒
劑對照組相比。藉由連接至落射螢光顯微鏡之攝影機收集資料且使用適當軟體進行定量。將藉由使用Excel軟體計算505 nm發射與340 nm/380 nm之比率來處理原始信號。
除細胞分析外,可利用特定疾病病況之動物模型。在各情況下,將基於特定標靶疾病或病狀來選擇動物。已知動物表現或能夠表現SCN1A多肽或其變異體。本發明化合物可用於診斷、治療及預防,以及作為研究試劑及套組之組份。此外,一般技術者通常使用能夠調節基因表現之化合物來說明特定基因之功能或區分生物路徑之不同成員的功能。使用該等化合物來製造用於治療任何本文所述疾病之藥物為所主張之發明的一個特點。
為用於套組及診斷劑及各種生物系統中,單獨或與其他化合物或治療劑組合之本發明化合物適用作差異及/或組合分析之工具以說明細胞及組織內所表現之基因之一部分或整個補體的相互依賴性表現模式。
如本文中所使用,術語「生物系統」或「系統」係定義為表現或使得能夠表現基因之電壓門控鈉離子通道α次單元(SCNxA)家族之產物的任何生物體、細胞、細胞培養物或組織。此等包括(但不限於)人類、轉殖基因動物、細胞、細胞培養物、組織、異種移植物、移植物及其組合。
作為一個非限制性實例,比較經一或多種化合物處理之細胞或組織內之表現模式與未經該等化合物處理之對照細胞或組織內之表現模式,且分析所產生之模式的差異性基因表現量,因為該等模式例如與所研究之基因的疾病相關
性、信號傳導路徑、細胞定位、表現量、大小、結構或功能有關。可對經刺激或未經刺激之細胞且在存在或不存在影響表現模式之其他化合物的情況下進行此等分析。
此項技術中已知之基因表現分析方法之實例包括DNA陣列或微陣列、SAGE(基因表現之連續分析)、READS(經消化cDNA之限制酶擴增)、TOGA(總體基因表現分析)、蛋白質陣列及蛋白質組研究、所表現序列標籤(EST)定序、消減RNA指紋法(SuRF)、消減選殖法、差異呈現法(DD)、比較基因組雜交法、FISH(螢光原位雜交)技術及質譜法。
對於治療劑,疑似患有可藉由調節I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸或蛋白質之表現而加以治療之疾病或病症的動物(較佳為人類)係藉由投與本發明之化合物進行治療。舉例而言,在一個非限制性實施例中,該等方法包含以下步驟:向需要治療之動物投與治療有效量之I型電壓門控鈉離子通道α次單元(SCN1A)調節劑。本發明之I型電壓門控鈉離子通道α次單元(SCN1A)調節劑有效調節I型電壓門控鈉離子通道α次單元(SCN1A)之活性或調節I型電壓門控鈉離子通道α次單元(SCN1A)蛋白質之表現。在一個實施例中,動物體內I型電壓門控鈉離子通道α次單元(SCN1A)之活性或表現與對照組相比被抑制約10%。動物體內SCN1A之活性或表現較佳被抑制約30%。動物體內I型電壓門控鈉離子通道α次單元(SCN1A)之活性或表現更佳被抑制50%或50%以上。因此,小化合物與對照組相比將I型電壓門控鈉離子通道α次單元(SCN1A)mRNA
或蛋白質之表現調節至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%。
在一個實施例中,動物體內I型電壓門控鈉離子通道α次單元(SCN1A)之活性或表現與對照組相比增加約10%。動物體內I型電壓門控鈉離子通道α次單元(SCN1A)之活性或表現較佳增加約30%。動物體內I型電壓門控鈉離子通道α次單元(SCN1A)之活性或表現更佳增加50%或50%以上。因此,該等化合物與對照組相比將I型電壓門控鈉離子通道α次單元(SCN1A)mRNA之表現調節至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%或100%以上。
舉例而言,可在動物之血液、脂肪組織、肝臟或任何其他體液、組織或器官中量測I型電壓門控鈉離子通道α次單元(SCN1A)之表現的減少或增加。所分析之該等體液、組織或器官內所含之細胞較佳含有編碼I型電壓門控鈉離子通道α次單元(SCN1A)肽之核酸分子及/或I型電壓門控鈉離子通道α次單元(SCN1A)蛋白質自身。
本發明化合物可藉由將有效量之化合物添加至適合醫藥學上可接受之稀釋劑或載劑中而以醫藥組合物形式利用。本發明之化合物及方法的用途亦可用於預防。
本發明化合物亦可與其他分子、分子結構或化合物之混合物混合、用其囊封、與其結合或締合,例如脂質體、受體靶向分子、經口調配物、經直腸調配物、局部調配物或其他調配物,以幫助攝取、分佈及/或吸收。教示製備該等有助於攝取、分佈及/或吸收之調配物之代表性美國專利包括(但不限於)美國專利第5,108,921號;第5,354,844號;第5,416,016號;第5,459,127號;第5,521,291號;第5,543,165號;第5,547,932號;第5,583,020號;第5,591,721號;第4,426,330號;第4,534,899號;第5,013,556號;第5,108,921號;第5,213,804號;第5,227,170號;第5,264,221號;第5,356,633號;第5,395,619號;第5,416,016號;第5,417,978號;第5,462,854號;第5,469,854號;第5,512,295號;第5,527,528號;第5,534,259號;第5,543,152號;第5,556,948號;第5,580,575號;及第5,595,756號,各專利係以引用的方式併入本文中。
在一個實施例中,本發明實踐涉及向需要治療之患者投與至少一種上述化合物:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、埃索美拉唑(esomeprazole)、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽、異構體、對映異構體、同功異型物、多晶型物、水合物、溶劑合物或前藥。
本發明化合物涵蓋任何醫藥學上可接受之鹽、酯或該等酯之鹽,或在投與動物(包括人類)後能夠提供(直接或間接)生物學活性代謝物或其殘餘物之任何其他化合物。
術語「醫藥學上可接受之鹽」係指本發明化合物之生理學上及醫藥學上可接受之鹽:亦即保留母體化合物之所要生物活性且不賦予其不合需要之毒理學作用的鹽。
本發明亦包括包括本發明化合物之醫藥組合物及調配物。本發明之醫藥組合物可以多種方式投與,視需要局部治療抑或全身性治療以及欲治療之區域而定。投藥可為局部投藥(包括眼用及針對黏膜投藥,包括***及直腸遞送);經肺投藥(例如藉由吸入或吹入散劑或氣霧劑,包括藉由噴灑器;氣管內投藥;鼻內投藥;經表皮投藥及經皮投藥);經口投藥或非經腸投藥。非經腸投藥包括靜脈內、動脈內、皮下、腹膜內或肌肉內注射或輸注;或顱內(例如鞘內或心室內)投藥。
對於治療中樞神經系統中之組織,可藉由例如注射或輸注至腦脊髓液中來進行投藥。
當意欲本發明化合物投與中樞神經系統中之細胞時,投藥可與一或多種能夠促進標的化合物穿透過血腦屏障之藥劑一起進行。當藉由注射進行時,投藥可快速進行,或當藉由緩慢輸注或投與緩慢釋放調配物時,投藥可經一段時期。
標的化合物亦可與提供理想醫藥學或藥效學性質之藥劑鍵聯或結合或組合。舉例而言,該等化合物可與此項技術
中已知可促進跨越血腦屏障之穿透或轉運的任何物質偶合,諸如轉鐵蛋白受體抗體,且藉由靜脈內注射進行投藥。滲透血腦屏障破壞亦可藉由例如輸注以下各物來實現:糖,包括(但不限於)內消旋赤藻糖醇(meso erythritol)、木糖醇(xylitol)、D(+)半乳糖、D(+)乳糖、D(+)木糖、半乳糖醇(dulcitol)、肌醇(myo-inositol)、L(-)果糖、D(-)甘露糖醇、D(+)葡萄糖、D(+)***糖、D(-)***糖、纖維二糖、D(+)麥芽糖、D(+)棉子糖、L(+)鼠李糖、D(+)蜜二糖、D(-)核糖、核糖醇(adonitol)、D(+)***糖醇、L(-)***糖醇、D(+)海藻糖、L(-)海藻糖、D(-)來蘇糖、L(+)來蘇糖及L(-)來蘇糖;或胺基酸,包括(但不限於)麩醯胺酸、離胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、麩胺酸、甘胺酸、組胺酸、白胺酸、甲硫胺酸、***酸、脯胺酸、絲胺酸、蘇胺酸、酪胺酸、纈胺酸及牛磺酸。增強血腦屏障穿透之方法及材料描述於例如美國專利第4,866,042號「Method for the delivery of genetic material across the blood brain barrier」、第6,294,520號「Material for passage through the blood-brain barrier」及第6,936,589號「Parenteral delivery systems」中,該等專利均以全文引用的方式併入本文中。
標的化合物可與其他分子、分子結構或化合物之混合物混合、用其囊封、與其結合或締合,例如脂質體、受體靶向分子、經口調配物、直腸調配物、局部調配物或其他調配物,以幫助攝取、分佈及/或吸收。舉例而言,陽離子
脂質可包括在調配物中以促進化合物攝取。顯示會促進攝取之一種此類組合物為LIPOFECTIN(獲自GIBCO-BRL,Bethesda,MD)。
用於局部投藥之醫藥組合物及調配物可包括經皮貼片、軟膏、洗劑、乳膏、凝膠、滴劑、栓劑、噴霧劑、液體及散劑。可能必需或需要習知醫藥載劑、水性、粉末狀或油性基質、增稠劑及其類似物。亦可使用經塗佈之保險套(condom)、手套及其類似物。
宜以單位劑型呈現之本發明醫藥調配物可根據製藥工業中熟知的習知技術來製備。該等技術包括使活性成份與醫藥載劑或賦形劑締合之步驟。一般而言,藉由使活性成份與液體載劑或細粉狀固體載劑或兩者均勻且密切締合,接著在必要時使產物成形來製備調配物。
本發明組合物可調配成許多可能劑型中之任一者,諸如(但不限於)錠劑、膠囊、凝膠膠囊、液體糖漿、軟凝膠、栓劑及灌腸劑。本發明組合物亦可調配成於水性、非水性或混合型介質中之懸浮液。水性懸浮液可另外含有增加懸浮液黏度之物質,包括例如羧甲基纖維素鈉、山梨糖醇及/或聚葡萄糖。懸浮液亦可含有穩定劑。
本發明之醫藥組合物包括(但不限於)溶液、乳液、泡沫劑及含脂質體調配物。本發明之醫藥組合物及調配物可包含一或多種加強滲透劑、載劑、賦形劑或其他活性成份或非活性成份。
乳液通常為其中一種液體以直徑通常超過0.1 μm之小液
滴形式分散於另一種液體中的非均質系統。除分散相及可呈水相、油相之溶液或本身即呈分相(separate phase)存在之活性藥物外,乳液亦可含有其他組份。包括微乳液作為本發明之一個實施例。乳液及其用途係此項技術中熟知者,且進一步描述於美國專利第6,287,860號中。
本發明之調配物包括脂質體調配物。如本發明中所使用,術語「脂質體」意謂由以球形雙層排列之兩親媒性脂質構成的囊胞。脂質體為單層或多層囊胞,其具有由親脂性物質形成之膜及含有欲遞送之組合物之水性內部。
脂質體亦包括「空間穩定」脂質體,如本文中所使用,該術語係指包含一或多種特殊化脂質之脂質體。當併入脂質體中時,此等特殊化脂質使得脂質體相對於缺乏該等特殊化脂質之脂質體具有延長之循環壽命。空間穩定脂質體之實例為以下脂質體:脂質體中形成囊胞之脂質部分之一部分包含一或多種醣酯或經一或多種親水性聚合物,諸如聚乙二醇(PEG)部分體衍生化。脂質體及其用途進一步描述於美國專利第6,287,860號中。
本發明之醫藥調配物及組合物亦可包括界面活性劑。界面活性劑在藥品、調配物及乳液中之用途係此項技術中熟知者。界面活性劑及其用途進一步描述於美國專利第6,287,860號中,該專利係以引用的方式併入本文中。
在一個實施例中,本發明採用各種加強滲透劑以便有效遞送小分子。除了有助於非親脂性藥物跨細胞膜擴散外,加強滲透劑亦增強親脂性藥物之通透性。加強滲透劑可分
類為屬於以下五大類之一,亦即界面活性劑、脂肪酸、膽汁鹽、螯合劑及非螯合性非界面活性劑。加強滲透劑及其用途進一步描述於美國專利第6,287,860號中,該專利係以引用的方式併入本文中。
熟習此項技術者應認識到調配物係根據其所欲用途,亦即投藥途徑而按常規方式加以設計。
用於局部投藥之較佳調配物包括用於本文所述用途之本發明化合物與諸如脂質、脂質體、脂肪酸、脂肪酸酯、類固醇、螯合劑及界面活性劑之局部遞送劑混合的調配物。較佳脂質及脂質體包括中性(例如二油醯基-磷脂醯基DOPE乙醇胺、二肉豆蔻醯基磷脂醯基膽鹼DMPC、二硬脂醯基磷脂醯基膽鹼)、帶負電荷型(例如二肉豆蔻醯基磷脂醯基甘油DMPG)及陽離子型(例如二油醯基四甲基胺基丙基DOTAP及二油醯基-磷脂醯基乙醇胺DOTMA)。
對於局部或其他投藥而言,本發明化合物可囊封於脂質體內或可與其形成複合物,尤其是與陽離子脂質體形成複合物。或者,化合物可與脂質複合,尤其是與陽離子脂質複合。較佳脂肪酸及酯、其醫藥學上可接受之鹽及其用途進一步描述於美國專利第6,287,860號中。
用於經口投藥之組合物及調配物包括散劑或顆粒、微顆粒、奈米顆粒、於水或非水性介質中之懸浮液或溶液、膠囊、凝膠膠囊、藥囊、錠劑或小錠劑。可能需要增稠劑、調味劑、稀釋劑、乳化劑、分散助劑或黏合劑。較佳經口調配物為與一或多種加強滲透劑、界面活性劑及螯合劑一
起投與本發明化合物之調配物。較佳界面活性劑包括脂肪酸及/或其酯或鹽、膽汁酸及/或其鹽。較佳膽汁酸/鹽及脂肪酸及其用途進一步描述於美國專利第6,287,860號中,該專利係以引用的方式併入本文中。加強滲透劑之組合亦較佳,例如脂肪酸/鹽與膽汁酸/鹽之組合。尤其較佳組合為月桂酸、癸酸及UDCA之鈉鹽。其他加強滲透劑包括聚氧乙烯-9-月桂基醚、聚氧乙烯-20-十六基醚。本發明化合物可以包括噴霧乾燥粒子或複合形成微米或奈米粒子之顆粒形式經口遞送。
用於非經腸、鞘內或心室內投藥之組合物及調配物可包括無菌水溶液,其亦可含有緩衝液、稀釋劑及其他適合添加劑,諸如(但不限於)加強滲透劑、載劑化合物及其他醫藥上可接受之載劑或賦形劑。
本發明之某些實施例提供含有一或多種化合物及一或多種其他有效藥劑成份之醫藥組合物。該等有效藥劑成份之實例包括(但不限於)適用於與本發明化合物一起治療需要治療之患者之病狀的任何活性成份。兩種或兩種以上組合化合物可一起或依序使用。
在另一相關實施例中,本發明組合物可含有一或多種靶向第一核酸標靶之化合物及一或多種靶向第二核酸標靶之其他化合物。舉例而言,該第一標靶可為I型電壓門控鈉離子通道α次單元(SCN1A)之特定反義序列,且該第二標靶可為另一核苷酸序列之區域。或者,本發明組合物可含有兩種或兩種以上調節同一I型電壓門控鈉離子通道α次單
元(SCN1A)核酸或蛋白質標靶之不同區域的化合物。兩種或兩種以上組合化合物可一起或依序使用。
據信治療組合物之調配及其隨後投藥(給藥)處於技術人員之技能範圍內。給藥視欲治療之疾病病況之嚴重性及反應性而定,其中治療過程持續數天至數月,或直至實現治癒或減弱疾病病況。最佳給藥時程可由患者體內藥物積聚之量測值加以計算。一般技術者可容易地確定最佳劑量、給藥方法及重複率。最佳劑量可視個別有效藥劑成份之相對功效而變化,且一般可基於發現在活體外及活體內動物模型中有效之EC50進行評估,且亦可根據各批准及銷售藥物之處方資訊來確定。一般而言,劑量為每公斤體重0.01 μg至100 mg,且可每天、每週或每月給予一或多次。一般技術者可基於藥物在體液或組織中之量測滯留時間及濃度而容易地估計給藥重複率。成功治療後,可能需要對患者進行維持療法以防止疾病病況復發,其中每日一或多次以每公斤體重0.01 μg至100 mg範圍內之維持劑量投與化合物。
在實施例中,用以下藥物劑量治療患者,即每公斤體重至少約1 mg、至少約2 mg、至少約3 mg、至少約4 mg、至少約5 mg、至少約6 mg、至少約7 mg、至少約8 mg、至少約9 mg、至少約10 mg、至少約15 mg、至少約20 mg、至少約25 mg、至少約30 mg、至少約35 mg、至少約40 mg、至少約45 mg、至少約50 mg、至少約60 mg、至少約70 mg、至少約80 mg、至少約90 mg或至少約100 mg。
雖然上文已描述本發明之各種實施例,但應理解,該等實施例僅以實例方式提供且不具限制性。可根據本文之揭示內容在不脫離本發明之精神或範疇的情況下對所揭示之實施例進行許多變化。因此,本發明之廣度及範疇不應受任何上述實施例限制。
本文提及之所有文獻均以引用的方式併入本文中。本申請案中引用之所有公開案及專利文獻均出於所有目的而以引用的方式併入本文中,該引用之程度如同個別地表述各個公開案或專利文獻一般。就在本文件中引用各種參考文獻而言,申請人不承認任何特定參考文獻為其發明之「先前技術」。在以下實例中說明本發明組合物及方法之實施例。
以下非限制性實例用於說明本發明之所選實施例。應瞭解,所示組份中要素之比例變化及替代物應為熟習此項技術者顯而易知且在本發明實施例之範疇內。
使用以下化合物來評定對SCN1A mRNA含量之調節:a)米那普侖鹽酸鹽(1R(S),2S(R)-[2-(胺基甲基)-N,N-二乙基-1-苯基環丙烷羧醯胺鹽酸鹽);b)托西邁(1-異丙基-3-[(4-間甲苯胺基-3-吡啶基-磺醯基]脲);c)利培酮(3-[2-[4-(6-氟-1,2-苯并異噁唑-3-基)-1-哌啶基]-乙基]-6,7,8,9-四氫-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮);
d)吡那地爾(N-氰基-N'-吡啶-4-基-N"-(1,2,2-三甲基丙基)胍);e)貝尼地平鹽酸鹽(5-O-甲基-3O-[(3R)-1-(苯基甲基)-哌啶-3-基]-2,6-二甲基-4-(3-硝基苯基)-1,4-二氫吡啶-3,5-二甲酸酯);f)酮康唑(1-[4-(4-{[(2R,4S)-2-(2,4-二氯苯基)-2-(1H-咪唑-1-基甲基)-1,3-二氧戊環-4-基]甲氧基}苯基)哌嗪-1-基]乙-1-酮);g)依布硒(2-苯基-1,2-苯并硒唑-3-酮);h)他達那非((6R-反)-6-(1,3-苯并二氧雜環戊烯-5-基)-2,3,6,7,12,12a-六氫-2-甲基-吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮);i)折侖諾((3S,7R)-7,14,16-三羥基-3-甲基-3,4,5,6,7,8,9,10,11,12-十氫-1H-2-苯并氧雜環十四-1-酮);j)萘法唑酮鹽酸鹽(2-[3-[4-(3-氯苯基)-1-哌嗪基]丙基]-5-乙基-2,4-二氫-4-(2-苯氧基乙基)-3H-1,2,4-***-3-酮單鹽酸鹽;k)洛美利嗪二鹽酸鹽(1-[雙(4-氟苯基)甲基]-4-[2,3,4-三甲氧基苯基甲基]二鹽酸鹽);l)淫羊藿苷(5-羥基-2-(4-甲氧基苯基)-8-(3-甲基丁-2-烯基)-7-[(2S,3R,4S,5S,6R)-3,4,5-三羥基-6-(羥基甲基)噁烷-2-基]氧基-3-[(2S,3R,4R,5R,6S)-3,4,5-三羥基-6-甲基噁烷-2-基]氧基烯-4-酮);
m)奧美拉唑鎂(6-甲氧基-2-((4-甲氧基-3,5-二甲基吡啶-2-基)甲亞磺醯基)-1H-苯并[d]咪唑鎂);n)埃索美拉唑鎂((S)-6-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲亞磺醯基)-1H-苯并[d]咪唑鎂);o)L-694,247(N-[4-[[5-[3-(2-胺基乙基)-1H-吲哚-5-基]-1,2,4-噁二唑-3-基]甲基]苯基]甲磺醯胺);p)尼群地平((RS)-2,6-二甲基-4-(3-硝基苯基)-1,4-二氫吡啶-3,5-二甲酸乙酯甲酯);q)尼美西泮(2-甲基-9-硝基-6-苯基-2,5-二氮雜雙環[5.4.0]十一碳-5,8,10,12-四烯-3-酮);r)胺來呫諾(2-胺基-7-異丙基-5-側氧基-5H-烯并[2,3-b]吡啶-3-甲酸);s)莫沙必利檸檬酸鹽(2-羥基-1,2,3-丙烷三甲酸4-胺基-5-氯-2-乙氧基-N-[[4-[(4-氟苯基)苯基]-2-嗎啉基]甲基]-苯甲醯胺);t)舍曲林鹽酸鹽((1S,4S)-4-(3,4-二氯苯基)-N-甲基-1,2,3,4-四氫萘-1-胺);及u)司坦唑醇(17β-羥基-17-甲基-5α-雄留烷并[3,2-c]-吡唑)。
在實例1中,用小化合物以1 μM之最終濃度處理攜帶德拉韋特相關SCN1A突變之初級人類皮膚纖維母細胞。以下資料顯示,在處理24小時至48小時後,此等化合物能夠上
調SCN1A mRNA。
在37℃及5% CO2下,使由N.Kenyon博士(University of Miami)引入培養物中之攜帶德拉韋特相關SCN1A突變之初級人類皮膚纖維母細胞在由以下組成之生長培養基中生長:a-MEM(Gibco,目錄號:12561-056)+10% FBS(Mediatech,目錄號:35-015 CV)+1%抗黴菌劑-抗生素(Gibco,目錄號:15240-062)。在實驗前一天,將細胞以每孔約4×104個之密度接種於24孔盤中之生長培養基中,且在37℃及5% CO2下培育隔夜。第二天,將24孔盤中之培養基換成新鮮生長培養基(1毫升/孔)且給予細胞小化合物。所有化合物均獲自市售來源。用DMSO製備1 mM濃度之化合物儲備液。在實驗時,用生長培養基將1 mM儲備溶液稀釋至1 μM之濃度。對於對照孔,使用1/1000之DMSO稀釋液。在37℃及5% CO2下培育24小時至48小時之後,移出培養基且使用得自Promega(目錄號Z3105)之SV總RNA分離系統,按照製造商說明書自細胞中萃取RNA。將600奈克經純化之總RNA添加至使用得自Invitrogen之SuperScript VILO cDNA合成套組(目錄號11754-250)如製造商方案中所述進行之反轉錄反應中。使用得自此反轉錄反應之cDNA,藉由即時PCR,使用ABI Taqman基因表現混合物(目錄號4369510)及由ABI設計之引子/探針(針對人類SCN1A之分
析Hs00374696_m1、Hs00897350_m1或Hs00897341_m1)來監測基因表現。使用所有三種分析法所獲得之結果極其相似(資料未顯示)。使用以下PCR循環:50℃,2分鐘;95℃,10分鐘;40個循環(95℃,15秒;60℃,1分鐘);使用StepOne Plus即時PCR系統(Applied Biosystems)。針對18S之分析由ABI製造(目錄號4319413E)。用化合物處理後之基因表現倍數變化係基於經化合物處理之樣品與經媒劑處理之樣品之間的經18S校正之dCt值之差來計算。
結果顯示,具有不同化學性質之小化合物能夠將攜帶德拉韋特相關突變之初級皮膚纖維母細胞中之SCN1A mRNA上調2至4倍(表1)。
在實例2中,用小化合物以1 μM之最終濃度處理初級人類角質細胞。以下資料顯示,在處理24小時至48小時後,此等化合物能夠上調SCN1A mRNA。
在37℃及5% CO2下,使得自PromoCell(Heidelberg,Germany,目錄號C-12003)或LifeLine Cell Technology (Frederick,MD,目錄號FC-0025)之成熟初級人類角質細胞在製造商所供應之生長培養基中生長。在實驗前一天,將細胞以每孔約4×104個之密度接種於24孔盤中之生長培
養基中,且在37℃及5% CO2下培育隔夜。第二天,將24孔盤中之培養基換成新鮮生長培養基(1毫升/孔)且給予細胞小化合物。所有化合物均獲自市售來源。用DMSO製備1 mM濃度之化合物儲備液。在實驗時,用生長培養基將1 mM儲備溶液稀釋至1 μM之濃度。對於對照孔,使用1/1000之DMSO稀釋液。在37℃及5% CO2下培育24小時至48小時之後,移出培養基且使用得自Promega(目錄號Z3105)之SV總RNA分離系統,按照製造商說明書自細胞中萃取RNA。將600奈克經純化之總RNA添加至使用Invitrogen之SuperScript VILO cDNA合成套組(目錄號11754-250)如製造商方案中所述進行之反轉錄反應中。使用得自此反轉錄反應之cDNA,藉由即時PCR,使用ABI Taqman基因表現混合物(目錄號4369510)及由ABI設計之引子/探針(針對於人類SCN1A之分析Hs00374696_m1、Hs00897350_m1或Hs00897341_m1)來監測基因表現。使用所有三種分析法所獲得之結果極其相似(資料未顯示)。使用以下PCR循環:50℃,2分鐘;95℃,10分鐘;40個循環(95℃,15秒;60℃,1分鐘);使用StepOne Plus即時PCR系統(Applied Biosystems)。針對18S之分析由ABI製造(目錄號4319413E)。用化合物處理後之基因表現倍數變化係基於經化合物處理之樣品與經媒劑處理之樣品之間的經18S校正之dCt值之差來計算。
結果顯示,具有不同化學性質之小化合物能夠將成熟初
級角質細胞中之SCN1A mRNA上調2至5倍(表1)。
表1顯示用小化合物以1 μM之濃度處理後,攜帶德拉韋特相關突變之初級皮膚纖維母細胞(第1欄)及成熟初級角質細胞(第2欄)中SCN1A mRNA含量之增加倍數。Avg-平均上調;STE-平均值標準誤差。
此實驗之目的在於使用稱為免疫組織化學之技術,根據
化合物上調不同細胞中SCN1A蛋白質表現之能力對化合物進行分級。
材料與方法。將藉由免疫組織化學偵測細胞內之SCN1A蛋白質。為達成此目的,將使用適當生長條件使細胞在24孔盤中生長。在添加小化合物後48小時,移出培養基且用無鈣及鎂之杜爾貝科氏磷酸鹽緩衝生理鹽水(PBS)(Mediatech目錄號21-031-CV)將細胞洗滌3次。接著丟棄PBS,且在-20℃下使用300 μl 100%甲醇將細胞固定於24孔盤中15分鐘。移除甲醇且用PBS洗滌後,在21℃下將細胞與3%過氧化氫(Fisher Chemical目錄號H325-100)一起培育5分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl含0.1%牛血清白蛋白(BSA)(Sigma目錄號A-9647)之PBS一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl抗生物素蛋白溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞簡單沖洗3次,接著在21℃下與生物素溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞洗滌3次,接著在4℃下與300微升/孔以1:250用PBS/BSA 0.1%稀釋之針對對應於大鼠Scn1a之C端胺基酸1491-1508的合成肽(EEQKKYYNAMKKLGSKKP)而產生之兔抗體(Abcam目錄號ab24820;已知可識別大鼠Scn1a、人類SCN1A及小鼠Scn1a)一起培育隔夜。在21℃下使培養盤平衡5分鐘後,用PBS將細胞洗滌三次,每次5分鐘,接著在21℃下與以1:200用PBS/BSA 0.1%稀釋之山羊抗兔抗體一
起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著與300 μl Vectastain Elite ABC試劑A+B溶液(Vector Laboratories目錄號PK-6101)一起培育30分鐘;該Vectastain Elite ABC試劑A+B溶液將在與細胞一起培育前30分鐘,在21℃下,藉由依序將2滴試劑A添加至5 ml PBS中並混合,接著添加2滴試劑B並混合來製備。在21℃下用PBS將細胞洗滌3次,每次5分鐘,接著與二胺基聯苯胺(DAB)過氧化酶受質溶液(Vector Laboratories目錄號SK-4105)一起培育直至細胞被染色;在添加至細胞中之前,藉由混合1 ml ImmPACTTM DAB稀釋劑與30 μl ImmPACTTM DAB色原體濃縮物使DAB過氧化酶受質溶液復原。此時,用PBS將細胞簡單洗滌3次且各孔中留有300 μl PBS。使用配備有與Nikon數位觀測設備耦聯之Nikon DS-Ril攝影機的反向Nikon Eclipse TS100顯微鏡,在Dell Latitude D630膝上型電腦之螢幕上直接分析24孔盤之各孔內的細胞染色。個別孔之相片將使用與Nikon攝影機一起提供之軟體NIS-Elements D 3.0來拍攝。
此實驗之目的在於使用稱為酶聯免疫吸附分析法(ELISA)之技術,根據化合物上調不同細胞中SCN1A蛋白質表現之能力對化合物進行分級。
材料與方法:將藉由ELISA對細胞所產生之SCN1A蛋白質之量進行定量。為達成此目的,將使用適當生長條件使
細胞在24孔盤中生長。在添加小化合物後48小時,移出培養基且用無鈣及鎂之杜爾貝科氏磷酸鹽緩衝生理鹽水(PBS)(Mediatech目錄號21-031-CV)將細胞洗滌3次。接著丟棄PBS,且在-20℃下使用100 μl 100%甲醇將細胞固定於24孔盤中15分鐘。移除甲醇且用PBS洗滌後,在21℃下將細胞與3%過氧化氫(Fisher Chemical目錄號H325-100)一起培育5分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與100 μl含0.1%牛血清白蛋白(BSA)(Sigma目錄號A-9647)之PBS一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl抗生物素蛋白溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞簡單沖洗3次,接著在21℃下與生物素溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞洗滌3次,接著在4℃下與100微升/孔以1:250用PBS/BSA 0.1%稀釋之針對對應於大鼠Scn1a之C端胺基酸1491-1508的合成狀(EEQKKYYNAMKKLGSKKP)而產生之兔抗體(Abcam目錄號ab24820;已知至少可識別大鼠Scn1a、人類SCN1A以及小鼠Scn1a)一起培育隔夜。在21℃下使培養盤平衡5分鐘後,用PBS將細胞洗滌三次,每次5分鐘,接著在21℃下與以1:200用PBS/BSA 0.1%稀釋之山羊抗兔抗體一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著與300 μl Vectastain Elite ABC試劑A+B溶液(Vector Laboratories目錄號PK-6101)一起培育30分鐘;該Vectastain Elite ABC試劑A+B溶液將在與細胞一起培育前
30分鐘,在21℃下,藉由依序將2滴試劑A添加至5 ml PBS中並混合,接著添加2滴試劑B並混合來製備。在21℃下用PBS將細胞洗滌3次,持續5分鐘,接著與四甲基聯苯胺(TMB)過氧化酶受質溶液(Thermo Scientific目錄號N301)一起培育。在上清液變藍後,將其轉移至新的96孔ELISA盤(Greiner bio one目錄號65121)中且添加1 M硫酸。使用Multiskan Spectrum光譜儀(Thermo Scientific)在450 nm下讀取吸光度。將用作為初級抗體之兔抗小鼠IgG(Abcam目錄號ab6709)染色之孔中讀取的背景信號自所有SCN1A及肌動蛋白讀數中減去。使用得自Abcam之兔抗肌動蛋白抗體(目錄號ab1801)。針對肌動蛋白信號校正各條件之SCN1A信號且比較各實驗變異體之校正值。
此實驗之目的在於使用稱為即時PCR之技術來確定上調SCN1A mRNA之化合物均不對不同細胞中之肌動蛋白mRNA具有任何作用。
材料與方法。自在適當培養條件下生長之細胞中收集總RNA。為達成此目的,在添加小化合物後48小時移出培養基,且使用得自Promega之SV總RNA分離系統(目錄號Z3105)或得自Qiagen之RNeasy總RNA分離套組(目錄號74181)按照製造商說明書自細胞中萃取RNA。將600奈克RNA添加至使用得自Thermo Scientific之Verso cDNA套組(目錄號AB1453B)或大容量cDNA反轉錄套組(目錄號4368813)或得自Invitrogen之SuperScript VILO cDNA合成
套組(目錄號11754-250)如製造商方案中所述進行之反轉錄反應中。使用得自此反轉錄反應之cDNA,藉由即時PCR,使用ABI Taqman基因表現混合物(Applied Biosystems Inc.,Foster City CA,目錄號4369510)及由ABI設計之肌動蛋白特異性引子/探針(Applied Biosystems Taqman基因表現分析,用於人類肌動蛋白為目錄號Hs99999903_m1*、用於獨猴肌動蛋白為目錄號Rh03043379_gH或用於小鼠肌動蛋白為目錄號Mm00607939_s1*)來監測基因表現。將使用以下PCR循環:50℃,2分鐘;95℃,10分鐘;40個循環(95℃,15秒;60℃,1分鐘);使用StepOne Plus即時PCR機器(Applied Biosystems Inc.,Foster City CA)。用反義寡核苷酸處理後之基因表現倍數變化將基於經處理樣品與經假轉染樣品之間的經18S校正之dCt值之差來計算。
此實驗之目的在於確定上調SCN1A蛋白質之化合物均不對相同條件下所偵測之肌動蛋白具有任何作用,如藉由免疫組織化學所見。若上調SCN1A之化合物不改變肌動蛋白之量,則將假定肌動蛋白可作為用於校正之對照組用於對SCN1A蛋白質進行ELISA定量。
材料與方法。將藉由免疫組織化學偵測細胞內之肌動蛋白。為達成此目的,在添加小化合物後48小時,移出培養基且用無鈣及鎂之杜爾貝科氏磷酸鹽緩衝生理鹽水(PBS)(Mediatech目錄號21-031-CV)將細胞洗滌3次。接著
丟棄PBS,且在-20℃下使用300 μl 100%甲醇將細胞固定於24孔盤中15分鐘。移除甲醇且用PBS洗滌後,在21℃下將細胞與3%過氧化氫(Fisher Chemical目錄號H325-100)一起培育5分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl含0.1%牛血清白蛋白(BSA)(Sigma目錄號A-9647)之PBS一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著在21℃下與300 μl抗生物素蛋白溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞簡單沖洗3次,接著在21℃下與生物素溶液(Vector Laboratories目錄號SP-2001)一起培育30分鐘。用PBS將細胞洗滌3次,接著在4℃下與300微升/孔以1:250用PBS/BSA 0.1%稀釋之針對源自於人類肌動蛋白殘基350-450內之合成肽而產生之兔抗體(Abcam目錄號ab1801;已知可識別β及γ人類、小鼠及大鼠肌動蛋白)一起培育隔夜。在21℃下使培養盤平衡5分鐘後,用PBS將細胞洗滌三次,每次5分鐘,接著在21℃下與以1:200用PBS/BSA 0.1%稀釋之山羊抗兔抗體一起培育30分鐘。用PBS將細胞洗滌3次,持續5分鐘,接著與300 μl Vectastain Elite ABC試劑A+B溶液(Vector Laboratories目錄號PK-6101)一起培育30分鐘;該Vectastain Elite ABC試劑A+B溶液將在與細胞一起培育前30分鐘,在21℃下,藉由依序將2滴試劑A添加至5 ml PBS中並混合,接著添加2滴試劑B並混合來製備。在21℃下用PBS將細胞洗滌3次,持續5分鐘,接著與二胺基聯苯胺(DAB)過氧化酶受質溶液(Vector Laboratories目錄
號SK-4105)一起培育直至細胞被染色;在添加至細胞中之前,藉由混合1 ml ImmPACTTM DAB稀釋劑與30 μl ImmPACTTM DAB色原體濃縮物使DAB過氧化酶受質溶液復原。此時,用PBS將細胞簡單洗滌3次且各孔中留有300 μl PBS。使用配備有與Nikon數位觀測設備耦聯之Nikon DS-Ril攝影機的反向Nikon Eclipse TS100顯微鏡,在Dell Latitude D630膝上型電腦之螢幕上直接分析24孔盤之各孔內的細胞染色。個別孔之相片將使用與Nikon攝影機一起提供之軟體NIS-Elements D 3.0來拍攝。
此實驗之目的在於確定由小化合物上調SCN1A蛋白質將增加海馬GABA激導性中間神經元中之鈉電流振幅,此處據顯示在德拉韋特症候群中受影響。
材料與方法:藉由在以95% O2及5% CO2連續氧化之緩衝液中依序用鏈黴蛋白酶及嗜熱菌蛋白酶消化而自11至16天齡大鼠中離散出海馬GAD陽性雙極性細胞(GABA激導性中間神經元)。將離散細胞接種於組織培養盤中且用所選小化合物處理24小時,此後進行電生理學記錄。使用全細胞膜片鉗技術用EPC-9膜片鉗放大器(HEKA)記錄電流。使用P-97型Flaming-Brown微電極拉製儀(Sutter Instrument)製造膜片吸移管。使用PULSE程式(7.5版;HEKA Elektronik)進行刺激及資料獲取。
對於電壓鉗實驗,使用蠕動泵將含有19.1 mM NaCl、
19.1 mM氯化四乙銨、0.95 mM BaCl2、1.90 mM MgCl2、52.4 mM CsCl、0.1 mM CdCl2、0.95 mM CaCl2、9.52 mM HEPES、117 mM葡萄糖之灌注緩衝液(pH 7.35)持續灌注於細胞上。膜片吸移管將含有157 mM N-甲基-d-葡糖胺、126 mM HCl、0.90 mM NaCl、3.60 mM MgCl2、9.01 mM EGTA、1.80 mM ATP-Na2、9.01 mM HEPES、4.50 mM肌酸-磷酸鹽,pH 7.2。將細胞保持在-100 mV下且自-60 mV至-15 mV以5 mV增量施加去極化步驟。測定且比較經處理與未經處理之神經元的最大電流密度。
此實驗之目的在於確定由小化合物上調SCN1A蛋白質不改變海馬GABA激導性中間神經元中之鈉電流特徵,此處據顯示在德拉韋特症候群中受影響。
材料與方法。藉由在以95% O2及5% CO2連續氧化之緩衝液中依序用鏈黴蛋白酶及嗜熱菌蛋白酶消化而自11至16天齡大鼠中離散出海馬GAD陽性雙極性細胞(GABA激導性中間神經元)。將離散細胞接種於組織培養盤中且用所選小化合物處理24小時,此後進行電生理學記錄。使用全細胞膜片鉗技術用EPC-9膜片鉗放大器(HEKA)記錄電流。使用P-97型Flaming-Brown微電極拉製儀(Sutter Instrument)製造膜片吸移管。使用PULSE程式(7.5版;HEKA Elektronik)進行刺激及資料獲取。對於電壓鉗實驗,使用蠕動泵將含有19.1 mM NaCl、19.1 mM氯化四乙銨、0.95
mM BaCl2、1.90 mM MgCl2、52.4 mM CsCl、0.1 mM CdCl2、0.95 mM CaCl2、9.52 mM HEPES、117 mM葡萄糖之灌注緩衝液(pH 7.35)持續灌注於細胞上。膜片吸移管將含有157 mM N-甲基-d-葡糖胺、126 mM HCl、0.90 mM NaCl、3.60 mM MgCl2、9.01 mM EGTA、1.80 mM ATP-Na2、9.01 mM HEPES、4.50 mM肌酸-磷酸鹽,pH 7.2。將細胞保持在-100 mV下且自-60 mV至-15 mV以5 mV增量施加去極化步驟。活化曲線(電導/電壓關係)將根據g=INa/(V-ENa)由電流/電壓關係計算,其中INa表示在電位V下所量測之峰值鈉電流,且ENa表示平衡電位。將擬合波耳茲曼函數以校正活化及不活化曲線,且確定曲線特徵。將藉由使電流衰減擬合單指數函數來評估不活化時間常數。將比較經處理與未經處理之細胞的活化及不活化概況以確定處理是否改變電流特徵。
對於電流鉗實驗,將細胞保持在-80 mV下,且在以10 pA之增量施加800 ms脈衝後記錄其放電模式。電極緩衝液將含有135 mM葡萄糖酸鉀、20 mM KCl、2 mM MgCl2、2 mM ATPNa2、0.3 mM GTP-Na及10 mM HEPES、0.2 mM EGTA,pH 7.3。灌注緩衝液將含有140 mM NaCl、5 mM KCl、2 mM CaCl2、1 mM MgCl2、10 mM HEPES及10 mM葡萄糖,pH值用NaOH調節至7.4。將量測並比較經處理與未經處理之海馬抑制性中間神經元的輸入-輸出關係(作用電位/注入pA之數值)、作用電位半寬度、尖峰幅度及尖峰衰減。
單通道電流記錄將在外部/外膜片組態下使用與上文關於全細胞膜片記錄所述相同之溶液及方案來進行。
此實驗之目的在於檢查細胞中SCN1A蛋白質上調是否引起細胞內鈉含量變化。在給予小化合物後給表現不同量之SCN1A之細胞加載Na+特異性染料。作為細胞內Na+濃度變化之陽性對照組,將使用作為Na+離子載體之莫能菌素及短桿菌肽。
材料與方法。使細胞在96孔盤中生長且給予不同濃度之小化合物。48小時後,用洛克緩衝液(8.6 mM HEPES、5.6 mM KCl、154 mM NaCl、5.6 mM葡萄糖、1.0 mM MgCl2、2.3 mM CaCl2、0.0001 mM甘胺酸,pH 7.4)洗滌細胞。在將染料加載於細胞內之前量測螢光背景。藉由在37℃下將細胞與染料以及含10 μM SBFI-AM(結合Na+之染料)、0.04% Pluronic F-127(Molecular Probes,OR,USA)及2.5 mM丙磺舒之洛克緩衝液(50微升/孔)一起培育1小時來將染料加載於細胞內。此時,用含2.5 mM丙磺舒之洛克緩衝液(150微升/孔)將細胞洗滌兩次。將含有經加載之細胞的培養盤置於諸如FLEXstationTM II(Molecular Devices,Sunnyvale,CA,USA)之讀數器內。在340 nm及380 nm下激發加載有染料之細胞;在505 nm下記錄發射信號。此時量測信號基線。量測信號基線後,將莫能菌素(EMD,Gibbstown,NJ,USA,目錄號475895)或短桿菌肽(EMD,Gibbstown,NJ,USA,目錄號368020-25MG)添加
至含細胞之個別孔中作為陽性對照組。將使用TTX(1 μM)處理作為陰性對照組。接著將確定經活性化合物預處理之細胞中活性SCN1A於質膜處之相對表現(與媒劑對照組相比)。將使用Excel軟體以505 nm下之發射與340 nm/380 nm之比率來計算信號。
此實驗之目的在於檢查細胞中SCN1A蛋白質上調是否引起個別細胞之細胞內鈉含量變化。在給予小化合物後給表現不同量之SCN1A之細胞加載Na+特異性染料。作為細胞內Na+濃度變化之陽性對照組,將使用作為Na+離子載體之莫能菌素及短桿菌肽。
材料與方法。使細胞在蓋玻片上或在96孔盤中生長且給予不同濃度之小化合物。48小時後,用洛克緩衝液(8.6 mM HEPES、5.6 mM KCl、154 mM NaCl、5.6 mM葡萄糖、1.0 mM MgCl2、2.3 mM CaCl2、0.0001 mM甘胺酸,pH 7.4)洗滌細胞。在將染料加載於細胞內之前量測螢光背景。藉由在37℃下將細胞與染料以及含10 μM SBFI-AM(結合Na+之染料)、0.04%普洛尼克酸F-127及2.5 mM丙磺舒之洛克緩衝液(50微升/孔)一起培育1小時而將染料加載於細胞內。此時用含2.5 mM丙磺舒之洛克緩衝液將細胞洗滌兩次(150微升/孔)。將96孔盤中或蓋玻片上之細胞置於裝備有用於激發及發射之汞燈及適當濾光片的落射螢光顯微鏡(得自Omega Optical Inc,Brattleboro,VT,USA,目錄號:套件X-F04-2;或得自Chroma Technology Corp,
Falls,VT,USA,目錄號79001)下。在340 nm及380 nm下激發加載有染料之細胞;在505 nm下記錄發射信號。量測信號基線後,將莫能菌素(EMD,Gibbstown,NJ,USA,目錄號475895)或短桿菌肽(EMD,Gibbstown,NJ,USA,目錄號368020-25MG)添加至含細胞之個別孔中作為陽性對照組。為確定活性SCN1A於質膜處之相對上調,將經活性化合物預處理之細胞與媒劑對照組相比。藉由連接至落射螢光顯微鏡之攝影機收集資料且使用適當軟體進行定量。將藉由使用Excel軟體計算505 nm發射與340 nm/380 nm之比率來處理原始信號。
雖然已關於一或多個實施例說明及描述本發明,但熟習此項技術者在閱讀及理解本說明書及附圖後應能想到等效變化及改進。另外,儘管可能僅關於若干實施例之一來揭示本發明之特定特點,但當任何既定或特定應用可能需要及對任何既定或特定應用有利時,該特點可與其他實施例之一或多個其他特點組合。
本發明之摘要將允許讀者快速確定技術揭示內容之性質。其呈遞如下理解:其將不會用於解釋或限制以下申請專利範圍之範疇或意義。
圖1展示用小化合物以1 μM之濃度治療後攜帶德拉韋特相關突變之初級皮膚纖維母細胞(陰影線條柱)及成熟初級角質細胞(空心條柱)中SCN1A mRNA含量之增加。
<110> 美商可娜公司
<120> 以小分子治療與電壓門控鈉離子通道α次單元(SCNxA)相關之疾病
<130> SCNxA
<140> 101132597
<140> 2012/09/06
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<151> 2011/09/06
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Claims (17)
- 一種上調生物系統中一或多種電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸或蛋白質之功能及/或表現的活體外方法,該方法包括:使該系統與至少一種選自由以下組成之群的化合物接觸:米那普侖(milnacipran)、托西邁(torsemide)、利培酮(risperidone)、吡那地爾(pinacidil)、貝尼地平(benidipine)、酮康唑(ketoconazole)、依布硒(ebselen)、他達那非(tadalafil)、折侖諾(zeranol)、萘法唑酮(nefazadone)、洛美利嗪(lomerizine)、淫羊藿苷(icariin)、奧美拉唑(omeprazole)、埃索美拉唑(esomeprazole)、L-694,247、尼群地平(nitrendipine)、尼美西泮(nimetazepam)、胺來呫諾(amlexanox)、莫沙必利(mosapride)、舍曲林(sertraline)或司坦唑醇(stanozolol)或其醫藥學上可接受之鹽,藉此調節該生物系統中X型電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸之功能及/或表現。
- 一種活體外上調患者細胞或組織中一或多種I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸或蛋白質之功能及/或表現的方法,該方法包括:使該細胞或組織與至少一種選自由以下組成之群的化合物接觸:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽,藉此活體外調節患者細胞或組織中該I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸之功能及/或表現。
- 如請求項2之方法,其中在活體外該I型電壓門控鈉離子通道α次單元(SCN1A)之功能及/或表現比對照組提高。
- 一種調節至少一種電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸之表現的化合物之用途,其係用於製造供預防或治療與至少一種I型電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸及/或至少一種其編碼產物相關之疾病的藥物,其中該化合物係選自由以下組成之群:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、埃索美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽。
- 如請求項4之用途,其中該疾病為神經疾病。
- 如請求項4之用途,其中該疾病為心血管疾病。
- 如請求項4之用途,其中與該至少一種I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸相關之該疾病係選自:痙攣、疼痛、涉及鈉離子通道功能障礙之電興奮性受損、與鈉離子通道功能障礙相關之疾病、與電壓門控鈉離子通道α次單元活性之失調相關之疾病、由於腸神經系統功能障礙所致之胃腸道疾病;高血壓或充血性心臟衰竭;涉及交感神經及副交感神經分佈之生殖泌尿道疾病;與神經肌肉系統相關之疾病及SCN1A相關之癲癇發作症。
- 如請求項7之用途,其中該與神經肌肉系統相關之疾病係肌肉萎縮症、多發性硬化症、癲癇症、自閉症、偏頭痛、嬰兒期嚴重肌陣攣性癲癇或全身性癲癇伴熱性痙攣附加症(generalized epilepsy with febrile seizure plus(GEFS+))。
- 如請求項8之用途,其中該嬰兒期嚴重肌陣攣性癲癇係德拉韋特症候群。
- 如請求項8之用途,其中該偏頭痛係偶發性或家族性偏癱性偏頭痛。
- 如請求項7之用途,其中該疼痛係慢性疼痛。
- 如請求項7之用途,其中該與電壓門控鈉離子通道α次單元活性之失調相關之疾病係麻痺、高血鉀性週期性麻痺、先天性肌強直病、鉀加重性肌強直、長Q-T症候群3、運動終板疾病或運動失調。
- 如請求項7之用途,其中該由於腸神經系統功能障礙所致之胃腸道疾病係結腸炎、迴腸炎或發炎性腸症候群。
- 如請求項7之用途,其中該涉及交感神經及副交感神經分佈之生殖泌尿道疾病係良性***增生或無力。
- 一種化合物用於製造藥物之用途,該藥物係用於上調生物系統中一或多種電壓門控鈉離子通道α次單元(SCNxA)聚核苷酸或蛋白質之功能及/或表現,其中該化合物係選自由以下組成之群:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、埃索美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽。
- 一種化合物用於製造藥物之用途,該藥物係用於在活體內上調患者細胞或組織中一或多種I型電壓門控鈉離子通道α次單元(SCN1A)聚核苷酸或蛋白質之功能及/或表現,其中該化合物係選自由以下組成之群:米那普侖、托西邁、利培酮、吡那地爾、貝尼地平、酮康唑、依布硒、他達那非、折侖諾、萘法唑酮、洛美利嗪、淫羊藿苷、奧美拉唑、L-694,247、尼群地平、尼美西泮、胺來呫諾、莫沙必利、舍曲林或司坦唑醇或其醫藥學上可接受之鹽。
- 如請求項16之用途,其中該I型電壓門控鈉離子通道α次單元(SCN1A)之功能及/或表現比對照組提高。
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CN103874486A (zh) | 2014-06-18 |
EA029151B1 (ru) | 2018-02-28 |
TW201317360A (zh) | 2013-05-01 |
US20140309181A1 (en) | 2014-10-16 |
WO2013036403A1 (en) | 2013-03-14 |
JP2014525446A (ja) | 2014-09-29 |
JP6125505B2 (ja) | 2017-05-10 |
KR101991980B1 (ko) | 2019-06-21 |
CA2847811C (en) | 2019-10-22 |
CA2847811A1 (en) | 2013-03-14 |
EA201490420A1 (ru) | 2014-12-30 |
MX2014002668A (es) | 2014-06-04 |
KR20140147800A (ko) | 2014-12-30 |
EP2753317A1 (en) | 2014-07-16 |
EP2753317A4 (en) | 2015-04-08 |
CL2014000550A1 (es) | 2014-09-22 |
MX365525B (es) | 2019-06-06 |
EP2753317B1 (en) | 2020-02-26 |
BR112014005234A2 (pt) | 2017-04-11 |
CN108272782B (zh) | 2021-04-23 |
US10583128B2 (en) | 2020-03-10 |
CN108272782A (zh) | 2018-07-13 |
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