TW201408280A - 以斑馬魚模組進行藥物篩選之方法及篩選所得藥物 - Google Patents
以斑馬魚模組進行藥物篩選之方法及篩選所得藥物 Download PDFInfo
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Abstract
本發明係關於一種以斑馬魚近視實驗篩選治療及/或預防近視及錐狀角膜疾病之候選藥物之平台。本發明主要係以透明蛋白(Lumican)、數種富含白氨基酸小多醣蛋白家族(small leucine-rich proteoglycan,SLRP)之一為基礎,其係於膠原纖維生成或影響斑馬魚眼球軸長之基因之調控上扮演重要角色,另外,亦於臨床近視上扮演重要角色。據此,本發明係採用所建立之斑馬魚近視實驗模組,進一步鑑定影響透明蛋白及膠原蛋白原纖維生成之表現之藥物、及/或影響眼球軸長及/或錐狀角膜疾病之調控之藥物。該等藥物係治療近視及/或錐狀角膜疾病之具潛力之候選藥物。
Description
本發明係主張西元2012年5月21日申請之美國臨時專利申請案第61/649,611號之優先權。
本發明係關於一種以斑馬魚作為模組之藥物篩選之方法。尤其是,本發明係關於一種鑑定可影響透明蛋白(Lumican)之表現及膠原蛋白原纖維生成(fibrillogenesis)並可用於治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病之候選化合物之方法,及據此鑑定出之候選化合物。更進一步而言,該方法係鑑定出用以治療及/或預防近視及/或錐狀角膜(keratoconus)疾病之藥物。
近視為全球最常見之眼睛疾患。在西方國家,近視盛行率約為16%~27%,而亞洲國家則可能更高。舉例而言,新加坡華人之近視盛行率為82%。當屈光不正(refractive error)等於或小於-6屈光度(D)時,定義為高度近視;由於其潛在併發症(包含白內障、青光眼、黃斑部病變、及視網膜剝離)可能導致失明,故又稱為「病理性近視」。遺傳因子及環境因子均可能造成近視。已有評估顯示,約一半或更多之人所罹患之近視為軸性近視,由眼球延視軸拉長所造成。出生時,人類眼球軸長約為成人眼球
的三分之二,於軸向上相對較短;因此可推論,年幼孩童應傾向遠視。對於孩童時期之眼睛成長,會發生角膜及水晶體之視力特性之補充性精細調整而增加眼球長度。上述全部過程通常會實際上完美無缺的發生,且眼睛可成為正視(emmetropic)。然而,當此種精細調整過程失敗時,通常會產生拉長之眼球,結果就是較遠的景象會具焦在視網膜平面之前,而造成軸性近視。於臨床試驗中,只有抗膽鹼藥物(anti-cholinergic drugs,例如阿托平(atropine))可用於控制近視之進程。然而,長期使用阿托平控制近視之進程會導致副作用,如視線模糊、便秘、出汗減少、入睡困難、昏眩、困倦、口鼻或皮膚乾燥、頭痛、食慾不振、喪失味覺、噁心、或神經質。因此,發展能控制、預防及/或治療近視之替代藥物仍有需求。
鞏膜薄化,特別是在後極(posterior pole)處,是人類高度近視發展之重要特徵。於靈長類中,鞏膜為纖維狀胞外基質(ECM),由膠原蛋白(主要為第I型膠原蛋白)、彈性蛋白、蛋白聚醣及其他成分所組成,其係排列於由鞏膜纖維母細胞所產生之瓣膜中(參考文獻:Alex Gentle etal.,The Journal of Biological Chemistry,2003,Vol.278,No.19,pp.16587-16594)。鞏膜重塑係關於眾多基因產物(例如膠原蛋白、蛋白聚醣、基質金屬蛋白酶(MMPs)、及金屬蛋白酶之組織抑制劑(TIMPs))之調控作用,包含較小直徑膠原蛋白纖絲(fibrils)、減少之醣胺聚多醣(GAG)成分、減少之核心蛋白聚醣合成、及增加之MMP-2。亦已發現,對於包含膠原蛋白I、MMP-2、MT1-MMP、TIMP-3、及TGF-β之某些蛋白質在mRNA階段之選擇性改變,顯示了視網膜衍生之信號係調控鞏膜基因表現以重塑該鞏膜組織,並調控鞏膜潛變率(參考文獻:John T.Siegwart Jr and Thomas T.Norton,Invest Ophthalmol Vis Sci.2002 July;43(7):2067-2075)。鞏膜重塑係涵蓋於近視進程中,且該等生化改變確實為鞏膜生物機轉性能之改變之前驅者,且最終與近視發生有關。成年人類之鞏膜包含三種主要的蛋白聚醣:聚集蛋白聚醣(aggrecan)、雙糖聚醣(biglycan)、及核心蛋白聚醣(decorin),係建構鞏膜之結構性能。該等蛋白聚醣之比例係隨鞏膜條件而改變。核心蛋白聚醣及雙糖聚醣屬於小型富含白胺酸之蛋白聚醣(SLRPs)類,其亦包含lumican(透明蛋白)、DSPG-3(硫酸皮膚素蛋白多醣-3,PG-L骺蛋白聚糖)、fibromodulin(纖調蛋白)、PRELP(富含脯胺酸-精胺酸及富含白胺酸重複之蛋白質)、keratocan(基質蛋白)、chondroitin(軟骨蛋白)、及骨誘導因子(osteoglycin)。核心蛋白聚醣、雙糖聚醣、透明蛋白、及纖調蛋白結合至第一型膠原蛋白,並影響矩陣(influence matrix)式裝配及組織化。動物實驗顯示該蛋白多醣合成速率係顯著地影響眼球生長及近視發生。於絨猴之鞏膜中,核心蛋白聚醣之合成速率與玻璃體室伸長率呈負相關。雙糖聚醣及透明蛋白於鞏膜中之mRNA表現量,會在實驗誘導性近視期間降低,並於復原期間增加。透明蛋白,為小型富含白胺酸之蛋白聚醣家族之一員,其為角膜基質、大動脈、皮膚、骨骼肌、肺臟、腎臟、骨骼、軟骨及椎間盤等之間質膠原蛋白基質中的主要胞外成分之一。
於角膜組織中,透明蛋白係包含硫酸角質素鍊,以一蛋白多醣而存在;而於非角膜組織中,透明蛋白係以低或非硫酸化之醣蛋白(50-57kDa)存在。此種廣泛分佈之透明蛋白係暗示了其具有複數功能,關於組織型態及維持組織動態平衡。於剔除透明蛋白之小鼠中可觀察到多種臨床表現而良好地證實此點,該小鼠係展現角膜混濁、皮膚及肌腱脆弱、傷
口延遲癒合、及低繁殖力。確實,已顯示透明蛋白在角膜透明性上扮演必要角色,藉由調控膠原蛋白原纖維生成;在傷口癒合上則藉由調控上皮細胞移動;及在受傷水晶體之上皮-間葉組織轉變。透明蛋白缺陷之小鼠及Lum(-/-)Fmod(-/-)小鼠顯示膠原蛋白纖維直徑改變及高度近視之特徵,表示該等蛋白聚醣在鞏膜之生物機轉特性上扮演重要角色。另外,高度近視之相關研究鑑定出潛在基因座MYP1 Xq28)及MYP3(12q21-23),座落於接近或包含數個SLRP基因(包含雙糖聚醣(Xq27ter)、核心蛋白聚醣(12q21-22)、透明蛋白(12q21.3-22)及DSPG3(12q21))。MYP3亦為英國之25%家族性之自體顯性高度近視負責。因此,在以往研究中已找出MYP3基因座與近視發生相關之候選基因,包含核心蛋白聚醣、透明蛋白、及DSPG3受到極高關注。近來,於SLRP基因中之14個新穎突變已展現與高度近視相關;例如,c.893-105G>A於LUM基因中可能具有保護作用、或與一保護性對偶基因具有連鎖性失衡。
斑馬魚為用以研究生物學及發生學之分子遺傳學之受歡迎之脊椎動物模組。在實驗室中,易於管理大量斑馬魚(成魚為3-4cm長)。結合胚胎學及遺傳方法學能夠將斑馬魚建構成極為有力的研究工具。透明胚胎能夠進行研究基礎脊椎動物發展由原腸胚形成至器官發生的過程。另外,可清楚並容易地觀察其胚胎之眼睛、心跳及血液循環。接觸、視覺及行為反應亦可於解剖顯微鏡下監視。多種特徵,如3-4個月之短世代時間,使斑馬魚特別適用於遺傳研究。大多數先前研究,係以化學突變劑ENU產生之多種眼睛突變,報導了縮小之眼睛尺寸及眼軸長度、未組織化之視網膜、獨眼畸形、縮減之神經節細胞層、及光受器減少。Lung-Kun Yeh已單
離出並確認該斑馬魚基質蛋白及透明蛋白基因,並發現於斑馬魚發展時期剔除透明蛋白後,眼球軸長增加,其與兒童近視之臨床發現可相容且有關連性。於兒童近視中,具有孩童眼球軸性延長之類似發現,其在人類透明蛋白基因啟動子處具有SNP之改變。斑馬魚透明蛋白啟動子降低之活性被認為與此種SNP相關。曾提出,身為富含白胺酸之小型胜肽之一員之透明蛋白,係於調控原纖維生成及眼睛發育上扮演重要角色,其可能影響眼球軸長(參考文獻:Lung-Kun Yeh et al.,Journal of Biological Chemistry,2010,Vol.285,No.36,pp.28141-28155)。該文獻亦暗示,藉由反義zlum嗎啉寡聚核苷酸對於zlum表現之下游調控,證實眼部伸長所致軸性近視係肇因於鞏膜中的膠原蛋白纖維排列被破壞,導致鞏膜薄化;以及,於斑馬魚幼魚體內分析顯示,投予蕈鹼類受體拮抗劑(例如,阿托平及派倫西平(pirenzepine))可有效減緩由嗎啉寡聚核苷酸造成之眼部拉長。因此,該文獻係建議斑馬魚可用作篩選近視治療化合物之體內分析模組。
然而,仍有需要進一步探討斑馬魚近視實驗模組於實際近視藥物篩選、以及找出用於控制、預防及/或治療近視之有效藥物之應用。
本發明係提供以具有大眼(big eye)或眼軸長增長(axial length increase)之斑馬魚鑑定出候選化合物之方法,該候選化合物可用於影響透明蛋白之表現及/或膠原蛋白原纖維生成,及/或治療近視及/或錐狀角膜疾病;該方法係包括將一待測化合物與該具有大眼之斑馬魚接觸,以及,若斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
本發明亦提供以透明蛋白基因及/或膠原蛋白原纖維生成相
關基因剔除之斑馬魚鑑定出候選化合物之方法,該候選化合物可用於影響透明蛋白之表現及/或膠原蛋白原纖維生成,及/或治療近視及/或錐狀角膜疾病;該方法係包括將一待測化合物與透明蛋白基因及/或膠原蛋白原纖維生成相關基因剔除之斑馬魚接觸,測定該斑馬魚之大眼數量,以及,若斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
110‧‧‧視網膜
210‧‧‧鞏膜寬度
212‧‧‧RPE寬度
310‧‧‧角膜基質(CS)
312‧‧‧前鞏膜(AS)
314‧‧‧後鞏膜(PS)
316‧‧‧野生型(WT)
318‧‧‧zLum-MO-注射型
本發明包含至少一彩圖。
第1圖係表示,依據本發明之一實施例,該zLum基因抑制斑馬魚於第3-7dpf中之一系列表型變化;第2圖係表示,依據本發明之一實施例,該抑制透明蛋白基因後於眼睛尺寸及眼軸長度之效果;第3(A)-3(H)圖係表示,依據本發明之一實施例,zLum-MO(morpholino)基因抑制係誘發角膜基質(CS)、前鞏膜(AS)、及後鞏膜(PS)之超微結構改變;第4(A)-4(C)圖係表示,依據本發明之一實施例,於該zLum-MO組之鞏膜薄化之超結構改變;第5圖係表示,依據本發明之一實施例,於44個斑馬魚胚胎之受精後2-4天之zLum表現;第6圖係表示,依據本發明之一實施例之西方墨點分析及mRNA治癒分析;第7(A)-7(D)圖係表示,依據本發明之一實施例之斑馬魚藥物篩檢分析;
第8(A)-8(F)圖係表示,依據本發明之一實施例,以處理型式為基礎之於7dpf階段之不同表現型;第9圖係表示,依據本發明之一實施例,阿托平係治癒zLum-基因抑制-嗎啉突變體(morphant);第10圖係表示,依據本發明之一實施例,以馬立馬司他、多西環素、卡特普、美諾四環素氯化氫、阿托平、阿斯匹靈、異丙酚及N-乙醯半胱胺酸處理之斑馬魚之大眼率;第11(A)-11(E)圖係表示,依據本發明之一實施例,以四環黴素(第11(A)圖)、美諾四環素(第11(B)圖)、多西環素(第11(C)圖)、馬立馬司他(第11(D)圖)及巴馬司他(第11(E)圖)處理之斑馬魚之大眼率。
本發明係描述一種使用斑馬魚之平台,用於篩選治療及/或預防近視及錐狀角膜疾病之候選藥物。本發明發現,透明蛋白(SLRPs之一員)於調控原纖維生成及影響斑馬魚眼球軸長之基因上扮演重要角色,另外亦於臨床近視上扮演重要角色。因此,本發明係使用已建立之斑馬魚近視實驗模組進一步鑑定出影響透明蛋白表現及膠原蛋白原纖維生成、及調控眼球軸長之藥物。該等藥物為具有治療近視及錐狀角膜疾病之潛力之候選藥物,包括但不限於,金屬蛋白酶(MMP)抑制劑、TGF-β抑制劑、抗膽鹼或蕈鹼化合物、及COX抑制劑。
於本說明書及申請專利範圍中,除非另有指示,否則單數形式之冠詞「一」、「一種」及「該」係包含其複數型態。例如,術語「一細胞」包含一群細胞,或其混合物。
如此處所用,「表現」係指一聚核苷酸轉錄成mRNA之過程,及/或該聚核苷酸轉錄成mRNA(亦稱為「轉錄產物」)後接著轉譯成胜肽、多肽或蛋白質之程序。
「對照組」係為實驗中,用於比較之一替代主體或樣本。
術語「待測化合物」及「候選化合物」意指任何化學品、藥學品、藥物等,其為一候選藥物,用以達成此處所述之用途,例如增加透明蛋白表現及膠原蛋白原纖維生成、及/或治療或預防近視及/或錐狀角膜疾病。待測化合物包括已知化合物及具有療效之潛力之化合物。經由本發明之方法可決定一待測化合物是否具有療效。
術語「大眼(big eye)或眼軸長增長(axial length increase)」意指眼部之視網膜色素上皮層軸長除以鞏膜軸長之值少於0.7者。
術語「治療」意指延緩疾患發展及/或減輕預期會產生之症狀之嚴重程度。該術語進一步包含改善已存在的症狀或預防症狀。
術語「治療有效量」意指一藥物或藥劑之量,其可以引發一組織系統、動物或人類之生物性或藥學性反應,該反應可被研究者或臨床醫師察覺,該反應係對至少具統計上顯著性之部分之病患造成有益效果,如改善症狀、痊癒、減少疾病負擔。
術語「標的(subject)」意圖包含活的有機體,其對一般所知之條件或疾病、疾病狀態或條件為敏感性,但非限於本說明書所列示。標
的之實例包含人類、狗、貓、牛、羊及小鼠。該術語標的係進一步包含基因轉殖者。
此處所述之術語「烷基」意指一飽和直鍊或支鍊非環狀之烴,具有所示之碳原子數目(如C1-C20、C1-C10、C1-C8、C1-C6、C1-C4等)。代表性飽和直鍊烷基係包含-甲基、-乙基、-正丙基、-正丁基、-正戊基、-正己基、-正庚基、-正辛基、-正壬基及-正癸基;而代表性飽和支鍊烷基係包含-異丙基、-第二丁基、-異丁基、-第三丁基、-異戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基等。
此處所述之術語「烯基」本身或作為其他取代基之部分,意指一不飽和支鍊、直鍊、或環狀之烷基,具有至少一個碳-碳雙鍵,由親代烷之單個碳原子上移除一個氫原子所衍生。此群依雙鍵型式可為順式或反式構形。典型烯基包含,但非限於,乙烯基;丙烯基如1-丙烯-1-基、1-丙烯-2-基、2-丙烯-1-基、2-丙烯-2-基、1-環丙烯-1-基、2-環丙烯-1-基;丁烯基如1-丁烯-1-基、1-丁烯-2-基、2-甲基-1-丙烯-1-基、2-丁烯-1-基、2-丁烯
-2-基、1,3-丁二烯-1-基、1,3-丁二烯-2-基、1-環丁烯-1-基、1-環丁烯-3-基、1,3-環丁二烯-1-基等。於較佳實施例中,該烯基為(C2-C6)烯基。
此處所述之術語「炔基」本身或作為其他取代基之部分,意指一不飽和支鍊、直鍊、或環狀之烷基,具有至少一個碳-碳三鍵,由親代烷之單個碳原子上移除氫原子所衍生。典型炔基包含,但非限於,乙炔基;丙炔基如1-丙炔-1-基、2-丙炔-1-基等;丁炔基如1-丁炔-1-基、1-丁炔-3-基、3-丁炔-1-基等。於一較佳實施例中,該炔基為(C2-C6)炔基。
此處所述之術語「芳基」本身或作為其他取代基之部分,意指具有所示之碳原子數目(即C5-C15意指5至15個碳原子)之單價芳香烴基,係由親代芳香環系之單個碳原子上移除氫原子所衍生。典型芳基包含,但非限於,衍生自醋蒽烯、苊、醋菲烯、蒽、薁、苯、、暈苯、熒、芴、稠六苯、己芬、己烯、不對稱苯并二茚、對稱苯并二茚、二氫茚、茚、萘、十八烯、八苯(octaphene)、艾氏劑(octalene)、卵苯、戊-2,4-二烯、駢苯、併環戊二烯、二苯并菲、苝、菲那烯、菲、苉、七曜烯、芘、吡蒽、玉紅省(rubicene)、苯并菲、三萘等之基團,以及其不同之氫異構物。於一較佳實施例中,該芳基為(C5-C15)芳基,且以(C5-C10)為更佳。
此處所述之術語「雜芳基」本身或作為其他取代基之部分,意指具有所示數目之環原子之單價雜芳基(如:5-14員意指5至14個環原子),藉由自親代雜芳環系之單原子移除一氫原子所衍生。典型的雜芳基係包含,但非限於,衍生自吖啶、苯并咪唑、苯并異噁唑、苯并噁唑、苯并二噁茂、苯并呋喃、苯并哌喃酮、苯并噻二唑、苯并噻唑、苯并三唑、苯并噁嗪、苯并噁唑、苯并噁唑啉、咔唑、β-咔啉、色原烷、色原烯、噌啉、呋喃、咪
唑、吲唑、吲哚、吲哚啉、吲嗪、異苯并呋喃、異色原烯、異吲哚、異吲哚啉、異喹啉、異噻唑、異噁唑、萘啶、噁二唑、噁唑、呸啶、啡啶、菲羅啉、吩嗪、酞嗪、喋啶、嘌呤、哌喃、哌嗪、吡唑、嗒嗪、吡啶、嘧啶、吡咯、吡咯嗪、喹唑啉、喹啉、喹嗪、喹噁啉、四唑、噻二唑、噻唑、噻吩、三唑、呫噸等之基團,以及其不同之氫異構物。於一較佳實施例中,該雜芳基為一5-14員雜芳基,且以5-10員雜芳基為更佳。
於此處所用術語「醫藥上可接受之鹽類及前藥」意指該等羧酸鹽類、酸加成鹽類或鹼加成鹽類,及本發明之該等化合物之前藥,於醫學上足夠的理由,其為適用於與病患組織接觸,無不適當之毒性、刺激性、過敏反應等,具有合理的有益/風險比例,並對本發明化合物之預期應用有效。術語「鹽類」意指本發明化合物之相對無毒性、無機與有機之酸加成鹽類。可於該化合物最終分離及純化期間於原位製備該等鹽類;或將經純化之化合物分開反應,以自由鹼型式與一適當之有機或無機酸反應,再將所形成之鹽類分離出而得。其可包含陽離子,係以鹼金族及鹼土族金屬為基礎者,如鈉、鋰、鉀、鈣、鎂等;及胺類陽離子,包含但不限於,銨、四甲基銨、四乙基銨、甲基胺、二甲基胺、三甲基胺、三乙基胺、乙基胺等(參見例如Berge S.M.,et al.,"Pharmaceutical Salts," J.Pharm.Sci.,1977;66:1-19,以參考文獻之方式併入本文)。
第1圖係描述本發明之一實施例之zLum-基因抑制之魚於3-7dpf之一系列表型改變。伴隨眼睛發育,zLum抑制後之魚逐步形成鞏膜軸長拉長。於第5天,可經由顯微鏡清楚觀察到鞏膜軸長拉長甚至視網膜剝離現象。
第2圖係描述透明蛋白基因-基因抑制對於眼睛尺寸及眼軸長度之效果。如第2圖所示,鞏膜寬度之型態測量以紅線10表示,而RPE寬度以白線212表示。比較透明蛋白嗎啉突變體與野生型在RPE寬度/鞏膜寬度之比例,結果顯示,因鞏膜擴張之透明蛋白基因抑制係導致軸性延長。
第3(A)-(H)圖係描述zLum-MO基因抑制可誘導角膜基質(CS)、前鞏膜(AS)、及後鞏膜(PS)之超微結構改變。第3(A)圖係描述於12dpf階段之野生型斑馬魚之甲苯胺藍染色。該圖係指示角膜基質(CS)310、前鞏膜(AS)312、及後鞏膜(PS)314。第3(B)圖顯示該12dpf齡之野生型WT 316及zLum-MO-注射型318群組,其角膜基質、前與後鞏膜中之膠原蛋白纖維直徑之分析。於zLum-MO組中,角膜基質310及前鞏膜312之膠原蛋白纖維直徑為顯著增加;而後鞏膜314之膠原蛋白纖維直徑於兩組中並無顯著區別。第3(C)-(H)圖係膠原蛋白纖維結構之表型比較,第3(C)及(D)圖為角膜基質、第3(E)及(F)圖為前鞏膜組織、第3(G)及(H)圖為後鞏膜組織;對照組為第3(C、E、G)圖,而zLum-MO-注射組為第3(D、E、F)圖,於12dpf階段。第3(C)圖係TEM顯微照相,顯示野生型組中,規則且較小的角膜基質內之膠原蛋白纖維結構。第3(D)圖係zLum-MO-注射組之角膜基質,可發現膠原蛋白纖維直徑增加且不規則排列。第3(E)圖係TEM顯微照相,顯示野生型組中,前鞏膜內之膠原蛋白呈相對規則之纖維結構。第3(F)圖係zLum-MO-注射組之前鞏膜,膠原蛋白纖絲不規則且纖維直徑增加。第3(G)圖係相鄰視網膜之頂部,TEM顯微照相顯示於野生型組中,座落於後鞏膜之膠原蛋白之纖維結構。第3(H)圖係相鄰視網膜之頂部,TEM顯微照相顯
示於zLum-MO-注射組中,後鞏膜中不規則的膠原蛋白纖維結構。第3(C)-(H)圖之比例尺為100nm。
第4(A)-(C)圖為zLum-MO組之鞏膜薄化之超微結構改變。於第4(A)圖中,該頂部係相鄰視網膜;於7dpf階段之野生型斑馬魚之後鞏膜中,可發現兩到三層之鞏膜纖維母細胞之細胞,其具有膠原蛋白纖維形成於層間。於第4(B)圖中,該頂部係相鄰視網膜;於7dpf階段之zLum-MO-注射型斑馬魚之後鞏膜中,僅發現僅一至兩層之纖維母細胞之細胞。於第3(C)圖中,可明顯觀察到於7dpf階段之zLum-MO-注射型斑馬魚之鞏膜薄化。於12dpf階段之zLum-MO-注射型斑馬魚中,該表現型會更為顯著。尤其是,與野生型相較,可觀察到zLum-MO-注射型斑馬魚於7及12dpf階段之後鞏膜之鞏膜薄化明顯。第4(A)及(B)圖中,比例尺為1.5um。
第5圖係描述受精後2~4日之44個斑馬魚胚胎之zLum表現。以全胚原位雜交法,zLum mRNA自3dpf起,係專一性表現於斑馬魚之鞏膜中。
第6圖係描述西方墨點法及mRNA復原分析。如第6圖所示,左欄為西方墨點法分析,於透明蛋白嗎啉突變體中之透明蛋白、膠原蛋白1a1、TGF-β、及TIMP2降低。反之,如右欄所示,MMP2表現增加。以透明蛋白及膠原蛋白1a1之mRNA可復原異常大眼。然而,異常大眼亦可由ppih、hsp 47、及rx1之mRNA復原,其係分別關於膠原蛋白纖維形成及眼睛發育。
第7(A)-(D)圖係描述一種斑馬魚藥物篩選分析。第7(A)及(B)圖係說明並定義斑馬魚中之視網膜色素上皮層之外緣(RPE(紅色))及鞏
膜直徑(D(綠色))。第7(C)圖係說明於7dpf階段之zLum-MO-注射型斑馬魚之過度軸伸長,於0.5%阿托平(A)及0.25%派倫西平(P)處理後,係顯著降低;而以0.01%美索屈明(M)處理後則無明顯改變;行1:WT、行2:MO+0.5%A、行3:MO+0.25%P、行4:MO+0.01%M、行5:MO。以0.5%阿托平及0.25%派倫西平處理後,於7dpf階段之zLum-MO-注射型斑馬魚之鞏膜直徑顯著降低,而以0.01%美索屈明處理之zLum-MO-注射組則無明顯改變,行6:WT、行7:MO+0.5%A、行8:MO+0.25%P、行9:MO+0.01%M、行10:MO。第7(D)圖係說明因zLum蛋白質減少所致之眼部拉長期間,RPE/鞏膜之比例(%)明顯降低。一些蕈鹼受體拮抗劑(阿托平及派倫西平)可弱化因zLum蛋白質減少所致之該RPE/鞏膜之降低之比例,而美索屈明處理組之RPE/鞏膜之降低比例則無明顯改變,行1:WT、行2:MO+0.5%A、行3:MO+0.25%P、行4:MO+0.01%M、行5:MO。
第8(A)-(F)圖係描述於7dpf階段之野生型斑馬魚之正常表現型(第8(A)圖)、於7dpf階段之RS-MO-注射之胚胎之正常表現型(第8(B)圖)、於7dpf階段之zLum-MO-注射型斑馬魚之明顯拉長之眼球(第8(C)圖)、以0.5%阿托平處理2天後,於7dpf階段之zLum-MO-注射之幼魚之眼部拉長係明顯減少(第8(D)圖)、以0.25%派倫西平處理2天後,於7dpf階段之zLum-MO-注射之幼魚之眼部拉長係明顯減少(第8(E)圖)、及以0.01%美索屈明處理後,於7dpf階段之zLum-MO-注射型斑馬魚之表現型無明顯改變(第8(F)圖)。
第9圖係描述阿托平可復原zLum基因抑制嗎啉突變體。其可反轉透明蛋白、膠原蛋白1a1、TGF-β、MMP2及TIMP2之表現,其於透明蛋白嗎啉突變體中表現降低。
第10圖係以馬立馬司他(marimastat)、多西環素、卡特普、美諾四環素氯化氫、阿托平、阿斯匹靈、異丙酚及N-乙醯半胱胺酸處理之斑馬魚之大眼率。
第11(a)-(e)圖係描述以四環黴素(第11(a)圖)、美諾四環素(第11(b)圖)、多西環素(第11(c)圖)、馬立馬司他(第11(d)圖)、及巴馬司他(第11(e)圖)處理之斑馬魚之大眼率。
於一面向中,本發明係提供以具有大眼之斑馬魚鑑定出候選化合物之方法,該候選化合物可用於影響透明蛋白之表現及/或膠原蛋白原纖維生成,及/或治療近視及/或錐狀角膜疾病;該方法係包括將一待測化合物與該具有大眼之斑馬魚接觸,以及,若斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。於一實施例中,若相對於對照組之斑馬魚(未以該待測化合物處理)之大眼之總數量,該受測斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
於另一面向中,本發明係提供以透明蛋白基因及/或膠原蛋白原纖維生成相關基因剔除之斑馬魚鑑定出候選化合物之方法,該候選化合物可用於影響透明蛋白之表現及/或膠原蛋白原纖維生成,及/或治療近視及/或錐狀角膜疾病;該方法係包括將一待測化合物與透明蛋白基因及/或膠原蛋白原纖維生成相關基因剔除之斑馬魚接觸,測定該斑馬魚之大眼數量,以及,若斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。於
一實施例中,若相對於該斑馬魚之眼睛之總數量、或對照組斑馬魚(未以該待測化合物處理)之大眼之總數量,該受測斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
於一實施例中,本發明係提供一種鑑定候選化合物之方法,該候選化合物係影響透明蛋白之表現及膠原蛋白原纖維生成,及/或眼球軸長之調控,該方法包括:(a)於複數斑馬魚之受精胚胎中,導入該透明蛋白基因及/或膠原蛋白原纖維生成相關基因之反義mRNA或該反義mRNA之類似物;(b)將由步驟(a)所得斑馬魚暴露於一待測化合物下達足夠長之時間,接著收集該斑馬魚;以及(c)測定該斑馬魚之大眼數量,以及,若該斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
步驟(a)之反義mRNA為透明蛋白或基質蛋白反義mRNA。較佳地,步驟(b)之該基因抑制(knockdown)之斑馬魚係於其眼球形成期暴露於該待測化合物下。較佳地,步驟(b)之斑馬魚係於其角膜發育階段被收集。較佳地,若相對於該斑馬魚之眼睛總數量或對照組斑馬魚之大眼總數量,該斑馬魚之大眼率降低,則可將步驟(c)之待測化合物定義為候選化合物。綜上述,該方法係包括下列步驟:(a)於複數斑馬魚之受精胚胎中,導入該透明蛋白基因及/或膠原蛋白原纖維生成相關基因之反義mRNA或該反義mRNA之類似物;(b)將由步驟(a)所得斑馬魚暴露於一待測化合物下達足夠長之時間,接著收集該斑馬魚;以及
(c)測定該斑馬魚之大眼數量,以及,若相對於該斑馬魚之眼睛之總數量、或對照組斑馬魚(未以該待測化合物處理)之大眼之總數量,該受測斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
於另一實施例中,本發明係提供一種鑑定治療及/或預防近視及/或錐狀角膜疾病之候選化合物之方法,包括:(a)於複數斑馬魚之受精胚胎中,導入該透明蛋白基因及/或膠原蛋白原纖維生成相關基因之反義mRNA或該反義mRNA之類似物;(b)將由步驟(a)所得斑馬魚暴露於一待測化合物下達足夠長之時間,接著收集該斑馬魚;以及(c)測定該斑馬魚之大眼數量,以及,若該受測斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
較佳地,步驟(a)之反義mRNA為透明蛋白或基質蛋白之反義mRNA。較佳地,步驟(b)之該基因抑制之斑馬魚係於其視環形成期暴露於該待測化合物下。較佳地,該步驟(b)所得斑馬魚係於其角膜發育階段進行收集。較佳地,若相對於該斑馬魚之眼睛之總數量、或對照組斑馬魚之大眼之總數量,該受測斑馬魚之大眼率降低,則可定義步驟(c)之該待測化合物為候選化合物。如上述,該方法係包括下列步驟:(a)於複數斑馬魚之受精胚胎中,導入該透明蛋白基因及/或膠原蛋白原纖維生成相關基因之反義mRNA或該反義mRNA之類似物;(b)將由步驟(a)所得斑馬魚暴露於一待測化合物下達足夠長之時間,接著收集該斑馬魚;以及
(c)測定該斑馬魚之大眼數量,以及,若相對於該斑馬魚之眼睛之總數量、或對照組斑馬魚(未以該待測化合物處理)之大眼之總數量,該受測斑馬魚之大眼率降低,則可定義該待測化合物為候選化合物。
此處所述之篩選分析係提供鑑定可影響透明蛋白之表現、及膠原蛋白原纖維生成、及調控眼球軸長、及治療及/或預防近視及錐狀角膜疾病之化合物之方法,利用降低透明蛋白基因抑制之斑馬魚之拉長之眼球之比例作為可影響透明蛋白之表現、及膠原蛋白原纖維生成、及治療及/或預防近視及錐狀角膜疾病之化合物之指示。
於此處所述分析法鑑定出之化合物,為候選化合物,其可用於(i)影響透明蛋白之表現、及膠原蛋白原纖維生成、及調控眼球軸長,及/或(ii)作為先導化合物,以建構可用於治療及/或預防近視及錐狀角膜疾病之相關化合物。
透明蛋白為數種SLRP之一員,於斑馬魚中調控原纖維生成或影響眼球軸長之基因上扮演重要角色,另外,於臨床近視上亦扮演重要角色。類似於人類及小鼠之基質蛋白及透明蛋白基因,斑馬魚之基質蛋白及透明蛋白基因具有SLRP之所有結構特徵,即,一富含白胺酸重複片段之中心域(domain),兩側為具有保留性半光胺酸之N端域及C端域。斑馬魚之基質蛋白及透明蛋白聚醣基因之尺寸及結構,與哺乳類之基質蛋白及透明蛋白聚醣基因相似。有趣的是,斑馬魚之透明蛋白及基質蛋白基因兩者係可定位至相同基因組。另外,相似於哺乳類之基質蛋白及透明蛋白聚醣基因,該斑馬魚之基質蛋白及透明蛋白聚醣基因為少-TATA基因。又,於
斑馬魚及哺乳類之間,於角膜表現之基質蛋白及透明蛋白聚醣之最顯著差異為,於前者係主要表現於角膜上皮層,而非基質層(角膜細胞)。其亦為研究發育生物學之具潛力領域。
令人驚訝地,眼球軸長增加(即,大眼)係與斑馬魚發育期間之斑馬魚透明蛋白、基質蛋白及/或膠原蛋白原纖維生成相關基因之基因抑制有關,其臨床表現近似於孩童近視之臨床發現。於孩童近視之患者中,孩童之眼球軸性拉長係與人類透明蛋白基因啟動子之SNP改變相關。藉由反義股或其類似物達成之基因抑制,以降低斑馬魚之透明蛋白、基質蛋白及/或膠原蛋白原纖維生成相關基因之表現量,可模擬造成於患者中觀察所得此SNP所致之軸性拉長之分子機制。依據本發明,係將透明蛋白之反義mRNA導入斑馬魚之受精胚胎中,以獲得一透明蛋白基因抑制之斑馬魚。於一實施例中,該透明蛋白反義股為嗎啉寡聚核苷酸(morpholino)。較佳地,該嗎啉寡聚核苷酸具有下列序列:5’-GATCCCAGAGCAAACATGGCTGCAC-3’。
胚胎發育期間之外部發育及視覺清晰度使得早期發育程序之觀察分析為可行,且高產率及世代時間短亦有利於基因分析。斑馬魚成魚之眼睛為正視,且可傳送可見光波長及紫外線波長,此由成魚對紫外線波長之反應可證實。斑馬魚眼睛發育係類似於其他魚類及哺乳類之眼睛發育。於受精後(postfertilization,縮寫hpf)約12小時由眼原基開始。至約24hpf時眼杯發育良好,及至約30hpf時,於腹側鼻部(ventronasal)視網膜之小區
域中發現神經節細胞。至約50hpf時,該視網膜層成為該視網膜之明顯穿越部分。斑馬魚幼魚為遠視並於72hpf成為正視,此時亦為眼球外肌呈現成魚化及光動反應明顯之相同時期。
依據本發明,該基因抑制之斑馬魚係於其視環形成階段時,暴露於一待測化合物下。通常在受精後約24小時,斑馬魚之視環形成。該基因抑制之斑馬魚可於其視環形成階段時,暴露於該待測化合物下。該基因抑制之斑馬魚與該待測化合物接觸之後,待測化合物若為潛在候選化合物,則可開始活化透明蛋白之表現及膠原蛋白原纖維生成,從而降低眼球拉長現象,並可治療及/或預防近視及/或錐狀角膜疾病。視網膜水晶體約於受精後48小時發育,而鞏膜及角膜約於受精後72小時發育。於鞏膜及角膜發育階段收集該斑馬魚。
斑馬魚大眼為近視之指標。如此處所採,「大眼」意指眼球軸長拉長之眼睛,及表示視網膜色素上皮層軸長除以鞏膜軸長之值少於0.7者。視網膜色素上皮層軸長及鞏膜軸長可由本領域已知任何方式測量,如解剖顯微鏡。
若相對於該斑馬魚之眼睛總數量或對照組斑馬魚(未以該待測化合物處理)之大眼總數量而言,大眼率降低,則該待測化合物可被定義為影響透明蛋白之表現及/或膠原蛋白原纖維生成及/或調控眼球軸長,及/或治療及/或預防近視及/或錐狀角膜疾病。較佳地,若相對於該斑馬魚之眼睛總數量或對照組斑馬魚(未以該待測化合物處理)之大眼總數量而言,大眼數量之比例低於30%,則該待測化合物可被定義為候選化合物。較佳
地,該比例係低於15%。更佳地,該比例降低至約0%至約30%、約0%至約25%、約0%至約20%、約0%至約15%、約0%至約10%、約1%至約30%、約1%至約25%、約1%至約20%、約1%至約15%。
於進一步之面向中,待測化合物之篩選係藉由鑑定出該待測化合物之群組中可降低斑馬魚大眼率至低於30%者而完成。可降低該大眼率之待測化合物於此處亦稱為「候選化合物」。
本發明之篩選方法亦可用於鑑定可降低該透明蛋白基因抑制之斑馬魚之大眼率之化合物,例如:有機或無機小分子(分子量低於1,000Da)、寡胜肽、寡核苷酸、或碳水化合物。如此處所採,一「待測化合物」可為任何化學化合物,例如:巨分子(如胜肽、蛋白質複合物、醣蛋白、或核酸)或小分子(如胺基酸、核苷酸、有機或無機化合物)。待測化合物可具有每莫耳低於約10,000公克之化學式量、低於5,000公克每莫耳、低於1,000公克每莫耳、或低於500公克每莫耳。該待測化合物可為天然發生(如藥草或天然產物)、合成者、或可包含天然及合成成分兩者。待測化合物之實例包含金屬蛋白酶抑制劑、膠原蛋白酶抑制劑、TGF-β途徑活化劑、TGF-β抑制劑及Cox抑制劑。
於一實施例中,本發明係提供一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之MMP抑制劑予一病患。
金屬蛋白酶(MMPs)亦被認為於例如細胞增殖、移動(貼附/分散)、分化、血管生成、凋亡及宿主防禦之細胞行為上扮演主要角色。金屬蛋白酶之抑制劑為已知。實例包含天然生化物質,如金屬蛋白酶之組織抑制劑(TIMPs)、α2-巨球蛋白、及其類似物或衍生物。已報導過許多類胜肽較小化合物可抑制金屬蛋白酶。含硫基之醯胺或以肽基醯胺為基礎之金屬蛋白酶(MMP)抑制劑為已知,如下述參考文獻所示,例如WO95/12389、WO96/11209及美國專利公告號4,595,700。含異羥肟酸鹽基之MMP抑制劑亦揭露於許多已公開之專利申請案中,如WO 95/29892、WO 97/24117、WO 97/49679及EP 0 780 386,其揭露碳骨架化合物,以及WO 90/05719、WO 93/20047、WO 95/09841、及WO 96/06074,其揭露具有肽基骨架或擬肽物骨架之異羥肟酸鹽。另外,亦已報導其他以嘧啶為基礎之MMP抑制劑、以羥基吡喃酮為基礎之MMP抑制劑、以磷為基礎之MMP抑制劑、及以四環黴素為基礎之MMP抑制劑(參考文獻:Cancer Metastasis Rev.,2006,25:115-136)。
依據本發明之一實施例,該MMP抑制劑為一擬肽物異羥肟酸鹽MMP抑制劑,具有下式(I)或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物:
其中,
Q不存在或;X為C1-10伸烷基、C2-10伸烯基或C2-10伸炔基,未經取代或經一個或多個OH取代、C1-10直鍊或支鍊烷基、C2-10直鍊或支鍊烯基、C1-10烷基C5-15芳基、C1-10烯基C5-15芳基、C1-10炔基C5-15芳基、C1-10烷基巰基C5-15芳基、C1-10烷基磺醯基C5-15芳基、C1-10烷基亞磺醯基C5-15芳基、C1-10烷氧基或C5-15芳基;Y為C1-10伸烷基、C2-10伸烯基或C2-10伸炔基,未經取代或經一個或多個OH取代、C1-10直鍊或支鍊烷基、C2-10直鍊或支鍊烯基、C1-10烷基C5-15芳基、C1-10烯基C5-15芳基、C1-10炔基C5-15芳基、C1-10烷基巰基C5-15芳基、C1-10烷基磺醯基C5-15芳基、C1-10烷基亞磺醯基C5-15芳基、C1-10烷氧基、C5-15芳基、C1-10烷基C5-15芳基、C5-14雜芳基、C1-10烷基C5-14雜芳基、或C1-10烷基巰基C5-14雜芳基,惟當Q不存在時,Y為C5-14雜芳基;其中,該雜芳基視需要經取代且具有1至3個獨立選自N、O及S之雜原子;及R1為H、OH、C1-10烷基、C2-10烯基、C2-10炔基、C5-15芳基、C1-10烷基C5-15芳基、C5-14雜芳基、或C1-10烷基C5-14雜芳基。
較佳地,當Q不存在時,Y為;更佳地,當Q不存在時,Y為且R1為C5-15雜芳基;最佳地,當Q不存在時,Y為且R1為。
較佳地,當Q為時,X為-CH2-、-CH(CH2CH2(CH3)2)-、或-CH2CH2、-CH(CH2CH2(CH3)2)CH(CH3)-、-CH(CH2CH2(CH3)2)CH(CH2-S-苯基)-、-CH(CH2CH2(CH3)2)CH(OCH3)-、-CH(CH2CH2(CH3)2)-、或-CH2CH2-、-CH(CH2CH2(CH3)2)CH(CH3)-、-CH(CH2CH2(CH3)2)CH2-、-CH(CH2CH2(CH3)2)CH(OH)-,或-CH(CH2CH2(CH3)2)CH(CH2-S-噻吩基)-;Y為-CH(CH2-苯基)-、-CH(C(CH3)3)-或-CH(CH2-吲哚基)-;以及R1為CH3或苯基。
更佳地,該式(I)之化合物係選自下列所成群組:
、、及
、或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
依據本發明之其他實施例,該MMP抑制劑為一種四環基底MMP抑制劑,具有下式(II)或其互變異構物或醫藥上可接受之鹽類、前藥或溶劑化物:
其中,R1及R6各自獨立為H、C1-10烷基C5-14雜芳基、或C1-10NR7R8;R2為氫或OH;R3及R4各自獨立為H、OH、NH2、NO、CN、C1-10烷基、C1-10烯基或C1-10炔基;R5為氫、鹵素、NH2、OH、NO、CN、C1-10烷基、NHC1-10烷基、N(C1-10烷基)2、C5-15芳基或C5-14雜芳基;及R7及R8各自獨立為H、C1-10烷基、C1-10烷基NH2COOH或以該氮原子而各自接附以共同形成3至8員雜芳基;其中,該雜芳基具有1至3個獨立選自N、O及S之雜原子。
較佳地,R1為H;R6為H、-CH2-吡咯基、-CH2-NH-CH2-CH2-CH2-CH2-CH(NH2)-COOH;R2為H或氧基;R3為H或OH;R4為H或OH切R5為NH2、N(CH3)2或鹵素。
更佳地,該式(II)之化合物係選自下列所成群組:
或其互變異構物或醫藥上可接受之鹽類、前藥或溶劑化物。
依據本發明之其他實施例,該MMP抑制劑為一種二芳基醚異羥肟酸鹽,具有下列式(III)或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物:
其中,R1為鹵素、OH、NH2、OC1-10烷基,未經取代或經1-3個鹵素取代、或NH2;Q不存在或O;X為O或S(O)2;Y為CH2或NH;Z為C5-14雜芳基,具有1至3個獨立選自N、O及S之雜原子或,及R2、R3及R4各自獨立為H、C1-10烷基、、、或未經取代或經取代之C5-14雜芳基,其具有1至3個獨立選自N、O及S之雜原子;或R2及R4係以碳原子而各自接附以共同形成一5員飽和雜環,其為未經取代或經CN或C1-10烷基、C1-10烷基C5-15芳基取代。
較佳地,當Q不存在時,R1為OC(鹵素)3、X為O、Y為CH2、Z為,且R2、R3及R4各自獨立為H、、或,或R2及R4以碳原子或氮原子而共同形成、、或。
較佳地,當Q為O時,R1為鹵素或OC(鹵素)3、X為S(O)2、及Z為。
較佳地,當Q為O時,R1為鹵素或OC(鹵素)3、X為S(O)2、Y為NH;Z為;且R2、R3及R4各自獨立為H、C1-10烷基、、或。
更佳地,該式(III)之化合物係選自下列所成群組:
或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
依據本發明之又一實施例,該MMP抑制劑為具有下式之化合物:
或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
更佳地,該MMP抑制劑為馬立馬司他、巴馬司他、CL-82198、美諾四環素、四環黴素、或多西環素。
於其他實施例,本發明係提供一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之TGF-β抑制劑予一病患。
轉形生長因子-β(TGF-β)屬於一多功能具胜肽因子之龐大超級家族。TGF-β於多種細胞類型中(包含上皮細胞)為生長休止之潛在誘導劑。此種活性為TGF-β訊息系統於癌症中作為腫瘤抑制劑之基礎。其他活性,包含TGF-β-誘導之上皮-向-間葉分化作用,係造成癌症進程。PCT
專利申請案WO 02/0948332揭露一類之二氫吡咯并吡唑化合物,係有用於治療與增強之TGF-β訊息活性或過量相關之疾病。US 7,638,537及US 7,635,702係揭露吡唑化合物及咪唑化合物作為TGF-訊息途徑之潛在抑制劑。
依據本發明之一實施例,該TGF-β抑制劑係選自下列所成群組:
或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
較佳地,該TGF-β抑制劑為氯沙坦鉀、N-乙醯半胱胺酸、異丙酚、及卡特普。
於又一實施例中,本發明係提供一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之COX/LOX抑制劑予一病患。
COX酵素係將花生四烯酸轉變為前列腺素內過氧化物PGH2,由此可形成其他前列腺素。多種藥物可抑制該COX或LOX酵素之此種活性。
依據本發明,該COX/LOX抑制劑係選自下列所成群組:
或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
較佳地,該COX/LOX抑制劑為阿斯匹靈。
於又一實施例中,本發明係提供一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之抗膽鹼或蕈鹼化合物抑制劑予一病患。
依據本發明,該抗膽鹼或蕈鹼化合物係選自下列所成群組:
或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物。
較佳地,該抗膽鹼或蕈鹼化合物為阿托平。
該候選化合物之例示性實施例係如下表所列:
較佳實例包括,但不限於,下表所示者:
任何上述化合物均可與一醫藥上可接受之載體組合以形成一劑型、組合物、組成、或製劑(該等術語可互通)。於此處所用,術語「醫藥上可接受之載體」意指一醫藥上可接受之材料、組成物、或傳播媒介,如液體或固體填料、稀釋劑、賦形劑、溶劑或包埋材料,係關於攜帶或運送本發明之化合物於其中或至該標的物,而使該化合物可發揮其預期功能。典型地,該等化合物係由一器官或身體之一部份被攜帶或運送至另一器官或身體另一部份。各載體,在與配方其他成分之相容性及對病患無害上,必須為「可接受的」。可作為醫藥上可接受之載體之材料之部分實例包含:糖類,如乳糖、葡萄糖、及蔗糖;澱粉類,如玉米澱粉及馬鈴薯澱粉;纖維素及其衍生物,如羧甲基纖維素鈉、乙基纖維素、及乙酸纖維素;黃蓍膠粉;麥芽;明膠;滑石;賦形劑,如可可脂及栓劑蠟;油,如花生油、
棉籽油、紅花籽油、芝麻油、橄欖油、玉米油、及大豆油;二醇類,如丙二醇;多元醇,如甘油、山梨糖醇、甘露醇、及聚乙二醇;酯類,如油酸乙酯及月桂酸乙酯;洋菜;緩衝劑,如氫氧化鎂及氫氧化鋁;褐藻酸;無熱原水;等張食鹽水;林格氏液;乙醇;磷酸鹽緩衝溶液;以及於醫藥配方中其他無毒可相容物質。
濕潤劑、乳化劑、及潤滑劑,如月桂硫酸鈉及硬脂酸鎂,以及著色劑、釋放劑、塗覆劑、甜味劑、芳香劑及香料、防腐劑及抗氧化劑亦可用於該組成物中。
醫藥上可接受之抗氧化劑之實例包含:水溶性抗氧化劑,如抗壞血酸、半光胺酸氯化氫鹽、硫酸氫鈉、焦亞硫酸鈉、亞硫酸鈉等;油溶性抗氧化劑,如抗壞血酸棕櫚酸酯、丁基羥基茴香醚(BHA)、二第三丁基對甲酚(BHT)、卵磷脂、丙基沒食子酸、α-生育酚等;以及金屬螯合劑,如檸檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
包含上述之本發明之配方係適用於靜脈、口服、鼻部、局部、皮膚、口腔、舌下、直腸、陰道、及/或非腸胃道投藥。該配方,方便起見,可為單劑量型式,且可以任何藥學領域之已知方法製備。該活性成分之量(可與一載體材料組合以製造單劑量型式者)通常為可產生療效之量。一般而言,百分之百比例中,此活性成分之量係自約1%至約99%,較佳係約5%至約70%,最佳係約10%至約30%。
製備該等配方或組成物之方法,係包含將本發明化合物與該載體及視需要之一種或多種輔助成分結合之步驟。一般而言,該配方均勻
且詳細地將本發明化合物與液態載體或細粒固態載體或兩者結合,以及,若需要的話,將該產品塑形。
適用於口服之本發明之配方可為膠囊(capsules、cachets)、片劑、錠劑、菱形錠劑(使用一香味基底,通常為蔗糖及阿拉伯膠或黃蓍膠)、粉劑、粒劑型式,或為液劑或於水性或非水性液體中之懸浮液,或為水包油或油包水之液態乳劑,或為酏劑或糖漿,或為喉片(使用一惰性基底,如明膠及甘油、或蔗糖及阿拉伯膠)及/或漱口水等型式,各自包含作為活性成分之一預定量之本發明化合物。本發明化合物亦可以食團(bolus)、舐劑、或糊劑之型式投藥。
用於口服之本發明之固態劑型(膠囊、錠劑、片劑、糖衣藥丸、粉劑、粒劑等)中,該活性成分係與一種或多種醫藥上可接受之載體(例如檸檬酸鈉或磷酸氫鈣)、及/或下列任一種混合:填料或增量劑,如澱粉、乳糖、蔗糖、葡萄糖、甘露醇及/或矽酸;黏結劑,如,舉例而言,羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯吡咯酮、蔗糖及/或阿拉伯膠;保濕劑,如甘油;崩解劑,如瓊脂、碳酸鈣、馬鈴薯或樹薯澱粉、褐藻酸、部分矽酸鹽、及碳酸鈉;阻溶液劑(solution retarding agents),如石蠟;加速吸收劑,如四級銨化合物;濕潤劑,如,舉例而言,鯨蠟醇及單硬脂酸甘油脂;吸收劑,如,高嶺土及膨潤土;潤滑劑,如滑石、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、月桂硫酸鈉、及其混合物;以及著色劑。在膠囊、錠劑及片劑之例中,該醫藥組成物亦可包括緩衝劑。利用如乳糖或牛乳糖類或高分子量聚乙二醇等賦形劑,相似類型之固態組成物亦可作為軟或硬質明膠膠囊之填料。
藉由壓製或壓模製備錠劑,視需要可具有一種或多種輔助成分。壓製之錠劑可使用黏結劑(例如,明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如,澱粉羥乙酸鈉或交聯羧甲基纖維素鈉)、界面活性劑或分散劑而製備。壓模之錠劑可藉由以惰性液態稀釋劑濕潤之粉末化之該化合物於適當機器中壓模而製備。
該錠劑及其他本發明之醫藥組成物固態劑型,如糖衣藥丸、膠囊、片劑、及粒劑,可視需要製備刻痕或塗層及外殼,例如腸衣塗佈或其他醫藥劑型領域為習知之塗層。亦可將其調配為活性成分之緩釋或控制釋放,其中,可使用例如不同比例之羥丙基甲基纖維素以提供所欲釋放曲線,其他聚合物基質、脂質體及/或微球體。其可藉由下列方式滅菌,例如:經由細菌截留濾器過濾,或將殺菌劑加入該無菌固態組成物之型式,其可於使用前即時溶解於無菌水或其他無菌注射用基質中。該等組成物亦可視需要包含失透劑,並可為僅釋放活性成分之一組成物,或,優先於腸胃道某些部分釋放,視需要可為延遲方式。可使用之包埋組成物之實例係包含聚合性物質及蠟。該活性成分亦可為微包囊型式,若需要,可具有一種或多種上述賦形劑。
除了惰性稀釋劑之外,該口服組成物亦可包含佐劑,如濕潤劑、乳化及懸浮劑、甜味劑、芳香劑、著色劑、香料、及防腐劑。
除了該活性化合物之外,懸浮劑型可包含懸浮劑如,舉例而言,乙氧基化異硬脂醇、聚氧代乙烯山梨醇及山梨醇酐脂、微晶纖維素、氫氧化鋁氧化物、膨潤土、瓊脂及黃蓍膠、及其混合物。
本發明之化合物之局部或皮膚投藥之劑型係包含粉劑、噴劑、油膏、糊劑、乳霜、化妝水、凝膠、溶液、貼片及吸入劑。該活性化合物可在無菌條件下與一醫藥上可接受之載體、及所需之任何防腐劑、緩衝液、或推進物混合。
除了本發明之活性化合物以外,該油膏、糊劑、乳霜、及凝膠可包含賦形劑,如動物及植物油脂、油、蠟、石蠟、澱粉、黃蓍膠、纖維素衍生物、聚乙二醇、聚矽氧烷、膨潤土、矽酸、滑石及氧化鋅、或其混合物。
除了本發明之活性化合物以外,該粉劑及噴劑可包含賦形劑,如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣、及聚胺粉末,或其混合物。噴劑可額外包含習知推進物,如氯氟代烴及未經取代之揮發性烴,如丁烷及丙烷。
皮膚貼片具有可將本發明化合物以控制之傳遞提供至人體。該劑型可藉由將化合物於適當基質中溶解或分散。吸收增進劑亦可用於增加該化合物穿越皮膚之通量(flux)。可藉由提供一速率控制膜或將該活性化合物分散於一聚合物基質或凝膠中,以控制該通量之速率。
眼藥配方、眼藥膏、藥粉、藥水等亦可涵蓋於本發明之範疇中。該等溶液係有用於治療任何眼睛疾病。
本發明之醫藥組成物可適用於非腸胃道投藥,係包括一種或多種本發明之化合物,與一種或多種醫藥上可接受之無菌等滲透壓水性或非水性溶液、分散劑、懸浮液、或乳劑之組合,或,為無菌粉末(可於使用前即時重組成無菌注射用溶液或懸浮液),其可包含抗氧化劑、緩衝劑、殺
菌劑、溶質(以使該配方與預期接受者之血液為等滲透)、或懸浮劑或稠化劑。
可用於本發明醫藥組成物之適當水性及非水性載體之實例,係包含水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)、及其適當混合物、植物油如橄欖油、及可注射有機酯如乙基油酸酯。適當流動性之維持,例如可藉由塗覆材料(如卵磷酯)之使用、在分散劑中維持所須顆粒尺寸、及使用界面活性劑。
該等組成物亦可包含佐劑,如防腐劑、濕潤劑、乳化劑、及分散劑。可藉由包含不同抗細菌劑及抗真菌劑,如對羥苯甲酸酯、氯丁醇、山梨酸苯酚等,而達到預防微生物之活動。包含等滲透劑,如糖類、氯化鈉等之該等組成物亦為所欲。另外,注射用醫藥劑型之延長吸收作用,可藉由添加延遲吸收作用之劑如單硬脂酸鋁及明膠而達成。
本發明之劑型可為口服型、非腸胃道型、局部型、或直腸型。該等劑型自然可依各投藥途徑而製備為適當型式。例如,它們可以錠劑或膠囊型式以注射、吸入途徑投藥,以眼藥水、藥膏、栓劑等型式以注射、點滴或吸入途徑投藥;以藥水或藥膏型式以局部投藥;及以栓劑以直腸投藥。以靜脈注射投藥為較佳。
於此處所用,術語「非腸胃道投藥」及「以非腸胃道型提供」意指除了腸道及局部投藥以外之模式,通常係藉由注射,且包含但非限於靜脈、肌肉、動脈、囊內、硬膜外、眶內、腔內、皮內、腹膜內、氣管、皮下、表皮下、關節腔內、包膜下、蛛網膜下腔、脊柱內、及胸骨內之注射及點滴。
該等化合物可藉由任何適當投藥途徑,包含口服、鼻腔(例如藉由噴劑)、直腸、陰道、非腸胃道、腦池內(intracisternally)、及局部性(例如藉由粉末、藥膏、或滴劑),含口腔及舌下,提供給人類及其他動物以達治療目的。
若不考慮所選投藥途徑,本發明之該等化合物可以適當水合型式使用,及/或本發明之醫藥組成物可以本領域具通常知識者所習知之方法配製成醫藥上可接受之劑型。
Actual dosage levels of the s in the於本發明之醫藥組成物中,該活性成分之確切劑量可加以變化,以獲得可達成對特定病患、組成物、及投藥方式之所欲治療反應,且對該病患無毒性之活性成分之量。
所選定之劑量係依不同因子而變化,該等因子包含所用本發明特定化合物或其酯類、鹽類或胺類之活性、投藥途徑、投藥時間、所用特定化合物之排除速率、治療期間、用以與所用特定化合物組合之其他藥物、化合物及/或材料、年齡、性別、體重、條件、一般健康狀況、及接受治療之病患之用藥史,以及於醫藥領域中習知之類似因子。
具有本領域通常知識之醫師或獸醫可輕易決定該醫藥組成物所需之量並開立處方。例如,該醫師或獸醫可使用低於達成所欲療效之必須劑量之本發明化合物作為起始劑量,且逐漸增加劑量直到達成所欲療效。
本發明係提出,屬於數種SLRP之一員之透明蛋白係於調控原纖維生成或影響斑馬魚眼球軸長之基因上扮演重要角色,另外,於臨床近視上扮演重要角色。本發明係使用所建立之斑馬魚近視實驗模組以進一
步鑑定影響透明蛋白表現及膠原蛋白原纖維生成及調控眼球軸長之藥物。以透明蛋白之調控及膠原蛋白合成為基礎,經由TGF-β途徑及後續MMP2及TIMP調控,進行待測化合物之測試。於本發明中,係測試約30種臨床可獲得且為FDA核准之藥物,其係目前臨床使用並為TGF-β途徑或MMP及TIMP活性調控相關者。結果顯示,MMP抑制劑(馬立馬司他(marimastat)、多西環素及美諾四環素)、膠原蛋白酶抑制劑(n-乙醯半胱胺酸)、TGF-β途徑活化劑(異丙酚)、TGF-β抑制劑(卡特普)及Cox抑制劑(阿斯匹靈)係有效候選化合物。
水生培養
依據先前已建立之方法培養並維持斑馬魚(參考文獻:Soules KA,Link BA.Morphogenesis of the anterior segment in the zebrafish eye.BMC Dev Biol 2005;5:12)。所有實驗均以Tuebingen AB品系之斑馬魚進行,於28℃下以14小時光照及10小時黑暗循環培養,並以標準方法維持。該等胚胎係依據表型標準(體節數)決定其階段(參考文獻:Kimmel CB,Ballard WW,Kimmel SR,et al.Stages of embryonic development of the zebrafish.Dev Dyn 1995;203(3):253-310),及依受精後之小時數而計時。如斑馬魚參考手冊所述,胚胎係以自然成對交配所產生(參考文獻:Westerfield M.The zebrafish Book;A Guide for the Laboratory Use of zebrafish(Brachydanio rerio).University of Oregon Press,Eugene,2nd edition 300P.,1993)。對於每次交配,係設定4±5對,且平均每對可產生100±150個胚胎。斑馬魚胚胎為透明,
使得無須犧牲或解剖個體而檢測內部器官之功能及表型變化為可行。以鑷子(Dumont Watchmaker’s Forceps No.5)手動移除絨毛膜。
目前斑馬魚基因體以被桑格中心定序,並由轉國家健康院之斑馬魚基因體先導計畫進行該基因體之實體註解。為鑑定該斑馬魚表現序列標籤(EST)品系,其編碼一與人類及小鼠SLRP家族蛋白質共享高序列相似度之假設性蛋白質,本發明人以人類透明蛋白總長度之cDNA序列應用至基因資料庫之BLAST分析。包含該斑馬魚透明蛋白基因之5’部分,約4.6kb之Not I/MluI斑馬魚基因體DNA片段,係經由聚合酶連鎖反應(PCR)及次選殖至該pBluescript SK載體(Stratagene,La Jolla,CA)。該插入段係於國立台灣大學之分子基因體部門之DNA定序核心,以T3、T7及未經預設之引子(walk-in primers)進行定序。該zLum之mRNA之5’-及3’-端係分別以5’-端之cDNA快速增幅(5’-RACE)及3’-RACE系統(Invitrogen,Carlsband,CA)放大。於該5’-RACE實驗,以1μg之斑馬魚眼睛之全RNA,以對應於zLum基因之外顯子2序列之第一透明蛋白專一性引子進行反轉錄。以RNase混合物處理以降解該RNA模版。以末端去氧核糖核酸轉移酶於該cDNA之3’-端增加聚dCTP尾巴。該cDNA之增幅係藉由對應於外顯子1及外顯子2間之接合序列之第二基因專一性引子及以刪節錨點引子(abridged anchor primer)結合進行。將所得PCR產物稀釋為100倍並作為模版以第三基因專一性引子及萬用增幅引子結合進行再增幅。對於3’-RACE,以對應於zLum基因之外顯子3序列之第四基因專一性引子進行PCR。該週期條件為:94℃ 1分鐘、55℃ 1分鐘、及72℃ 3分鐘進行34個週期,接
著於該等週期後以72℃進行10分鐘延長。最後以膠體純化該5’-RACE及3’-RACE之PCR產物,並以去雙氧定序法測定序列。藉由分別比對基因體DNA、該5’-RACE產物、及該3’-RACE產物之序列可測定該zLum基因之轉錄起始及終止位置(參考文獻:Yeh LK,Liu CY,Kao WW,et al.Knockdown of zebrafish lumican gene(zlum)causes scleral thinning and increased size of scleral coats.J Biol Chem 2010;285(36):28141-55)。
第一透明蛋白專一性引子:5’-AGTAGAGGTATTTGATTCCGGTC-3’;第二透明蛋白專一性引子:5’-GCACAAGAAGGTGATGAAACG-3’;第三透明蛋白專一性引子:5’-CAGACTTAGAAGTCCAGCCAAC-3’;第四基因專一性引子:5’-GCCTCAGAGATCATCTTTGAATAG-3’;刪節錨點引子:5’-GGCCACGCGTCGACTAGTACGGGIIGGGIIGGGIIG-3’;萬用增幅引子:5’-CUACUACUACUAGGCCACGCGTCGACTAGTAC-3’.
嗎啉為化學修飾之反義寡聚核苷酸,可設計成與特定mRNA之轉譯起始位置或拼接(splicing)接受/提供位置雜合(參考文獻:Nasevicius A,Ekker SC.Effective targeted gene 'knockdown' in zebrafish.Nat Genet 2000;26(2):216-20)。嗎啉反義寡聚核苷酸(Gene Tools,Philomath,OR)係設計並合成以標定該5’-未轉譯及/或側翼區,包含該各別基因之轉譯起始密碼。該MO序列係設計如下:zLum-MO,5’-GATCCCAGAGCAAACATGGCTGCAC-3’。此寡聚核苷酸係與轉譯起始
密碼之-8至+17之序列互補。作為zLum-MO之對照組之一任意序列MO(RS-MO):5’-CCTCTTACCTCAGTTACAATTTATA-3’。此RS-MO係得自Gene Tools,並無標的專一性,以作為標準對照組(參考文獻:Yeh LK,Liu CY,Kao WW,et al.Knockdown of zebrafish lumican gene(zlum)causes scleral thinning and increased size of scleral coats.J Biol Chem 2010;285(36):28141-55)。
將嗎啉重新溶散於無菌水中,達1mmol/L之濃度,並以無菌水稀釋為680ng/nL。將該嗎啉注射至體積為0.0023nL之單細胞階段。此處,係以西方墨點法鑑定該嗎啉於蛋白質層次之效果,以注射GAPDH之胚胎作為對照組。
全株原位雜交法之主要優點為,其為建立胚胎及早期幼體之基因時空表現之快速且有效之方法。取不同階段所得之胚胎並以於1x PBS之4%多聚甲醛於4℃固定隔夜。以PBS潤洗3次後,將該等胚胎移至100%之甲醇中,並貯存於-20℃直到使用時。所有胚胎以0.003%苯基硫脲(PTU)處理以預防黑素生成。依據一般方法進行全株RNA原位雜交(參考文獻:Thisse C,Thisse B.High-resolution in situ hybridization to whole-mount zebrafish embryos.Nat Protoc 2008;3(1):59-69)。依製造商所建議之流程,以地高辛抗體(DIG)-鹼性磷酸酶接合物顯示雜交訊號(Roche Applied Science,Indianapolis,IN)。
斑馬魚透明蛋白抗體-一種以親和性純化之抗zLum抗體,拮抗一合成胜肽N-端胜肽(N’-CNERNLKFIPIVPTGIKY-C’),其係對應於由該zLum cDNA衍生之18個N端胺基酸殘基,該抗體可用以檢測斑馬魚透明蛋白。該胜肽係結合至血藍蛋白(KLH),以於兔子進行抗體生成。依製造商所建議之流程,以前述斑馬魚透明蛋白寡胜肽接合至Sulfolink膠體之免疫吸附管柱(Pierce,Rockford,IL)純化該抗體。收集含有經純化之抗斑馬魚透明蛋白抗體之餾份並濃縮,且以分光光度計於280nm測定蛋白質濃度(參考文獻:Yeh LK,Liu CY,Kao WW,et al.Knockdown of zebrafish lumican gene(zlum)causes scleral thinning and increased size of scleral coats.J Biol Chem 2010;285(36):28141-55)。
使用數種抗體以評估透明蛋白之基因抑制效果,所有抗體均可由商業購得。抗TGFβ2兔子抗體、抗MMP-2兔子抗體、抗TIMP-2山羊抗體、抗Col1a1(L-19)山羊抗體、及抗PDI山羊抗體可購自Santa Cruz。抗GAPDH小鼠抗體可購自Abnova。
將人類鞏膜細胞以4×105細胞/孔接種於6孔培養盤中,並加入不同濃度之MMP抑制劑,於37℃培養24小時。未添加MMP抑制劑者作為對照組。於24小時培養後,收集細胞進行蛋白質萃取。蛋白質係萃取並於含有蛋白酶抑制劑之RIPA緩衝液中均質化。以光譜分析法定量蛋白質成分。以具有相同蛋白質含量之樣本於10%聚丙烯醯胺膠體上進行電泳,並轉移至PVDF膜。將該轉漬膜與包含5%脫脂牛奶之PBS溶液於4℃共培養隔夜以阻斷非專一性抗原,接著以稀釋之初級抗體培養1-2小時。於此實
驗中所使用之初級抗體如下:抗TGFβ1抗體、抗TGFβ2抗體、抗TGFβ3抗體、抗MMP2抗體、抗MMP9、抗TIMP2抗體、及GAPDH。初級抗體反應後,將該膜與做為二次抗體之辣根過氧化酶接合之山羊抗小鼠IgG或山羊抗兔子IgG之抗體於室溫下共培養1小時,以化學螢光試劑組(Chemiluminescence Reagent Plus)檢測,並暴露至膜上。比較以不同MMP抑制劑處理/未經處理之細胞之間的蛋白質表現圖譜。
以反義嗎啉寡聚核苷酸於斑馬魚中可快速且強力地研究基因功能(參考文獻:Nasevicius A,Ekker SC.Effective targeted gene 'knockdown' in zebrafish.Nat Genet 2000;26(2):216-20;Heasman J.Morpholino oligos:making sense of antisense?Dev Biol 2002;243(2):209-14)。又,已建立產生轉基因系、標的突變(反向遺傳)、及核轉移之選殖之技術(參考文獻:Davidson AE,Balciunas D,Mohn D,et al.Efficient gene delivery and gene expression in zebrafish using the Sleeping Beauty transposon.Dev Biol 2003;263(2):191-202;Kurita K,Burgess SM,Sakai N.Transgenic zebrafish produced by retroviral infection of in vitro-cultured sperm.Proc Natl Acad Sci U S A 2004;101(5):1263-7;Wienholds E,Schulte-Merker S,Walderich B,Plasterk RH.Target-selected inactivation of the zebrafish rag1 gene.Science 2002;297(5578):99-102;Lee KY,Huang H,Ju B,et al.Cloned zebrafish by nuclear transfer from long-term-cultured cells.Nat Biotechnol 2002;20(8):795-9)。此處,本發明人建立了於斑馬魚透明蛋白啟動子控制下表現之轉基因品系。由該zLum基因之5'未轉譯區域起算之基因體DNA,1.7kb及0.48kb兩者,
係以專一性PCR引子增幅,並插入至具有多重選殖位置並帶有EGFP序列之pBluescript II SK載體(Stratagene,La Jolla,CA)。該重組質體係於Escherichia coli DH5α中製備並以純化套組(QIAGEN Plasmid Purification Maxi kit)純化。將純化之質體DNA以蒸餾水調整至50ng/μl,並於解剖顯微鏡下以顯微注射至單細胞階段之斑馬魚胚胎。隔天以螢光解剖顯微鏡(Leica dissection scope)(MZFLII)將具有GFP表現之胚胎顯影並選出。僅將可展現螢光之胚胎培養至成魚。由帶有螢光之經注射胚胎長成之成魚同胞配對以鑑定生殖系種源種。接著,由陽性配對而來的獨立成體進行遠系雜交(outcross)以鑑定獨立種源種魚。由此透明蛋白啟動子轉基因魚可進一步強調該等功能及表型之改變。
PCR引子:
順向引子I:5’-ATAAGAATGCGGCCGCTCCATTAATTCGACAGACCAG-3’;順向引子II:5’-ATAAGAATGCGGCCGCAGGTAGACAACACGGTTATGT-3’;反向引子:5’-CGACGCGTGGCTGCACAACTTAAATTAAACCT-3’;
藥物篩選所用化學品及藥物包含TGF-受體抑制劑(阿托平、托平卡胺、異丙托溴銨(愛全樂)、奧昔布寧(塔沃爾)、東莨菪鹼溴化氫鹽、派倫西平二氯化氫鹽、SB431542、太莫西芬、SB-505124、RepSox(SB-4696)、鹽酸多西環素(Dermostat,Periostat)、金雀異黃酮、馬立馬司他、牛磺酸、美
諾四環素氯化氫鹽、n-乙醯半胱胺酸、氯沙坦鉀、阿斯匹靈、齊留通、SP600125、異丙酚、HMG-CoA還原酶抑制劑(Statin)、吲哚美辛、伊布洛芬、納普洛先、匹洛西卡、萘丁美酮、利考非隆、卡特普、前花青素、雜紫杉鹼原(Heterotaxin)、辛伐他汀、洛伐他汀、瑞舒伐他汀)。所有化合物,其拮抗由透明蛋白調控之膠原蛋白原纖維生成之假設途徑之藥學活性均已於先前被研究過。
本發明人已成功建立一斑馬魚近視實驗模組以研究眼睛發育與疾病,並確認了透明蛋白基因(zLum)於斑馬魚之角膜及鞏膜中之表現。zLum之基因抑制造成於斑馬魚眼睛發育期間之鞏膜薄化及鞏膜之膜尺寸增加,與兒童近視之臨床發現相符。如生物化學期刊2010年第285卷第36號第28141-28155頁之參考文獻之第4及5圖所示,其清楚證實,斑馬魚透明蛋白(zLum)於斑馬魚中之表現,尤其是在鞏膜、角膜、及眼週基質。有趣的是,於鞏膜之透明蛋白為非硫酸化,反之,於角膜基質者為硫酸化透明蛋白。
於透明蛋白經基因抑制後,於第1至5圖,鞏膜拉長且近似於人類近視(即軸性拉長)之鞏膜改變。如上所述,本發明人亦展示了於該透明蛋白啟動子之SNP改變及其單倍體型係與台灣族群之高度近視發生有強烈關連性。本動物實驗重現對於人類近視之該等發現,其中係強調透明蛋白基因於軸性拉長發生之重要性。
第6圖顯示,於斑馬魚中,透明蛋白基因抑制之表型可被TGF-β復原。該透明蛋白基因抑制斑馬魚亦證實MMP2之增量表現及TIMP之減量表現,其進一步確認透明蛋白對於鞏膜重塑之調控之角色係如其他物種之實驗性近視所示。重要地,於透明蛋白基因抑制斑馬魚中,提供阿托平可抑制該鞏膜拉長(第7至9圖)。以此治療後,MMP-2及TIMP之表現亦回歸正常表現量。
測試約30種與TGF-β途徑相關之臨床可得藥物。第一種藥物馬立馬司他(BB 2516)為一預期抗腫瘤藥物,為廣效基質金屬蛋白酶抑制劑,亦被認為是良好候選藥物。本發明初步結果顯示,馬立馬司他可於zLumMO基因抑制斑馬魚中非常有效地預防鞏膜拉長(實驗組為2%鞏膜拉長vs.對照組為30%鞏膜拉長)。馬立馬司他之結果確實顯示MMP為作用者(effectors)且標定至透明蛋白基因抑制後之鞏膜拉長。馬立馬司他可為用於預防近視及臨床藥物測試之具潛力標的物。
四環黴素可用於多種革蘭氏陰性細菌感染之系統性及局部性治療。近年來,已建立四環黴素之完全獨立於其抗微生物特性之其他生物功能。又,多種關於體外及體內之動物試驗之研究已顯示,四環黴素抗生素及其不具備抗微生物活性之化學修飾類似物可抑制哺乳類膠原蛋白酶之活性及破壞膠原蛋白。多西環素及美諾四環素為第二代四環黴素。多西環素及經化學修飾之四環黴素CMT-1及CMT-6具有對92-kDa(MMP-9)及72-kDa(MMP-2)明膠酶二者之直接抑制效果。美諾四環素亦可抑制不同MMP,包括MMP-9及MMP-2。該等藥物被認為是良好候選藥物。本發明之結果顯示,多西環素及美諾四環素可於zLum-嗎啉(MO)基因抑制模組中
非常有效地抑制鞏膜拉長(實驗組為6.8%及4.7%鞏膜vs.對照組為30%鞏膜拉長)。另一群抗生素,美諾四環素,亦展現出預防鞏膜拉長之效果。美諾四環素屬於為第二代四環黴素。美諾四環素具有與其他四環黴素相似範圍之抗感染特性,特別是拮抗披衣菌(Chlamydias)、梅毒螺旋菌(Treonema)、及丙酸痤瘡桿菌(Proprionibacterium acenes)。與此種抗感染作用相關之該抗發炎及抗膠原蛋白酶活性係高於第一代四環黴素,特別是對表皮細胞素有調節劑效果者。故,可合理預期四環黴素於鞏膜之膠原蛋白合成之功效。阿斯匹靈可於身體中造成不同效果,主要可降低發炎作用、止痛(疼痛緩解)、預防血栓、及退燒。阿斯匹靈可抑制前列腺素及血栓素之生成之能力係來自其對環氧合酶(COX)酵素之不可逆之不活化作用。環氧合酶為前列腺素及血栓素合成所必須。阿斯匹靈係作為乙醯化劑,將乙醯基共價結合至該COX酵素之活性位置之絲胺酸上。此舉使得阿斯匹靈不同於其他NSAID(如代克菲納及伊布洛芬)之可逆型抑制劑。本發明結果顯示,阿斯匹靈可於zLum-MO基因抑制模組中非常有效地預防鞏膜拉長(實驗組為9.6%鞏膜拉長vs.對照組為30%鞏膜拉長)。
N-乙醯半胱胺酸,為一種有效的抗氧化劑,可抑制胞外反應性氧中間產物之生成,亦為膠原蛋白酶抑制劑。數篇論文報導,N-乙醯半胱胺酸顯示基質MMP-2之表現及活性之抑制作用。本發明結果顯示,n-乙醯半胱胺酸可於zLum-MO基因抑制模組中非常有效地預防鞏膜拉長(實驗組為11.7%鞏膜拉長vs.對照組為30%鞏膜拉長)。
異丙酚(2,6-二異丙基酚)為用於手術中長效鎮靜之麻醉及治療急重症患者之術後噁心嘔吐之最常用藥劑之一。異丙酚可誘發內皮細胞
表現潛伏期TGF-β,於胞內可藉由PBMCs轉換成活化TGF-β。本發明結果顯示,異丙酚可於zLum-MO基因抑制模組中非常有效地預防鞏膜拉長(實驗組為12%鞏膜拉長vs.對照組為30%鞏膜拉長)。
簡言之,馬立馬司他、多西環素、美諾四環素、n-乙醯半胱胺酸、阿斯匹靈、異丙酚之結果顯示TGF-β及MMP為作用者且標定至透明蛋白基因抑制後之鞏膜拉長。該等藥物可為用於預防近視及臨床藥物測試之具潛力標的物。據此,本發明係證實斑馬魚為觀察軸性近視發生及篩選治療近視用化合物之優異之體內動物模組。以馬立馬司他、多西環素、卡特普、美諾四環素鹽酸鹽、阿托平、阿斯匹靈、異丙酚、及N-乙醯半胱胺酸處理之斑馬魚之大眼率係如第10圖所示。第11(a)-(e)圖係顯示以不同濃度之四環黴素、美諾四環素、多西環素、馬立馬司他、及巴馬司他處理之斑馬魚之大眼率。其他待測化合物及其大眼率係如下表所示。
上述特定實施例之內容係為了詳細說明本發明,然而,該等實施例係僅用於說明,並非意欲限制本發明。熟習本領域之技藝者可理解,
在不悖離後附申請專利範圍所界定之範疇下針對本發明所進行之各種變化或修改係落入本發明之一部分。
<110> 國立台灣大學
<120> 以斑馬魚近視實驗模組進行藥物篩選之方法及篩選所得藥物
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Claims (20)
- 一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之MMP抑制劑予一病患。
- 如申請專利範圍第1項之方法,其中,該MMP抑制劑為一擬肽物異羥肟酸鹽MMP抑制劑,具有下列式(I)或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物:
- 如申請專利範圍第2項之方法,其中,當Q為時,X為 -CH2-、-CH(CH2CH2(CH3)2)-、或-CH2CH2-、-CH(CH2CH2(CH3)2)CH(CH3)-、-CH(CH2CH2(CH3)2)CH(CH2-S-苯基)-、-CH(CH2CH2(CH3)2)CH(OCH3)-、-CH(CH2CH2(CH3)2)-、或-CH2CH2-、-CH(CH2CH2(CH3)2)CH(CH3)-、-CH(CH2CH2(CH3)2)CH2-、-CH(CH2CH2(CH3)2)CH(OH)-、或-CH(CH2CH2(CH3)2)CH(CH2-S-噻吩基)-;Y為 -CH(CH2-苯基)-、-CH(C(CH3)3)-或-CH(CH2-吲哚基)-;及R1為 CH3或苯基。
- 如申請專利範圍第2項之方法,其中,當Q不存在時,Y為;較佳地,當Q不存在時,Y為且R1為C5-15雜芳基;更佳地,當Q不存在時,Y為且R1為。
- 如申請專利範圍第2項之方法,其中,該式(I)係選自由下列所成群組:
- 如申請專利範圍第5項之方法,其中,該化合物為CL-82198、馬立馬司他、或巴馬司他。
- 如申請專利範圍第1項之方法,其中,該MMP抑制劑為一種四環基底之MMP抑制劑,具有下列式(II)、或其互變異構物、或其醫藥上可接受之鹽類、前藥或溶劑化物:
- 如申請專利範圍第7項之方法,其中,R1為H;R6為H、-CH2-吡咯基、-CH2-NH-CH2-CH2-CH2-CH2-CH(NH2)-COOH;R2為H或氧基;R3為H或OH;R4為H或OH;且R5為NH2、N(CH3)2或鹵素。
- 如申請專利範圍第7項之方法,其中,該式(II)之化合物係選自由下列所成群組:
- 如申請專利範圍第9項之方法,其中,該化合物為美諾四環素、四環黴素或多西環素。
- 如申請專利範圍第1項之方法,其中,該MMP抑制劑為一種二芳基醚異羥肟酸鹽具有下列式(III)或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物或鏡像異構物:
- 如申請專利範圍第11項之方法,其中,當Q不存在時,R1為OC(鹵素)3、X為O、Y為CH2、Z為,且R2、R3及R4各自獨立為H、、 或;或R2及R4以碳原子或氮原子而共同形成、或。
- 如申請專利範圍第11項之方法,其中,當Q為O時,R1為鹵素或OC(鹵素)3、X為S(O)2、及Z為。
- 如申請專利範圍第11項之方法,其中,當Q為O時,R1為鹵素或OC(鹵素)3、X為S(O)2、Y為NH;Z為;且R2、R3及R4各自獨立為H、C1-10烷基、、或。
- 如申請專利範圍第11項之方法,其中,該式(III)之化合物係選自由下列所成群組:
- 如申請專利範圍第1項之方法,其中,該MMP抑制劑為具有下式之化合物:金雀異黃酮、或其醫藥上可接受之鹽類、前藥、溶劑化物、立體異構物、或鏡像異構物。
- 一種治療由透明蛋白之表現及/或膠原蛋白原纖維生成所調控之疾病、及/或治療近視及/或錐狀角膜疾病之方法,包括提供一治療有效量之TGF-β抑制劑予一病患。
- 如申請專利範圍第17項之方法,其中,該TGF-β抑制劑係選自由下列所成群組:
- 如申請專利範圍第18項之方法,其中,該TGF-β抑制劑為氯沙坦鉀、N-乙醯半胱胺酸、異丙酚、及卡特普。
- 如申請專利範圍第1或17項之方法,其中,該方法係用以治療近視。
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KR102223999B1 (ko) * | 2019-08-12 | 2021-03-09 | 고려대학교 산학협력단 | 어류의 시력 등급화 방법 및 컴퓨터 판독 가능한 저장매체 |
KR102120159B1 (ko) * | 2018-10-31 | 2020-06-08 | 고려대학교산학협력단 | 어류의 시기능 평가 시스템 및 이를 이용한 안구 독성 약물 스크리닝 방법 |
WO2020091201A1 (ko) * | 2018-10-31 | 2020-05-07 | 고려대학교 산학협력단 | 어류의 시기능 평가 시스템 및 이를 이용한 안구 독성 약물 스크리닝 방법, 어류의 시력 등급화 방법 및 컴퓨터 판독 가능한 저장매체 |
CN117017959A (zh) * | 2018-11-14 | 2023-11-10 | 珠海岐微生物科技有限公司 | 用于眼内疾病或病症的动物模型、筛选方法和治疗方法 |
CN110463654B (zh) * | 2019-08-15 | 2021-09-07 | 贵州中医药大学 | 一种建立斑马鱼血管新生障碍模型的方法 |
CN113413471A (zh) * | 2021-06-11 | 2021-09-21 | 浙江警察学院 | 一种基于斑马鱼模型对莨菪类药物进行毒性评价的方法 |
CN115261306B (zh) * | 2022-07-19 | 2023-07-14 | 宜宾五粮液股份有限公司 | 斑马鱼心血管疾病模型、构建方法和用途 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4704383A (en) * | 1983-12-29 | 1987-11-03 | The Research Foundation Of State University Of New York | Non-antibacterial tetracycline compositions possessing anti-collagenolytic properties and methods of preparing and using same |
JPH04178359A (ja) * | 1990-07-01 | 1992-06-25 | Kuraray Co Ltd | テトラサイクリン誘導体 |
JPH08511509A (ja) * | 1993-04-07 | 1996-12-03 | グリコメド・インコーポレイテッド | 合成マトリックスメタロプロテアーゼ阻害剤およびその用途 |
US6172057B1 (en) * | 1997-02-27 | 2001-01-09 | American Cyanamid Company | N-Hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors |
TWI234467B (en) * | 1997-06-04 | 2005-06-21 | Univ Michigan | Composition for inhibiting photoaging of skin |
US6946453B2 (en) * | 1998-11-18 | 2005-09-20 | Collagenex Pharmaceuticals, Inc. | 4-dedimethylaminotracycline derivatives |
GB0004531D0 (en) * | 2000-02-25 | 2000-04-19 | Richards Andrew J M | The treatment of respiratory diseases |
AU2002341970B2 (en) * | 2001-10-05 | 2008-02-14 | Tetragenex Pharmaceuticals, Inc. | Tetracycline derivatives and methods of use thereof |
ES2435398T3 (es) * | 2004-04-08 | 2013-12-19 | Eye Co Pty Ltd. | Tratamiento de retinopatía exudativa con mineralocorticoides |
ES2524015T3 (es) * | 2005-12-30 | 2014-12-03 | Dyax Corporation | Proteínas de enlazamiento a la metaloproteinasa |
CN100579576C (zh) * | 2007-03-16 | 2010-01-13 | 王宁利 | 一种防止近视发展的眼内植入材料 |
GB0710522D0 (en) * | 2007-06-01 | 2007-07-11 | Royal Veterinary College The | Drug delivery system comprising matrix metalloproteinase inhibitors |
GB0722484D0 (en) * | 2007-11-15 | 2007-12-27 | Ucl Business Plc | Solid compositions |
GB2474930B (en) * | 2009-10-02 | 2012-07-04 | Foamix Ltd | Topical tetracycline compositions |
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TWI532480B (zh) | 2016-05-11 |
KR101953736B1 (ko) | 2019-03-04 |
SG11201407729VA (en) | 2014-12-30 |
JP2015517575A (ja) | 2015-06-22 |
US20140073611A1 (en) | 2014-03-13 |
KR20150013867A (ko) | 2015-02-05 |
EP2852383A4 (en) | 2016-03-16 |
JP6300856B2 (ja) | 2018-03-28 |
WO2013177170A2 (en) | 2013-11-28 |
KR20170086678A (ko) | 2017-07-26 |
JP2016130258A (ja) | 2016-07-21 |
SG10201701145UA (en) | 2017-03-30 |
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