TWI306120B - Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa - Google Patents

Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa Download PDF

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TWI306120B
TWI306120B TW092133160A TW92133160A TWI306120B TW I306120 B TWI306120 B TW I306120B TW 092133160 A TW092133160 A TW 092133160A TW 92133160 A TW92133160 A TW 92133160A TW I306120 B TWI306120 B TW I306120B
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David Frederick Horrobin
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Laxdale Ltd
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Description

1306120 玖、發明說明： 【發明所屬之技術領域】 本發明係有關亨丁頓舞蹈症。 【先前技術】 予丁頓舞蹈症（HD)為一種在人類4號染色體上由蛋白質 亨丁亭之基因突變所致之致命遺傳疾$。以任何合適醫藥 形式之脂肪酸，二十碳五烯酸（EPA)可用以治療hd(如述於 歐洲專利申請案號1 148873)。 【發明内容】 本發明有關HD之治療及基於以下之發現，即EpA之治療 作用特別發生在該等具特殊基因形SHD之病患。 本發明提供-種鑑定具肋之病患或在發展HD危險下之個 體，或特別彳能對以任何合適形式之EpA治療有反應者之方 法及包括之步驟為進行試驗，以測定亨丁亭基因中CAG重 複序列之數目及較該等具45個或更少重複序列之個體。 若個體具少於36個重複序列時，意示為正常個體。在較 佳之試驗中，選定之個體為該等具44個或更少，或36至44 個CAG重複序列者。 試驗可在取自個體僅供分析目的及不還給個體之樣品上 進行。診斷步驟將在體外分析。 本發明再提供一種治療HD之方法，及一種預防在發展1?〇 危險下之個體中發展症狀之方法，包括之步驟為測定個體 f因中了 丁苧之CAG重複序列數目，及其為45個或更少 才杈予任何生物有效形式之EPA至個體。在較佳之試驗
O:\89\89537.DOC 1306120 中I疋投予EPA之個體為該等具44個或更少，或36至44 個CAG重複序列者。 用於本發明方法之EPA較佳為乙基_EpA。 46個或更多之CAG重複序列數目在投予安慰劑或EpA之
全部處理組間不顯示任何差異。相反及未預期地，罹患HD 而具45個或更少之CAG重複序列數目之病患在投予EpA上 顯示很大的益處。 雖然全部HD病患在才目同基因中具有基因異常性，但並非 全部病患具有相同的異常性。亨丁亭之正常基因含有cag 重複序列之基因’其基因自身編碼聚麩胺酸序列。甚至在 正常個體中’聚麩胺酸序列為可變的長度，但只要其含有 >、於3 6個CAG重複序列及因此聚越胺酸序列中少於3 6個麩 胺酸，則個體將正常。然而，當序列含有36個或更多個CAg 重複序列及其後麩胺酸序列時，將發展HD。具HD‘病患會 有著自36至多於1〇〇個cag重複序列。 HD常以動作障礙開始，特別為影響臉部、頭和頸部及四 肢。此些進展及常伴隨著精神異常性及認知損傷，而導致 癡呆。異常性最初由亨丁亭傷害至紋狀體之神經元所致， 但其後會涉及更廣之腦部區域。最後，病患變成臥床不起 及70全不忐照顧自己。其常在疾病開始後丨〇至25年内死亡。 CAG重複序列之數目對疾病開始之年齡有著很強的影 響。具僅超過35個數目之病患不會生病直至其5〇或6〇多歲 或甚至更老。具超過60個重複序列之病患會在青少年或甚 至童年時生病。然而’多數病患傾向在3〇至5〇歲間生病。
O:\89\89537.DOC 1306120 EPA可為乙基-EPA之形式、鋰EPA、單-或雙-或三酸甘油 酯EPA或EPA之任何酯或鹽，或游離酸形式之epa ^ EPA亦 可為2-取代衍生物或其他衍生物之形式，其減緩其氧化速 率，此外並不改變其在精神或腦障礙上之生物作用至任何 貫質程度（N. Willumsen等人，Biochimica Biophysica Acta, 1998, 1369: 193-203)。 EPA可與主要作用在神經傳遞素代謝或受器上之藥物組 合。與EPA製備物共同投予之合適藥物為克洛沙平 (clozapine)及典型和非典型神經安定劑類中之任一，包括氯 丙麻井（chlorpromazine)鹵佩里醇（haloperidol)、里斯佩里g同 (ristperidone) > 歐藍沙平（olanzapine)、色提吲哚 (sertindole)、記普拉西酮（ziprasid〇ne)、佐提平（z〇tepine) 或阿米硫皮里德（amisulpiride)。用以減輕一些亨丁頓舞蹈 症狀之標準抗精神分裂藥物、抗抑鬱劑、鎮定劑及抗癲癇 藥物可與EPA調配物一起投藥。 取自EP申請案號1148873作為治療亨丁頓舞蹈症之實 例，96%純乙基-EPA之隨機試驗在亨丁頓舞蹈症最後階段 之7位嚴重失能病患中進行。全部需要24小時看顧，有著嚴 重動作障礙，暴躁且部分痴呆。其在雙盲試驗基礎下隨機 接受2克/天之乙基-EPA或2克/天之安慰劑共6個月。6個月期 間4位病患顯示進展性退化，而3位病患逆轉疾病之進程及 顯示具降低異常動作，降低情緒易變性和暴躁之改進及改 進記憶與認知功能。當密碼解開日夺’發現惡化之4位病患服 用安慰劑，而改進之全部3位病患皆服用乙基_EpA。在2位
O:\89\89537.DOC 1306120 服用乙基-EPA和2位安慰劑之4位病患中，腦部退化在研究 開始與結束時由磁共振造影（順)評估。_允許精確評估 侧腦室大小，即腦半球内之液體填充空間。當亨丁頓舞蹈 症進展時，側腦室擴大，指示著腦組織之損失。在服用安 慰劑之2位病患中’在6個月内側腦室如預期地擴大。在服 用：基舰之2位病患中，疆顯示側腦室大小之降低，指 示著腦組織損失之確實逆轉。 在由異常蛋白質蓄積所致之先前；^可治療,疾病末期之病 患中此些戲劇性結果展現在神經退化障礙中之乙基 值。 本發明在較可能對如此治療有反應之病患中由分析亨 丁亭基因而提供顯著進展。本發明提供以下優點，即可能 地，鑑定在發展疾病危險下之病患及投予EpA至病患以防止 或延緩疾病症狀之發展。 90%和較佳95%或甚至更純形式之EpA調配物可經熟諳 技藝者所知之傳送系統全部口服投藥，包括軟和硬明膠膠 囊；粉末、錠劑或膠囊形式之微膠囊；固體化合物鋰_EpA 之錠劑；或以適當天然或合成乳化劑，包括磷脂質或半乳 糖脂製成之乳化液。化合物亦可以腸外，直接或調配於不 同油或於乳化液或分散液投藥，使用靜脈内、腹膜内、肌 肉内或皮下途徑。使用貼片技術之局部投藥或陰道或直腸 形式之投藥亦在本發明範圍内。 當與用以緩和亨丁頓舞蹈症狀之藥物組合時，EPa化合 物和其他藥物可分開投藥’各以其自己之調配物。其可分
O:\89\89537.DOC •10- 1306120 開包裝或以相同之總包裝呈現。或者，使用熟諳技藝者已 知之技術’ EPA和其他藥物可一起調配，使得克至1〇克/ 天及較佳地0·5克至5克/天之EPA每曰劑量與其他藥物之正 常每日劑量一起提供。 當單獨投藥時，有用之ΕΡΑ每曰劑量可在〇.〇5克至5〇克/ 天，較佳地0.1克至10克/天及極佳地〇·5克至5克/天之範圍 【實施方式】 實例調配物 在以下之各實施例中，產品至少9〇%及較佳地95%或更 純。此很重要於其他脂肪酸將與ΕΡΑ競爭結合部位及降低其 效力。特別地，脂肪酸如DHA、ΑΑ、DPA-n-3分別將以少 於5 °/。及較佳少於3 %之濃度存在《如此競爭化合物之總聚集 物必須少於10%及較佳少於5%。此純度之程度亦有用於降 低每天必須消費之物質量’其為幫助精神病患順從性之重 要因子，而缺少順從性為其一個嚴重的問題。 1·由硬或軟明膠製成之膠囊，其含有250毫克、5〇〇毫克 或1〇〇〇毫克之乙基-EPA、三酸甘油酯EPA或其他合適形式 之 EPA。 2.含有250毫克、500毫克或1〇〇〇毫克鋰_EPA之錠劑，或 含有相似量之硬明膠膠囊。 3 乳化液、溶液或分散液，其中鋰-EPA、乙基-EPA、三 酸甘油酯EPA或其他合適形式之EPA，以美味液體形式製借 供口服投藥。 4.經調配5克EPA化合物之一至其中之栓劑或陰道藥栓。 O:\89\89537.DOC -11- 1306120 5.含有自10毫克至500毫克/毫升EPA化合物之一之靜脈 内溶液或乳化液。 6-10.如實例1-5，但使用EPA之2-取代衍生物。 11-20.如1-10，但其中EPA化合物與用以治療亨丁頓舞 蹈症狀之經常劑量任何其他藥物一起調配。 O:\89\89537.DOC -12-

Claims (1)

160號專利申請案 專利範圍替換本(97年8月） 拾、申請專利範圍： if I. 2曰更)正替換頁 ...... …_1 I _ 1. -種鑑定會對任何生物可利用形式之二十碳五烯酸㈣ 製備物冶療有反應之亨丁頓舞蹈症病患、或有發展亨丁 頓舞蹈症風險之個體之之方法，其中該EPA製備物中之所 有脂肪酸之至少90%為EPA形式且少於5%為二十二碳六 稀酸（DHA)形式’ S包括測定亨丁亭（Himtingtin)基因之 G重複序列數目之步驟，及識別具4 5個或更少重複序 列之個體。 士申叫專利範圍第1項之方法’其中該治療包括乙基φ 之投藥。 3 . 一種任何生物可利用形式之EPA製備物之用途，其中該 EPA製備物中全部脂肪酸之至少9〇%為EpA形式且少於 5%為二十二碳六烯酸（DHA)形式，其係用於製備用以 治療亨丁亭基因中具45或更少之CAG重複序列數目之亨 丁頓舞蹈症病患的藥劑。 4. 一種任何生物可利用形式之EPA製備物之用途，其中該 EPA製備物中全部脂肪酸之至少9〇%為EpA形式且少於 5%為二十二碳六烯酸（DHA)形式，其係用於製備用以 預防亨丁亭基因中具45或更少之CAG重複序列數目之有 發展予丁頓舞蹈症風險之病患的症狀發展的藥劑。 5. 如申請專利範圍第3或4項之用途，其中該EpA係乙基 形式。 6· 一種包含任何生物可利用形式之EPA製備物之醫藥組合 物’其中該EPA製備物中全部脂肪酸之至少9〇%為epa形 O:\89\89537.970826.DOC #』2辦(更)正替換ΐ 式且少於5%為二十二碳六烯酸（DHA)形式，其係用於 治療亨丁亭基因中具45或更少之CAG重複序列數目之亨 丁頓舞蹈症病患。 • 一種包含任何生物可利用形式之EPA製備物之醫藥組合 物’其中該EPA製備物中全部脂肪酸之至少90%為EPA形 式且少於5%為二十二碳六烯酸（DHA)形式，其係用於 預防予丁亭基因中具45或更少之CAG重複序列數目之有 發展亨丁頓舞蹈症風險之病患的症狀發展。
8.如申凊專利範圍第6或7項之醫藥組合物，其中該EPA係乙 基-EPA形式。
O:\89\89537.970826DOC
TW092133160A 2002-12-02 2003-11-26 Method of identifying hungtington's disease patients who will respond to epa treatment and related use of epa TWI306120B (en)

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