CN1717497A - 用epa治疗亨廷顿氏病 - Google Patents

用epa治疗亨廷顿氏病 Download PDF

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CN1717497A
CN1717497A CNA2003801044204A CN200380104420A CN1717497A CN 1717497 A CN1717497 A CN 1717497A CN A2003801044204 A CNA2003801044204 A CN A2003801044204A CN 200380104420 A CN200380104420 A CN 200380104420A CN 1717497 A CN1717497 A CN 1717497A
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戴维·F·霍罗宾
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Abstract

亨廷顿基因的分析提供了一种鉴定可能对用二十碳五烯酸(EPA)治疗亨廷顿氏病响应的病人的方法。

Description

用EPA治疗亨廷顿氏病
亨廷顿氏病(HD)是由于人4号染色体上的亨廷顿蛋白基因的突变而导致的致命性遗传疾病。呈任何合适药物剂型的脂肪酸-二十碳五烯酸(EPA)可用于治疗HD(如欧洲专利申请1148873所述)。
本发明涉及HD的治疗，并且本发明是基于下述发现：EPA的治疗效果特别地出现于那些具有HD特定遗传型的病人。
本发明提供了一种鉴别患有HD的病人、或那些处于HD发病危险中的的个体、那些特别可能对用呈任何合适形式的EPA治疗响应的个体的方法，其包括进行测试以确定亨廷顿蛋白基因中的CAG重复数和鉴定具有45或以下重复数的那些受试者的步骤。
如果受试者具有小于36的重复数，则表明其为正常个体。在优选的测试中，所选的受试者具有44或以下、或者36-44的CAG重复数。
仅仅出于分析的目的，可以从受试者上采集的样本进行测试且不用让样本返回受试者。该诊断步骤将在体外进行。
本发明还提供了一种治疗HD的方法，和一种预防处于HD发病危险中的的个体的症状发展的方法，其包括下述步骤：确定受试者的亨廷顿蛋白基因中的CAG重复数，并且如果CAG重复数为45或以下，则向受试者给予呈任何可生物利用形式的EPA。在优选的测试中，选定给药EPA的受试者具有44或以下、或者36-44的CAG重复数。
用于本发明方法的EPA优选是乙基-EPA。
CAG重复数46或以上的受试者对于给药安慰剂与给药EPA的治疗完全没有显示出任何不同。相反，出人意料地，CAG重复数45或以下的患HD病人对于给药EPA显示出很大的受益。
虽然所有的HD病人具有相同基因的遗传异常，但不是所有的病人具有相同的异常。亨廷顿蛋白的正常基因含有CAG重复序列，其编码该基因自身的聚谷氨酰胺序列。即使在正常个体中，聚谷氨酰胺序列也具有可变化的长度，但是只要其含有小于36的CAG重复数，也即是聚谷氨酰胺序列中含有小于36个谷氨酰胺，个体将是正常的。但是，当该序列含有36或以上的CAG重复数以及谷氨酰胺序列时，将发展为HD。患有HD的病人可具有36至大于100的CAG重复数中的任何CAG重复数。
HD通常从运动失调开始，特别是影响面部、头部和颈部及四肢。这些进展常伴随精神异常和认知缺损导致痴呆。该异常起初是由对纹状体的神经元的亨廷顿蛋白损伤而引起的，但随后涉及到大范围的脑部。最终，病人变得卧床不起并完全不能自理。他们通常在发病后10-25年死去。
CAG重复数对于发病年龄有强烈的影响。重复数恰好超过35的病人直到50岁或60岁或者更晚一些才会得病。重复数超过60的病人在青春期或者甚至在幼年期就会得病。但是，大多数病人在30-50岁得病。一旦开始发病，具有大的CAG重复数的病人趋向于病情发展得更快，虽然该作用与上述对发病年龄的强烈作用相比是微弱的。
CAG重复数可以通过基于聚合酶链反应(PCR)的诊断测试进行鉴定。这种测试提供了可靠的HD诊断，并且当然可应用于未显示出症状的病人。但是，那些处于HD基因携带者危险之中的相对少的未显示出症状的个体，和在某一时候必然发病的个体会给测试带来麻烦。许多具有HD症状的人也未进行测试。不进行测试的主要观点在于目前没有HD的治疗方法，即使能精确地知道该基因存在以及该基因的类型也没有意义。
二十碳五烯酸乙酯(乙基-EPA)的HD临床试验为EPA对HD的有益效果提供了强有力的证据，并且完全出人意料地，为CAG遗传测试的价值也提供了强有力的证据。
让135位已经遗传确认的HD病人进行1年的试验。将他们随机分组，给药2g/天的乙基-EPA或外观相同的安慰剂。在基线、6个月和12个月时用Unified Huntington’s Disease Rating Scale(UHDRS)的全运动计分(TMS)测量对他们进行评估。UHDRS是标准的分级评定，用于监测HD的发展。TMS是UHDRS的组成部分，其改变最可靠、快捷且一致，因而适合用来监测临床试验的结果。
一年结束时，比较安慰剂组和乙基-EPA组的TMS变化。总的说来，乙基-EPA比安慰剂有更好的结果，但统计学上不显著。但是，当按照CAG重复数将病人分层次时，揭示出乙基-EPA引人注目的益处。CAG重复数为46或以上的病人对于安慰剂和乙基-EPA完全没有显示出任何不同。相反，CAG重复数低于45的病人显示出乙基-EPA的很大益处。CAG重复数45及以下的安慰剂病人平均恶化了5.3％。相反，乙基-EPA组病人一年后改善了19.3％。该差别对于协方差分析或卡方检验均有很高的统计学意义。特别惊人的是，绝大多数乙基-EPA组病人实质上已有所改善。以前，对于神经变性疾病如HD最希望的是延缓的恶化而非任何实质的改善。由于一年之后，乙基-EPA组病人比安慰剂组病人改善了3.5倍还多，这意味着一年之后，EPA病人已与安慰剂病人相隔了大于4.5年的病程。换句话说，受治疗的病人获得了至少4.5年的有用生活。相反，CAG重复数46或以上的病人对于乙基-EPA和安慰剂治疗没有显示出任何不同。
优选地，在本发明治疗方法中和在延缓或预防亨廷顿氏病发病的方法中，所述EPA治疗实质上是在欧洲专利申请1148873中所述的。
优选使用纯的或几乎纯的EPA及EPA衍生物。DHA和相关的脂肪酸不仅无效，而且实际上会降低EPA及其衍生物的功效。
优选的制剂包含呈合适的可吸收形式的EPA，其中制剂中所有脂肪酸的至少90％、优选至少95％是EPA形式，小于5％并优选小于3％的脂肪酸是二十二碳六烯酸。
优选地，在存在的其它脂肪酸中各自分别有小于5％并优选小于3％的AA或DPA-n-3。同样的优选适用于任何会与EPA竞争的其它脂肪酸。
优选，DHA、AA和/或DPA-n-3的总含量小于总脂肪酸的10％，并优选小于5％。
EPA可以是乙基-EPA、EPA锂、EPA的甘油单酯、双酯或三酯、或者EPA的任何其它酯或盐、或者EPA的游离酸形式。EPA还可以是2-取代的衍生物或其它衍生物形式，其减慢了氧化的速率但并不在任何实质程度上改变其对精神或脑失调的生物作用(N.Willumsen等人，BiochimicaBiophysica Acta，1998，1369：193-203)。
EPA可以与主要作用于神经递质代谢或受体的药物联用。适合与EPA制剂联合用药的药物是氯氮平；和任何一种典型或非典型神经镇静剂，包括氯丙嗪、氟哌啶醇、利哌利酮、奥氮平、舍吲哚、齐拉西酮、佐替平或阿米舒必利(amisulpiride)。用于缓解亨廷顿氏病的一些症状的标准抗精神分裂症药、抗抑郁药、镇静剂、和抗癫痫药，可以与EPA制剂一起给药。
根据EP申请1148873的一个治疗亨廷顿氏病的例子，对7名处于亨廷顿氏病晚期的严重失能的病人设定了96％纯的乙基-EPA的随机试验。所有的病人均需要24小时护理，患有严重的运动失调，易怒且部分痴呆。根据双盲基准将他们随机分为给药2g/天乙基-EPA或2g/天安慰剂，并给药6个月。6个月期间，4名病人呈现进展恶化，而3名病人逆转了病程并呈现出下述改善：异常运动减少，情绪不稳定和易怒减少，以及记忆力和认识功能改善。当编号公开时发现恶化的4名病人均是给药安慰剂，而改善的3名病人均是给药乙基-EPA。在2名给药乙基-EPA和2名给药安慰剂的4名病人中，在研究开始和结束时用核磁共振成像(MRI)评定脑退化。MRI能提供侧脑室大小、脑半球中充液空间的准确评定。随着亨廷顿氏病的进展，侧脑室变大，这表明脑组织丧失。6个月后，给药安慰剂的2名病人的侧脑室如预料到的变大。MRI显示给药乙基-EPA的2名病人的侧脑室大小减小，这表明实质上逆转了脑组织丧失。
上述处于由异常蛋白质积聚导致的以前不能治疗疾病的末期的病人的引人注目的结果证明了乙基-EPA对于神经变性疾病的价值。
本发明提供了通过分析亨廷顿蛋白基因鉴定那些可能对上述治疗响应的病人的显著进展。本发明提供了下述优点：可以鉴定那些处于发病危险中的病人，并向他们给予EPA以预防或延缓该疾病症状的发展。
呈90％并优选95％或更纯一些的形式的EPA制剂均可以通过本领域熟练技术人员已知的输送体系口服给药，包括软和硬明胶胶囊、粉状微胶囊、片剂或胶囊剂、固体化合物EPA锂的片剂、或者用合适的天然或合成乳化剂包括磷脂或半乳糖脂形成的乳剂。该化合物还可以直接地给药或配制成各种油状或乳剂或分散剂经肠胃外给药，利用静脉、腹膜内、肌内或皮下途径。使用膜片术或者阴道或直肠应用剂型的局部应用也在本发明范围内。
当与用于减轻亨廷顿氏病症状的药物联合使用时，EPA化合物和其它药物可以以其各自的剂型分别给药。它们可以分别包装或者存在于同一总包装中。或者，使用本领域熟练技术人员已知的技术，可以将EPA和其它药物一起配制，由此EPA的每日剂量为0.1-10g/天，并优选0.5-5g/天，并伴有其它药物的正常日剂量。
当单独给药时，EPA的有效日剂量可以为0.05-50g/天，优选0.1-10g/天，更优选优选0.5-5g/天。
实施例制剂
在下述各个实施例中，产品纯度为至少90％，并优选95％或更纯。这一点非常重要，因为其它脂肪酸会与EPA竞争结合位点并降低其功效。具体地，脂肪酸例如DHA、AA、DPA-n-3各自存在的浓度小于5％并优选小于3％。上述竞争化合物的总累加值必须小于10％并优选小于5％。纯度还对于最小化每天必须服用的物质的体积有用，这是有助于精神病人顺从性的主要因素，其中缺乏顺从性是这类病人中的一个严重的问题。
1.由硬或软明胶制成的胶囊，其含有250mg、500mg、或1000mg的乙基-EPA、EPA甘油三酯或其它合适形式的EPA。
2.含有250mg、500mg、或1000mg EPA锂的片剂或含有类似量的硬明胶胶囊。
3.乳剂、溶液或分散剂，其中EPA锂、乙基-EPA、EPA甘油三酯或其它合适形式的EPA配制成适于口服给药的可口液体形式。
4.栓剂或阴道环，其中配制有100mg-5g的一种EPA化合物。
5.静脉注射溶液或乳剂，含有10mg-500mg/ml的一种EPA化合物。
6-10.与实施例1-5一样，但使用2-取代的EPA衍生物。
11-20.与实施例1-10一样，但其中将EPA化合物与有效量的用于治疗亨廷顿氏病症状的任何其它药物一起配制。

Claims (5)

1.一种鉴定患有亨廷顿氏病的病人、或那些处于亨廷顿氏病发病危险之中的个体、那些将会对用呈任何生物可利用形式的EPA治疗响应的个体的方法，包括确定亨廷顿蛋白基因中的CAG重复数，并鉴定具有45或以下重复数的那些受试者的步骤。
2.根据权利要求1的方法，其中治疗包括给药乙基-EPA。
3.一种治疗亨廷顿氏病的方法，其包括步骤：鉴定亨廷顿蛋白基因中的CAG重复数为45或以下的病人，并且向那些病人给予呈任何可生物利用形式的EPA。
4.一种预防处于亨廷顿氏病发病危险之中的个体的症状发展的方法，其包括步骤：鉴定亨廷顿蛋白基因中的CAG重复数为45或以下的病人，并且向那些个体给予呈任何可生物利用形式的EPA。
5.根据权利要求3或4的方法，其中给予的EPA是呈乙基-EPA形式。
CNA2003801044204A 2002-12-02 2003-11-26 用epa治疗亨廷顿氏病 Pending CN1717497A (zh)

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Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007524674A (ja) * 2004-01-19 2007-08-30 マーテック・バイオサイエンシーズ・コーポレーション リーリン欠損症または機能障害およびそれに関連する方法
WO2007123391A1 (en) 2006-04-20 2007-11-01 Academisch Ziekenhuis Leiden Therapeutic intervention in a genetic disease in an individual by modifying expression of an aberrantly expressed gene.
EP1857548A1 (en) 2006-05-19 2007-11-21 Academisch Ziekenhuis Leiden Means and method for inducing exon-skipping
ATE524547T1 (de) 2006-08-11 2011-09-15 Prosensa Technologies Bv Einzelsträngige oligonukleotide, welche komplementär zu repetitiven elementen sind, zur behandlung von dns-wiederholungen-instabilitäts- assoziierten erkrankungen
AU2008273094B2 (en) 2007-07-12 2013-05-09 Prosensa Technologies B.V. Molecules for targeting compounds to various selected organs, tissues or tumor cells
CA2693048C (en) 2007-07-12 2016-10-18 Prosensa Technologies B.V. Molecules for targeting compounds to various selected organs or tissues
CA2704049A1 (en) 2007-10-26 2009-04-30 Academisch Ziekenhuis Leiden Means and methods for counteracting muscle disorders
USRE48468E1 (en) 2007-10-26 2021-03-16 Biomarin Technologies B.V. Means and methods for counteracting muscle disorders
JP2011510678A (ja) 2008-02-08 2011-04-07 プロセンサ ホールディング ビーブイ Ｄｎａ反復不安定性関連遺伝性障害を治療するための方法及び手段
EP2119783A1 (en) 2008-05-14 2009-11-18 Prosensa Technologies B.V. Method for efficient exon (44) skipping in Duchenne Muscular Dystrophy and associated means
EP3578177A1 (en) 2008-09-02 2019-12-11 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same
KR20140007973A (ko) 2009-02-10 2014-01-20 아마린 파마, 인크. 고중성지방혈증 치료 방법
AU2010239779A1 (en) 2009-04-24 2011-11-17 Prosensa Technologies B.V. Oligonucleotide comprising an inosine for treating DMD
NZ624963A (en) 2009-04-29 2016-07-29 Amarin Pharmaceuticals Ie Ltd Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same
BRPI1011876B1 (pt) 2009-04-29 2020-03-31 Amarin Pharma, Inc. Composições farmacêuticas estáveis compreendendo etilácido eicosapentaenoico (etil-epa) e uso das mesmas para tratar ou prevenir uma doença relacionada ao cardiovascular
CN102625847A (zh) 2009-06-15 2012-08-01 阿马里纳制药公司 在相伴他汀类疗法的对象中降低甘油三酯、没有增加ldl-c水平的组合物和方法
AU2010298222B2 (en) 2009-09-23 2017-01-05 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
AU2010335039B2 (en) 2009-12-24 2015-03-26 Academisch Ziekenhuis Leiden H.O.D.N. Lumc Molecule for treating an inflammatory disorder
AU2011336856A1 (en) 2010-11-29 2013-07-04 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US20130131170A1 (en) 2011-11-07 2013-05-23 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US11291643B2 (en) 2011-11-07 2022-04-05 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
ES2891473T3 (es) 2012-01-06 2022-01-28 Amarin Pharmaceuticals Ie Ltd Composiciones y métodos para reducir los niveles de alta sensibilidad (hs-CRP) en un sujeto
CN104203289B (zh) 2012-01-27 2020-11-03 比奥马林技术公司 用于治疗杜兴型肌营养不良症和贝克型肌营养不良症的具有改善特性的rna调节性寡核苷酸
SG10201913645RA (en) 2012-06-29 2020-03-30 Amarin Pharmaceuticals Ie Ltd Methods of reducing the risk of a cardiovascular event in a subject on statin therapy
WO2014074552A2 (en) 2012-11-06 2014-05-15 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy
US20140187633A1 (en) 2012-12-31 2014-07-03 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
US9814733B2 (en) 2012-12-31 2017-11-14 A,arin Pharmaceuticals Ireland Limited Compositions comprising EPA and obeticholic acid and methods of use thereof
US9452151B2 (en) 2013-02-06 2016-09-27 Amarin Pharmaceuticals Ireland Limited Methods of reducing apolipoprotein C-III
US9624492B2 (en) 2013-02-13 2017-04-18 Amarin Pharmaceuticals Ireland Limited Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof
US9662307B2 (en) 2013-02-19 2017-05-30 The Regents Of The University Of Colorado Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof
US9283201B2 (en) 2013-03-14 2016-03-15 Amarin Pharmaceuticals Ireland Limited Compositions and methods for treating or preventing obesity in a subject in need thereof
US20140271841A1 (en) 2013-03-15 2014-09-18 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
US10966968B2 (en) 2013-06-06 2021-04-06 Amarin Pharmaceuticals Ireland Limited Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof
US20150065572A1 (en) 2013-09-04 2015-03-05 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing prostate cancer
US9585859B2 (en) 2013-10-10 2017-03-07 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US10561631B2 (en) 2014-06-11 2020-02-18 Amarin Pharmaceuticals Ireland Limited Methods of reducing RLP-C
WO2015195662A1 (en) 2014-06-16 2015-12-23 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense ldl or membrane polyunsaturated fatty acids
US10406130B2 (en) 2016-03-15 2019-09-10 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
US10966951B2 (en) 2017-05-19 2021-04-06 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject having reduced kidney function
US11058661B2 (en) 2018-03-02 2021-07-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L
MA51765A (fr) 2018-09-24 2020-12-16 Amarin Pharmaceuticals Ie Ltd Procédés de réduction du risque d'événements cardiovasculaires chez un sujet
US11986452B2 (en) 2021-04-21 2024-05-21 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2116280A1 (en) * 1993-03-05 1994-09-06 Marcy E. Macdonald Huntingtin dna, protein and uses thereof
CA2216057A1 (en) * 1997-09-19 1999-03-19 Ridha Joober Polymorphic cag repeat-containing gene, diagnosis of psychiatric diseases and therapeutic uses thereof
GB9901809D0 (en) * 1999-01-27 1999-03-17 Scarista Limited Highly purified ethgyl epa and other epa derivatives for psychiatric and neurological disorderes
EP1223937A2 (en) * 1999-10-07 2002-07-24 Novaneuron Inc. Gene necessary for striatal function, uses thereof, and compounds for modulating same

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