JP2018516231A - Crhr1拮抗薬を用いた治療に対する反応の遺伝子予測因子を用いた治療の方法 - Google Patents
Crhr1拮抗薬を用いた治療に対する反応の遺伝子予測因子を用いた治療の方法 Download PDFInfo
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- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
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Abstract
Description
本明細書において用いられる用語「含む(comprise)」または「含む(comprising)」は、「含む(containing)」または「含む(including)」と解釈されるべきであり、概して、他のエレメントまたはステップを排除しないが、任意選択の特定の実施態様として、用語「からなる(consisting of)」を包含する。したがって、特定の数の実施態様を含むと定義されるグループは、場合によりこれらの実施態様のみからなるグループの開示としても解釈されるべきである。単数名詞、例えば、「a」または「an」または「the」というときに、明白でない、または明白なアーティクルが用いられる場合は、特に述べられない限り、その名詞の複数形を含む。逆の場合も同様に、名詞の複数形が用いられる場合、それは単数形も指す。例えば、多型遺伝子型(複数)が言及される場合、これは、単一の多型遺伝子型としても理解されるべきである。
一態様では、本発明は、それを必要とする対象における、SSR−125543または薬学的に許容できるその塩によって治療可能な症状を治療する方法を提供し、有効量のSSR−125543または薬学的に許容できるその塩を対象に投与するステップを含み、ここで、対象は、SSR−125543または薬学的に許容できるその塩を用いた治療に対して反応することが予測されている、または、反応する可能性が高い。治療する方法は、SSR−125543または薬学的に許容できるその塩を用いた治療に対する対象(例えばヒト患者)の治療反応を予測するステップを含んでよい。
本開示は、治療の方法の検出ステップでの使用のための、ポリヌクレオチドを含む組成物(例えば、プローブ)、ならびに、キットおよびアレイをさらに提供する。ポリヌクレオチド組成物、キット、およびアレイは、例えば、(a)表2に開示される1つまたは複数の多型遺伝子型、(b)(a)の多型遺伝子型のいずれか1つと連鎖不平衡である1つまたは複数の多型遺伝子型、または、(a)および(b)の組み合わせの存在を検出するステップにおいて有用である。組成物、キットおよびアレイは、CRHR1拮抗薬を用いた治療に対する対象の治療反応を予測するステップにさらに有用である。
基礎科学の研究に基づき、CRHの役割を、鬱病で蔓延している兆候および症候の原因として認識して、実行可能な治療選択肢としてCRH/CRHR1シグナリングを阻害した。さらなる臨床知見は、CRHがコアの症候を引き起こす場合、鬱病を有する患者のサブグループにおいてCRHが上昇することを見いだした。化合物SSR−125543は、CRHの作用を阻害する特異的なCRHR1拮抗薬として、他のどこかで開発されている。プラセボおよび標準的な抗鬱薬と比較した、SSR−125543の有効性および忍容性を評価する臨床試験が、本発明による治療反応を予測せずに以前に行なわれている。しかしながら、さらなる試験(公表されず)に基づいて、大鬱病と診断された患者のうち、20〜30%のフラクションのみが中枢CRH過剰活性を有することが認識された。したがって、CRHR1拮抗薬を用いて治療された患者の約70〜80%が中枢CRH上昇を有さないことを考慮すると、層別されていない患者の相当なフラクションが治療反応を示さないだろう。薬理学的特異性を考慮すれば、中枢CRH過剰活性を有する患者のみが、SSR−125543を用いた治療から恩恵を受ける可能性がある。
表2に提供される多型遺伝子型のセットの有用性をさらに評価するために、予測変数として選択される最小限のサブセットを用いてさらなる予測を試験した。表2から選択されるわずか1個の多型遺伝子型、ならびに、表2から選択される2個、4個または8個の多型遺伝子型のサブセットは、例えばHAM−D尺度によって測定される臨床反応を予測する方法において有用であることが証明された。
前述の例示的な実施態様は、本明細書において開示される本発明の例示であると考えるべきであり、それに限定されない。様々な改変が、本発明の範囲または主旨を逸脱せずになされ得ることが、当業者に明らかである。したがって、本発明の範囲は、本来、添付の特許請求の範囲によって定義され、実施例として示されている具体的な実施態様によって制限されないことが理解されよう。特許請求の範囲と同等の意味および範囲内である全ての変更は、包含されることが意図される。
Claims (14)
- それを必要とする対象における、SSR−125543または薬学的に許容できるその塩によって治療可能な症状を治療する方法であって、
有効量のSSR−125543または薬学的に許容できるその塩を前記対象に投与するステップを含み、
ここで、前記対象は、SSR−125543または薬学的に許容できるその塩を用いた治療に対して反応することが予測されている、または、反応する可能性が高い、
方法。 - 請求項1の方法であって、
前記方法は:
前記対象から得られる生物学的サンプルを提供するステップ;
前記生物学的サンプル中の1つまたは複数の多型遺伝子型の存在または不存在を検出するステップ、
ここで、前記の1つまたは複数の多型遺伝子型は:
(a)rs34169260(A/G)、rs796287(A/C)、rs56149945(A/G)、rs6190(T/C)、rs7179092(T/C)、rs7614867(A/G)、rs920640(T/C)、rs7167722(T/C)、rs920638(T/C)、rs7165629(T/C)、rs80049044(T/A)、rs16941058(A/G)、rs112015971(A/G)、rs10894873(T/C)、rs117455294(T/G)、rs1170303(T/C)、rs16940681(C/G)、rs968519(T/C)、rs28381866(T/C)、rs79320848(T/G)、rs114653646(T/G)、rs2589496(T/C)、rs10482650(A/G)、rs17614642(A/G)、rs73200317(T/C)、rs1380146(T/A)、rs735164(T/C)、rs730976(T/G)、rs55934524(T/G)、rs4570614(A/G)、rs4458044(C/G)、rs77850169(A/G)、rs35339359(A/G)、rs34800935(T/C)、rs72945439(T/C)、rs113959523(A/G)、rs116798177(A/G)、rs11247577(T/G)、rs75869266(T/C)、rs74372553(T/C)、rs11691508(A/G)、rs6493965(A/G)、rs4869476(T/C)、rs3730170(T/C)、rs2145288(A/C)、rs2935752(A/C)、rs146512400(A/G)、rs62057097(T/C)、rs115061314(T/C)、rs34113594(T/G)、rs61751173(A/G)、rs74338736(A/C)、rs10851726(T/C)、rs4610906(T/C)、rs59485211(T/C)、rs7060015(T/G)、rs75710780(T/G)、rs6520908(T/C)、rs487011(T/G)、rs1383699(A/C)、rs67516871(A/G)、rs114106519(T/C)、rs7220091(A/G)、rs12489026(A/G)、rs876270(T/C)、rs4968161(T/C)、rs62056907(A/G)、rs2235013(T/C)、rs16878812(A/G)、rs6549407(A/G)、rs28381848(A/G)、rs79723704(A/C)、rs72814052(A/G)、rs10152908(T/C)、rs172769(A/C)、rs78596668(T/C)、rs73307922(T/C)、rs3842(A/G)、rs7210584(A/C)、rs62402121(T/C)、rs55709291(A/G)、rs72747088(A/G)、rs929610(G/C)、rs6766242(T/C)、rs1468552(G/C)、rs78838114(T/C)、rs62489862(T/C)、rs894342(A/G)、rs58882373(T/C)、rs3811939(A/G)、rs6984688(T/G)、rs1018160(T/C)、rs76602912(A/G)、rs80067508(A/G)、rs74888440(T/C)、rs12481583(T/C)、rs66794218(A/G)、rs16946701(A/G)、rs75726724(A/G)、rs67959715(T/A)、rs11871392(T/G)、rs2044070(A/G)、rs77612799(T/C)、rs6743702(T/C)、rs616870(T/C)、rs79590198(A/G)、rs75715199(A/G)、rs13087555(T/C)、rs4869618(T/C)、rs117397046(A/G)、rs8042817(A/G)、rs2258097(T/C)、rs2260882(C/G)、rs532996(A/G)、rs11747040(T/C)、rs10034039(T/G)、rs116909369(A/G)、rs79134986(A/G)、rs117615688(T/C)、rs8032253(T/C)、rs12818653(T/A)、rs4587884(A/C)、rs77122853(T/C)、rs117615061(T/C)、rs74682905(A/G)、rs2257468(T/C)、rs2032582(T/G)、rs2235015(T/G)、rs2729794(T/C)、rs77549514(A/G)、rs74790420(A/C)、rs73129579(T/C)、rs12913346(A/C)、rs117560908(T/C)、rs72747091(A/G)、rs2935751(A/G)、rs4331446(A/G)、rs7523266(T/C)、rs7648662(T/C)、rs117034065(A/G)、rs4836256(T/C)、rs80238698(T/C)、rs3730173(T/C)、rs11687884(T/C)、rs72693005(T/C)、rs2589476(T/C)、rs9813396(T/C)、rs10482667(A/G)、rs72784444(A/G)、rs75074511(T/C)、rs7951003(A/G)、rs79584784(A/G)、rs2214102(T/C)、rs28811003(A/G)、rs6100261(A/T)、rs77152456(A/G)、rs66624622(T/G)、rs140302965(A/G)、rs11653269(T/C)、rs74405057(A/G)、rs7121(A/G)、rs16977818(A/C)、rs12490095(T/C)、rs118003903(A/G)、rs62377761(T/C)、P1_M_061510_6_34_M(−/CACTTACCTTCTTTGTGCCACAGTTTCCCTATCTAAAACACAAGGTTATCAGTTATCAACATCTCTTGGGATTGTGAGGACTAAAGTAATGCACATAAAG)、rs375115639(−/AAATTACCCTGTTAGGTTTCAATGAAACACCTTTTCTCTTGTAACAAACATCTCCTCCAAGCTAGAATTTCAAAACAG)、rs1002204(A/C)、rs10062367(A/G)、rs10482642(A/G)、rs10482658(A/G)、rs1053989(A/C)、rs10851628(T/C)、rs10947562(T/C)、rs11069612(A/G)、rs11071351(T/C)、rs11091175(A/G)、rs11638450(T/C)、rs11715827(T/G)、rs11745958(T/C)、rs11834041(A/G)、rs1202180(T/C)、rs12054781(A/G)、rs12539395(A/G)、rs12720066(T/G)、rs1279754(A/C)、rs12872047(T/C)、rs12876742(A/C)、rs12917505(A/G)、rs13066950(T/G)、rs13229143(C/G)、rs1383707(T/C)、rs1441824(T/C)、rs1652311(A/G)、rs17064(T/A)、rs17100236(A/G)、rs17149699(A/G)、rs1724386(A/G)、rs17250255(A/G)、rs17327624(T/G)、rs17616338(A/G)、rs17687796(A/G)、rs17740874(T/C)、rs17763104(T/C)、rs1880748(T/C)、rs1882478(A/G)、rs1944887(T/C)、rs2028629(A/G)、rs2143404(A/G)、rs2173530(T/C)、rs220806(T/C)、rs2235047(A/C)、rs2242071(A/G)、rs2257474(T/C)、rs2295583(A/T)、rs234629(T/C)、rs234630(A/G)、rs2436401(A/G)、rs258750(T/C)、rs2589487(T/C)、rs28364018(T/G)、rs28381774(T/C)、rs28381784(A/G)、rs2963155(A/G)、rs3133622(T/G)、rs32897(T/C)、rs33388(A/T)、rs3730168(T/C)、rs3735833(T/G)、rs3777747(A/G)、rs3786066(T/C)、rs3798346(T/C)、rs3822736(A/G)、rs389035(T/C)、rs3924144(A/G)、rs4148737(T/C)、rs4148749(G/C)、rs417968(T/C)、rs4458144(T/C)、rs4515335(T/C)、rs4728699(A/G)、rs4758040(A/G)、rs4812040(A/G)、rs4912650(T/G)、rs4957891(T/C)、rs5906392(A/G)、rs6026561(T/C)、rs6026565(T/A)、rs6026567(A/G)、rs6026593(A/G)、rs6092704(T/G)、rs6100260(A/G)、rs6128461(T/C)、rs6415328(T/C)、rs6610868(T/C)、rs6686061(A/C)、rs6730350(T/G)、rs6746197(T/C)、rs6963426(T/C)、rs7121326(T/C)、rs7721799(A/G)、rs7787082(T/C)、rs7799592(A/C)、rs796245(T/C)、rs809482(A/C)、rs8125112(T/C)、rs919196(A/G)、rs920750(T/C)、rs9332385(A/G)、rs930473(T/G)、rs9324921(A/C)、rs9348979(A/G)、rs9571939(A/C)、およびrs9892359(T/C)からなる群より選択される少なくとも1つの多型遺伝子型;
(b)(a)の多型遺伝子型のいずれか1つと連鎖不平衡である少なくとも1つの多型遺伝子型;または
(c)(a)および(b)の組み合わせ、
を含む;および
(a)、(b)、または(c)の1つまたは複数の多型遺伝子型の存在または不存在から前記治療反応を予測するステップ、
を含む、
方法。 - 請求項2の方法であって、
前記の予測するステップは:
(a)前記対象が、SSR−125543または薬学的に許容できるその塩を用いた前記治療に対して反応するかどうか、または、反応する可能性が高いかどうか、判定するステップ;および/または
(b)前記対象が、SSR−125543または薬学的に許容できるその塩を用いた前記治療に対して反応しないかどうか、または、反応する可能性が低いかどうか、判定するステップ、
を含む、
方法。 - 請求項3の方法であって、
前記の判定するステップは、人工ニューラルネットワーク学習、決定木学習、決定木フォレスト学習(decision tree forest learning)、線形判別解析、非線形判別解析、遺伝子発現プログラミング、関連ベクターマシン、線形モデル、一般化線形モデル、一般化推定方程式、一般化線形混合モデル、弾性ネット、ラッソサポートベクターマシン学習、ベイジアンネットワーク学習、確率的ニューラルネットワーク学習、クラスタリング、および回帰分析からなる群より選択される1つまたは複数の統計分析方法を含み、
場合により、前記統計分析方法は、コンピューターで実行される、
方法。 - 請求項2から4のいずれか一項の方法であって、
前記の1つまたは複数の多型遺伝子型は:
請求項1で定義した多型遺伝子型の、
(a)少なくとも2個;
(b)少なくとも4個;
(c)少なくとも8個;
(d)少なくとも16個;
(e)少なくとも32個;または
(f)全て
を含む、
方法。 - 請求項2から4のいずれか一項の方法であって、
前記の1つまたは複数の多型遺伝子型は:
(a)表5に開示される多型遺伝子型の組み合わせから選択される少なくとも2個の多型遺伝子型;
(b)表6に開示される多型遺伝子型の組み合わせから選択される少なくとも4個の多型遺伝子型;
(c)表7に開示される多型遺伝子型の組み合わせから選択される少なくとも8個の多型遺伝子型;
(d)表2に開示される多型遺伝子型の全て
を含む、
方法。 - 請求項1から6のいずれか一項の方法であって、
SSR−125543または薬学的に許容できるその塩を用いた治療に対する前記治療反応は、臨床反応である、
方法。 - 請求項1から7のいずれか一項の方法であって、
前記対象は、鬱症状、不安症状、または鬱症状および不安症状の両方、または睡眠障害を有し;および/または
前記治療は、鬱症状、不安症状、または鬱症状および不安症状の両方、または睡眠障害の治療である、
方法。 - 請求項8の方法であって、
前記CRHR1拮抗薬を用いた治療に対する前記治療反応は、臨床反応であり、
前記臨床反応は、鬱症状および/または不安症状または睡眠障害の、予防、変更、軽減または完全寛解である、
方法。 - 請求項9の方法であって、
前記臨床反応は、HAM−D、BDI、MADRS、GDS、ZSRDS、HAM−AおよびSTAIからなる群より選択される尺度を用いて判定される、鬱症状および/または不安症状の予防、変更、軽減または完全寛解である、
方法。 - 請求項2から10のいずれか一項の方法であって、
前記生物学的サンプルは、口腔または血液サンプルである、
方法。 - 請求項2から11のいずれか一項の方法であって、
検出するステップは、前記の1つまたは複数の多型遺伝子型を含む少なくとも1つの核酸に特異的にハイブリダイズすることが可能な、1つまたは複数のポリヌクレオチドの使用を含む、
方法。 - 請求項2から12のいずれか一項の方法であって、
前記対象は、SSR−125543または薬学的に許容できるその塩が投与されていて、
SSR−125543または薬学的に許容できるその塩を用いた治療に前記対象が反応するという前記予測を、SSR−125543または薬学的に許容できるその塩の投与に対する前記対象の前記治療反応と、比較するステップをさらに含む、
方法。 - 請求項2から13のいずれか一項の方法であって、
SSR−125543または薬学的に許容できるその塩を用いた治療に前記対象が反応するという前記予測は、50%よりも高い感度および50%よりも高い特異性を有する、
方法。
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MA56226A (fr) * | 2018-12-07 | 2022-04-20 | Neurocrine Biosciences Inc | Antagoniste du récepteur crf1, formulations pharmaceutiques et ses formes solides pour le traitement de l'hyperplasie surrénale congénitale |
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WO2013160315A2 (en) * | 2012-04-23 | 2013-10-31 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Genetic predictors of response to treatment with crhr1 antagonists |
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US20180119221A1 (en) * | 2015-04-02 | 2018-05-03 | Hmnc Value Gmbh | Method of Treatment Using Genetic Predictors of a Response to Treatment with CRHR1 Antagonists |
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