CN114007600A - 与神经系统病症的治疗响应有关的遗传变异 - Google Patents
与神经系统病症的治疗响应有关的遗传变异 Download PDFInfo
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Abstract
描述了治疗抑郁症、重性抑郁症、自杀意念和相关病症的方法，通过基于受试者的基因型向受试者施用L‑4‑氯犬尿氨酸(L‑4‑Cl‑KYN)。
Description
相关申请的交叉引用
本申请要求2019年4月9日提交的美国申请62/831,417和2019年7月25日提交的美国申请62/878,433的优先权，其公开内容通过引用并入本文。
技术领域
本发明涉及治疗神经系统病症的方法，所述神经系统病症包括抑郁症、重度抑郁症、自杀意念以及至少部分由NMDA受体介导的其他病症，通过基于受试者的基因型向受试者施用L-4-氯犬尿氨酸(L-4-Cl-KYN)。
背景技术
抑郁症包括常见但严重的大脑病症，其特征是体征和症状的组合，可能包括绝望、内疚、无价值感和/或悲伤以及睡眠和/或饮食模式的改变。
虽然，大多数人在其一生当中的某些时刻都会经历抑郁的情绪，但是重度抑郁症(MDD)是不一样的。MDD是长期的普遍存在的完全不快乐和痛苦的感觉，这危害到了日常活动。MDD的症状包括对活动丧失兴趣、食欲上的改变导致体重的改变、失眠或者嗜睡、精神运动性兴奋、精力不足或疲惫增加、无价值感或不适当的内疚感、难以思考、难以集中注意力或者难以做出决定和有死亡或自杀的想法并且企图自杀。MDD是抑郁症最普遍的类型。
在抑郁症中，自杀的风险显著增高，但是，受试者对于药物相对整体抑郁症状的响应可能有所不同。自杀，又被称为自杀身亡，是“结束自己生命的行为”。自杀未遂或者非致命的自杀行为是渴望结束某人的生命而未导致死亡的自我伤害。自杀意念是医学术语，指关于自杀的想法或者对自杀的异常关注，或者是指结束某人生命的想法或者不希望继续存活，但是不一定采取了任何积极的行动去这样做。当自杀意念发生时，它通常会伴随着无价值感或者不合适的内疚感以及反复出现的死亡或者自杀意念的想法，并且内疚是自杀的公认的代表。自杀意念通常与抑郁症有关(约占所有病例的60-70％)。
自杀意念的范围变化大，从一闪而过到长期，并进展到详细的计划、角色扮演再到尝试不成功，有可能会故意造成失败或者被人发现，或者也可能是完全旨在导致死亡。虽然不是所有具有自杀意念的人都会进行自杀的尝试，但是自杀的比例很大。
美国专利号9,993,453描述了治疗抑郁症的方法，包括向有需要的人类受试者口服施用治疗有效量的L-4-Cl-KYN的步骤，L-4-Cl-KYN是7-氯犬尿喹啉酸(7-Cl-KYNA)的前药，7-Cl-KYNA是内源性神经调质犬尿喹啉酸的合成的氯化类似物。如Zanos et al.,JPharmacol.Exp.Ther.355:76-85，(2015)中所描述的，7-氯犬尿喹啉酸已被证明可防止兴奋毒性和缺血性神经元损伤，但像大多数GlyB拮抗剂一样不能穿越血脑屏障。因此，限制了它的临床使用。然而，相反，L-4-Cl-KYN在施用后容易进入中枢神经系统(CNS)。L-4-Cl-KYN在活化的星形胶质细胞内可以有效地转化为7-氯犬尿喹啉酸，并且，由于星形胶质细胞的活化，使得脑中的7-氯犬尿喹啉酸的水平在神经元损伤或兴奋毒性损害的位置处增高。
发明内容
本发明总体上涉及治疗患有神经系统病症的受试者的方法，所述神经系统病症包括抑郁症、重度抑郁症和/或自杀意念，通过基于受试者的基因型向受试者施用L-4-Cl-KYN。
一方面，本发明涉及通过检测犬尿氨酸3-单加氧酶(KMO)基因变异、SLC7A5中性氨基酸转运蛋白基因变异、脑源性神经营养因子(BDNF)基因变异，以及氨基羧基粘康酸半醛脱羧酶(aminocarboxymuconate semialdehyde decarboxylase，ACMSD)基因变异中的至少一种来预测患有抑郁症、重度抑郁症和/或自杀意念的受试者对L-4-Cl-KYN治疗的响应性，其中该方法包括从受试者获得样本；和化验样本以检测KMO中单核苷酸多态性(SNP)的rs61825638的T等位基因、SLC7A5中SNP的rs28582913的T等位基因、BDNF中rs6265位点的普通G等位基因和ACMSD中SNP的rs2121337的C等位基因中的一种或多种。
另一方面，本发明涉及治疗受试者的抑郁症、重度抑郁症和/或自杀意念的方法，其中，该方法包括从受试者获得样本；化验样本以检测KMO中单核苷酸多态性(SNP)的rs61825638的T等位基因、SLC7A5中SNP的rs28582913的T等位基因、BDNF中SNP的rs6265的A等位基因和ACMSD中SNP的rs2121337的C等位基因中的一种或多种；和基于样本中这些检测到的至少一种变异的存在，向受试者施用治疗有效量的L-4-Cl-KYN来治疗受试的者的抑郁症、重度抑郁症或自杀意念。
本发明的另外一方面涉及预测患有抑郁症、重度抑郁症和/或自杀意念并且向受试者施用L-4-Cl-KYN进行治疗的受试者的潜在响应性的方法，该方法包括从受试者获取样本；和化验样本以检测KMO中单核苷酸多态性(SNP)的rs61825638的T等位基因、SLC7A5中SNP的rs28582913的T等位基因、BDNF中SNP的rs6265的A等位基因和ACMSD中SNP的rs2121337的C等位基因中的一种或多种，且其中至少一种基因变异的缺失或存在表明受试者对于该治疗的响应性。
附图说明
图1示出了SLC7A5基因变异对L-4-氯犬尿氨酸穿过血脑屏障运输的影响。LAT1(SLC7A5)蛋白主动地将AV-101(L-4-氯犬尿氨酸)和其他中性氨基酸从血液穿过血脑屏障运输进入大脑。在人类中，LAT1存在于多种基因变异中。与其最常见的基因形式相比，含有rs28582913的C/T变异的LAT1基因变异会导致更多的AV-101通过主动运输进入大脑。这使得具有rs28582913的C/T变异的患者的大脑中局部产生相对较高水平的7-氯犬尿喹啉酸，它是L-4-氯犬尿氨酸(AV-101)的活化代谢物。
图2示出了KMO基因变异对大脑中7-氯犬尿喹啉酸水平的影响。在大脑中，AV-101主要有两种代谢途径。一种涉及犬尿氨酸转氨酶(KAT)，该酶可以产生AV-101的治疗活性分子7-氯犬尿喹啉酸。另外一种途径涉及KMO酶，该酶可以导致AV-101的降解。KMO降解途径越活跃，可以转化为具有活性的7-氯犬尿喹啉酸代谢物的AV-101就越少。在人类中，KMO基因的基因变异会影响KMO的功能活性。rs61825638的C/T的变异会导致KMO的功能相对降低，因此，导致较高的7-氯犬尿喹啉酸。
图3示出了犬尿氨酸途径的简化图，ACMSD，氨基-β-羧基粘康酸半醛脱羧酶；HAAO，羟基邻氨基苯甲酸3,4-双加氧酶；IDO，吲哚胺2,3-双加氧酶；KAT，犬尿氨酸转氨酶；KMO，犬尿氨酸3-单加氧酶；KYNU，犬尿氨酸酶；NAD，烟酰胺腺嘌呤二核苷酸；QPRT，喹啉酸磷酸核糖转移酶；TDO，色氨酸2,3-双加氧酶。该图还包括了ACMSD基因中SNP的rs2121337(T→C)功能关联性的描述。这种多态导致ACMSD的活性降低，并随之增加喹啉酸的水平，这与更高的自杀企图率有关。
具体实施方式
参考下述详细的说明性实施例，描述本发明。对本领域的技术人员来说很明显，本发明可能以多种形式表现出来，其中一些形式可能与公开的实施例的形式大不相同。因此，下面所公开的具体结构和功能性的细节仅具有代表性，并不限制本发明的范围。
人们认为，受试者对L-4-Cl-KYN的临床响应在一定程度上由受试者的基因型决定，该基因型与受试者对L-4-Cl-KYN的新陈代谢相关，也与L-4-Cl-KYN穿过受试者的血脑屏障的运输相关。
KMO是黄素腺嘌呤二核苷酸(FAD)依赖性单加氧酶，位于线粒体外膜，其在那里将L-犬尿氨酸转化为3-羟基犬尿氨酸。犬尿氨酸代谢途径水平的紊乱与一系列脑部病症的发病机制(Schwarcz,R.,Bruno,J.P.,Muchowski,P.J.&Wu,H.-Q.,Kynurenines in themammalian brain:when physiology meets pathology.Nature Rev.Neurosci.13,465-477(2012))，以及癌症(Platten,M.,Litzenburger,U.&Wick,W.The aryl hydrocarbonreceptor in tumor immunity.Oncoimmunology 1,396-397(2012),和Liu,X.,Newton,R.C.,Friedman,S.M.&Scherle,P.A.，lndoleamine 2,3-dioxygenase,an emergingtarget for anti-cancer therapy.Curr.Cancer Drug Targets 9,938-952(2009))和一些外周炎症状况(Filippini,P.et al.,Emerging concepts on inhibitors ofindoleamine 2,3-dioxygenase in rheumatic diseases.Curr.Med.Chem.19,5381-5393(2012),Marta Amaral et al.Nature，496,382-385(2013))有关。带有参考SNP簇，ID号为rs61825638的KMO基因座具有单核苷酸多态性，其中，位于染色体1上241550102位置处的次要等位基因T而非C存在于约3-30％的人群中，具体取决于种族(https://www.ncbi.nlm.nih.gov/snp/rs61825638#frequency_tab),并且导致KMO合成减少，同时KYNA的产量增加2.14倍。(Long et al.,2017,Nature Genetics,49:568-581.)
在不受任何特定理论约束的情况下，人们认为SNP的rs61825638的T等位基因与对L-4-Cl-KYN的响应性的增加有关，原因有两个：1)KMO代表远离KAT的可替代途径和7-Cl-KYNA产生；因此，大脑中KMO活性的降低会使得向受试者施用更多的L-4-Cl-KYN，并且增加了大脑中向活性代谢产物7-Cl-KYNA的转化；2)KMO在PBMC、肝脏、脾脏和肾脏中高度表达，并且外周活动的减少会使得向受试者施用更多可以传输至大脑的L-4-Cl-KYN。
L型氨基酸转运蛋白1(LAT1，SLC7A5)是SLC7家族中的一部分，通过二硫键与CD98形成异二聚体(Mastroberardino,L.et al.,Amino-acid transport by heterodimers of4F2hc/CD98and members of a permease family.Nature 395,288-291,doi:10.1038/26246(1998))。CD98(4F2hc,SLC3A2)是II型糖蛋白，作为LAT1的分子伴侣发挥作用，稳定并促进其向质膜的易位。LAT1是综合体的功能单元(Napolitano,L.et al.,LAT1 is thetransport competent unit of the LAT1/CD98 heterodimeric amino acidtransporter.The international journal of biochemistry&cell biology,doi:10.1016/j.biocel.2015.08.004(2015))，并且底物包括一系列大型中性氨基酸，如酪氨酸、亮氨酸、异亮氨酸、缬氨酸和苯丙氨酸以及包括L-DOPA和加巴喷丁的药物。(Dickens,D.et al.,Transport of gabapentin by LAT1(SLC7A5).Biochem Pharmacol 85,1672-1683,doi:10.1016/j.bcp.2013.03.022(2013)；Uchino,H.et al.,Transport of aminoacid-related compounds mediated by L-type amino acid transporter 1(LAT1):insights into the mechanisms of substrate recognition.Molecular pharmacology61,729-737(2002))。rsid号为rs28582913的SLC7A5基因座具有单核苷酸多态性，其中，位于在第16号染色体上87843494位点的次要等位基因T而非C存在于约18～56％的人群中，这具体取决于种族(https://www.ncbi.nlm.nih.gov/snp/rs28582913#frequency_tab)，并且导致犬尿氨酸代谢产物增加1.94倍。(Long et al.,2017，Nature Genetics,49：568-581.)AV-101是LAT1转运体的基质。过度表达LAT1的HEK-293细胞表明AV-101吸收量的大幅增加。当添加LAT1抑制剂JPH203时，AV-101吸收量显著降低。人脑内皮细胞也显示出AV-101的大量吸收。在JPH203的存在下，这种吸收显著减少。此外，生理氨基酸可减少LAT1介导的AV-101的转运。
在不受任何特定理论约束的情况下，人们认为SNP的rs28582913的T等位基因与对L-4-Cl-KYN的响应性的增加有关，因为L-4-Cl-KYN进入大脑的主动转运增加，导致产生更多的活性代谢物7-氯犬尿喹啉酸。
BDNF的上调与速效抗抑郁药的积极治疗效果有关，参见See Kato,T.,et al.,(2017)."BDNF release and signaling are required for the antidepressantactions of GLYX-13."Mol Psychiatry；Le pack,A.E.et al.,(2016).“Fast-actingantidepressants rapidly stimulate ERK signaling and BDNF release in primaryneuronal cultures."Neuropharmacology 111:242-252；Lepack,A.E.et al.,(2014).“BDNF release is required for the behavioral actions of ketamine."Int JNeuropsychopharmacol 18(1):10.1093/ijnp/pyu1033pyu1033；Quesseveur,G.,et al.,(2013)."BDNF overexpression in mouse hippocampal astrocytes promotes localneurogenesis and elicits anxiolytic-like activities."Transl Psychiatry 3:e253；Li,C.F.et al.,(2016)."Activation of hippocampal BDNF signaling isinvolved in the antidepressant-like effect of the NMDA receptor antagonist 7-chlorokynurenic acid."Brain Res 1630:73-82；Gerhard,D.M.和R.S.Duman(2018).“Rapid-Acting Antidepressants:Mechanistic Insights and Future Directions."Curr Behav Neurosci Rep 5(1):36-47；Haile,C.N.,et al.,(2014)."Plasma brainderived neurotrophic factor(BDNF)and response to ketamine in treatment-resistant depression."Int J Neuropsychopharmacol17(2):331-336；Laje,G.,et al.,(2012).“Brain-derived neurotrophic factor Val66Met polymorphism andantidepressant efficacy of ketamine in depressed patients."Biol Psychiatry 72(11):e27-28.)。BDNF中的rs6265(Val66Met，G→A SNP)已被证明可以减少BDNF的细胞内转运和活性依赖性分泌(Egan,M.F.et al.,(2003)."The BDNF val66met polymorphismaffects activity-dependent secretion of BDNF and human memory and hippocampalfunction."Cell 112(2):257-269.)。与Val/Val等位基因相比，BDNF中的rs6265(Val66Met，G→A SNP)与经受MDD发作的患者对氯胺酮的响应较低有关。(Laje,G.,et al.,(2012))。BDNF与MDD和自杀的病理生理学有关，具有Met等位基因的受试者患有抑郁症的风险增加。Youssef,M.,et al.,"Association of BDNF Val66Met Polymorphism and BrainBDNF Levels with Major Depression and Suicide",Int J Neuropsychopharmacol(2018)21(6):528-538。人们认为，rs6265的A等位基因与对L-4-Cl-KYN的响应性的降低有关。
喹啉酸(QA)是一种神经系统兴奋毒素，其水平的增加与各种神经系统病症有关(Brundin,L.et al.,(2016).“An enzyme in the kynurenine pathway that governsvulnerability to suicidal behavior by regulating excitotoxicity andneuroinflammation."Transl Psychiatry 6(8):e865)。QA是色氨酸代谢产生的晚期代谢产物(参见图3)。ACMSD酶可将QA的前体代谢为“有益”无毒的代谢物吡啶甲酸(PIC)而不是转化为QA。因此，人们认为导致ACMSD活性降低的突变会导致有毒性的QA的水平更高。SNP的rs2121337的次要C等位基因就是这样一种突变。rs2121337(T→C)除了在自杀患者中更普遍以外，还与CSF中较高的QA/PIC比值相关。Brundin,L.,et al.(2016)。在一项对137名患者和71名对照的研究中，在7组SNP中，只有rs211337显示出与自杀行为有显著的相关性。同上，犬尿氨酸代谢物的测量可以作为自杀风险的生物标志物进行探索，并且ACMSD是自杀行为的潜在治疗靶点。同上，人们认为，SNP的rs2121337的C等位基因的存在将与对L-4-Cl-KYN更高的响应有关。
已经通过美国专利号5,547,991和Salituro,F.G.et al.,J.Med.Chem.1994,37,34-336中的方法合成了L-4-Cl-KYN。优选的合成方法在美国专利号9,834,801和国际专利申请号PCT/US2019/07448中有描述。L-4-Cl-KYN也可以通过各种来源商业购买到，包括BOC科学(Shirley,NY,USA)、先进技术与工业有限公司(香港,中国)和剑桥重点实验室(日耳曼敦,WI,USA)。
本发明总体涉及对患有神经系统病症的受试者的治疗，所述神经系统病症包括但不限于抑郁症、重度抑郁症和/或自杀意念，通过基于受试者中是否具有KMO基因变异(其中，基因变异是SNP的rs61825638的T等位基因)、SLC7A5基因变异(其中，基因变异是SNP的rs28582913的T等位基因)、BDNF基因变异(其中，基因变异是rs6265位点的普通G等位基因)或ACMSD基因变异(其中，基因变异是rs2121337的C等位基因)中的至少一种，向受试者施加一定剂量的L-4-Cl-KYN。
本发明的方法包括在患有抑郁症、重度抑郁症和/或自杀意念的受试者中检测KMO基因变异、SLC7A5基因变异、BDNF基因变异和ACMSD基因变异中的至少一种，该方法包括：从所述受试者获取样本；和化验样本以检测一种或多种：(i)SNP的rs61825638的T等位基因；(ii)SNP的rs28582913的T等位基因；(iii)rs6265位点的普通G等位基因；和(iv)SNP的rs2121337的C等位基因。样本中单核苷酸多态性(SNP)的rs61825638的T等位基因的存在表明在受试者中存在KMO基因变异。SNP的rs28582913的T等位基因的存在表明受试者中存在SLC7A5中性氨基酸转运蛋白基因变异。SNP的rs6265的A等位基因的存在表明受试者中存在BDNF基因变异。SNP的rs2121337的C等位基因的存在表明受试者中存在ACMSD基因变异。
本发明的方法还包括通过检测KMO基因变异、SLC7A5基因变异、BDNF基因变异和ACMSD基因变异中的至少一种来预测患有抑郁症、重度抑郁症和/或自杀意念的受试者的潜在响应性，所述方法包括：从受试者获取样本；和化验样本以检测一种或多种：(i)单核苷酸多态性(SNP)的rs61825638的T等位基因；(ii)SNP的rs28582913的T等位基因；(iii)rs6265位点的普通G等位基因；和(iv)SNP的rs2121337的C等位基因。
样本可以是从受试者的组织或体液(例如血液或唾液)获得的基因组DNA样本、RNA样本、cDNA样本或蛋白质样本。可通过例如DNA测序、限制性内切酶消化、聚合酶链反应(PCR)、杂交、实时PCR、逆转录酶PCR或连接酶链反应以及免疫分析来执行化验步骤。在文献中，有一些检测SNP的方法可供选择。参见例如Kwok,et al.,“Detection of SingleNucleotide Polymorphisms."Curr.Issues Mol.Biol.(2003)5:43-60；Mast,A.和M.deArruda(2006).Invader assay for single-nucleotide polymorphism genotyping andgene copy number evaluation."Methods Mol.Biol.335:173-186；Zascavage,R.R.,etal.(2013).“Deep-Sequencing Technologies and Potential Applications inForensic DNA Testing."Forensic Sci.Rev.25(1-2):79-105；Ishikawa,T.,et al.(2010).“Emerging new technologies in Pharmacogenomics:rapid SNP detection,molecular dynamic simulation,and QSAR analysis methods to validate clinicallyimportant genetic variants of human ABC Transporter ABCB1(P-gp/MDR1)."Pharmacol.Ther.126(1):69-81；Chang,K.,et al.(2015)；“Novel biosensingmethodologies for improving the detection of single nucleotide polymorphism."Biosens.Bioelectron.66:297-307；Benitez,J.A.,et al.(2017).“Revealing allele-specific gene expression by single-cell transcriptomics."Int.J.Biochem.CellBiol.90:155-160。
抑郁症的症状包括情绪低落、活动兴趣减退、精神运动放缓或躁动、食欲变化、注意力不集中或犹豫不决、过度内疚或无价值感，自杀意念可能出现在抑郁症、双相情感障碍、由于一般医疗病症状况引起的情绪障碍、物质诱导的情绪障碍以及其他未指明的情绪障碍的情况下，也可能与一系列其他精神障碍相关，包括但不限于精神病性障碍、认知障碍、饮食失调、焦虑症和人格障碍。障碍的纵向病程、症状的病史和类型以及病因学因素有助于彼此区分各种形式的情绪障碍。
重度抑郁症被定义为存在不能更好的解释为精神障碍或双相性精神障碍的一次或多次严重抑郁发作。重度抑郁发作的特征是在相同的两周内满足以下标准中的五项或更多项，这些标准表示功能的改变，并且至少包括抑郁/悲伤的情绪或者失去兴趣和乐趣，冷漠或情感淡漠，或易怒，并且通常与许多植物神经系统功能的变化有关，包括睡眠模式、食欲和体重、运动性兴奋或迟钝、疲劳、注意力不集中和决策障碍、羞耻感或内疚感以及死亡或垂死的想法(Harrison's Principles of Internal Medicine,2000(《哈里森内科学手册》，2000年))。抑郁发作的症状包括情绪抑郁；对一天中大部分时间的所有或几乎所有活动的兴趣或乐趣减少；没有节食但体重减轻或体重增加，或食欲几乎每天减少或增加；几乎每天都失眠或嗜睡；几乎每天都精神运动性兴奋或迟钝；几乎每天都会感到疲劳或精力丧失；几乎每天都有无价值感或过度或不适当的内疚感；几乎每天思考或集中注意力的能力减弱，或犹豫不决；反复出现死亡的想法、没有具体计划的反复自杀意念或者自杀企图或者具体的自杀计划。此外，这些症状会在社会、职业或其它重要活动领域中引起临床上显著的抑郁或损害。(精神疾病诊断和统计手册，第4版，美国精神病学协会，1994(Diagnostic andStatistical Manual of Mental Disorders,第4版,American PsychiatricAssociation,1994))。
自杀意念可以包括例如自杀想法，也可以包括其他相关的病症和症状。一些症状或共病性状况可能包括无意中体重减轻、感到无助、感到孤独、过度疲劳、自卑、持续性狂躁、过度健谈、专注于以前已中止的目标、感觉脑子转个不停。类似于这些的症状出现时，无法摆脱或应付它们的影响，可能的心理僵化形式，这是与自杀意念相关联的一种可能性状。它们还可能引起心理困扰，这是与自杀意念相关的另一种症状。类似于这些与心理僵硬、复发模式或心理困扰相关的症状在某些情况下可导致出现自杀意念。其它可能的症状和前兆包括：绝望、快感缺乏、失眠、抑郁、严重焦虑、恐惧、注意力不集中、躁动、惊慌发作和严重悔恨。
如本领域技术人员所熟知的，用于评估自杀意念的评估量表包括贝克自杀意念量表(BSS)、哥伦比亚自杀严重程度评定量表(C-SSRS)、自杀意念和行为评估工具(SIBAT)以及凯斯勒心理困扰量表(K10)，凯斯勒心理困扰量表的测试不直接测量自杀意念，但其管理价值在于可作为自杀意念的早期标识。高得分的心理困扰在一些情况下也与自杀意念有关。
还有几种精神障碍似乎也与自杀意念共存或显著增加自杀意念的风险。以下病症已被证明是自杀意念/病症的最强预测因素，其中风险增加到最大程度：重度抑郁症(MDD)、精神抑郁、双相性精神障碍。自杀和/或自杀意念的主要治疗包括：住院治疗、门诊治疗和药物治疗。住院治疗使患者处于安全、被监督的环境中，以防止他们的自杀意念转变为自杀企图。在大多数情况下，个人有自由选择他们认为适合自己的治疗方法。然而，按照州法法规定，在多种情况下可强制个人住院，包括个人对自身或他人造成危险以及个人不能照顾自己的情况。
本发明包括治疗受试者的抑郁症、重度抑郁症和/或自杀意念的方法，该方法包括：a)从所述受试者获取样本；b)化验样本以检测KMO基因变异(其中，基因变异是SNP的rs61825638的T等位基因)、SLC7A5中性氨基酸转运体基因变异(其中，基因变异是SNP的rs28582913的T等位基因)、BDNF基因变异(其中，基因变异是rs6265位点的普通G等位基因)或ACMSD基因变异(其中，基因变异是rs2121337的C等位基因)中的至少一种；和c)向受试者施用治疗有效量的L-4-Cl-KYN来治疗受试者的抑郁症、重度抑郁症或自杀意念，其中剂量基于样本中的检测到至少一种变异的存在。
本发明的方法可以用于使用L-4-Cl-KYN可治疗的一系列神经系统病症的受试者，其中该药物在中枢神经系统中被代谢为7-氯犬尿喹啉酸之前需要运输穿过血脑屏障。例如，受试者可能是患有抑郁症或MDD的人类或哺乳动物。通过其他的例子来看，能响应L-4-Cl-KYN运输至大脑后其在CNS中被代谢为7-氯犬尿喹啉酸的其他适应症包括各种类型的神经病理性疼痛，包括痛觉过敏，以及与糖尿病、化疗或截肢有关的神经病理性疼痛。这种治疗的共同特征是根据本发明的方法，基于受试者的基因型，施加治疗有效量的L-4-Cl-KYN。其他适应症包括强迫症(OCD)、耳鸣、自身免疫性抗NMDA受体脑炎、焦虑、抑郁障碍(心境恶劣)、持续性抑郁症、非特定的抑郁、双相抑郁或躁狂抑郁、季节性情感障碍(SAD)、精神病性抑郁和产后抑郁、精神病性抑郁、经前综合症、经前烦躁症、焦虑、情绪障碍，以及例如癌症或慢性疼痛、化疗、慢性应激、创伤后应激障碍和自杀意念的风险等慢性疾病所引起的抑郁。
可选地，这种疗法包括联合施用L-4-Cl-KYN与另外一种抗抑郁剂或情绪提升疗法(包括认知疗法和心理疗法)。本发明的方法还包括治疗各种类型的神经系统病症、神经病变(中枢和外周)、疼痛和由以下原因引起的功能障碍，包括：a)损伤和药物毒性，如化疗和抗病毒药物所导致；b)疾病和神经退行性病症，如糖尿病、癌症、病毒感染、多发性硬化症、脊柱炎、多发性神经炎、手术、截肢、癫痫、抽搐、帕金森病、亨廷顿病、和阿尔茨海默病以及那些涉及可通过下调N-甲基-D-天冬氨酸受体信号来改善的谷氨酸传递过度活跃的疾病和症状；和c)与可以通过下调N-甲基-D-天冬氨酸受体信号来改善的抑郁症和其他精神障碍有关的神经递质、受体和信号通路的失衡。
在根据本发明的一些治疗方法中，L-4-Cl-KYN作为药物制剂施用。优选地，L-4-Cl-KYN的药物组合物包括配制用于口服施用的单位剂量的L-4-Cl-KYN，以及药学上可接受的载体和辅料。在其他实施例中，L-4-Cl-KYN作为栓剂施用。“药物单位剂量”、“单位剂量”或“单位剂型”是指施用至受试者的单剂量的L-4-Cl-KYN。在一些实施例中，单位剂量可以容易地处理和包装，仍然作为物理和化学稳定的单位剂量。例如，在特定实施例中，口服单位剂量可以是单个片剂，而在另一实施例中，口服单位剂量可以是多个片剂。
在根据本发明的一些治疗方法中，按照单位剂量施用L-4-Cl-KYN，可选地具有药学上可接受的载体或赋形剂，其中，单位剂量的L-4-Cl-KYN的量为大约50mg至大约1800mg。例如，单位剂量的L-4-Cl-KYN的量优选为大约260mg到大约1540mg，更优选为约260mg至约460mg，约310mg至约410mg，约460mg至约980mg，约980mg至约1180mg，约1030mg至约1130mg，约1340mg至约1540mg，约1390mg至约1490mg，且最优选为约360mg、720mg、1,080mg或1,440mg。在根据本发明的一些治疗方法中，单位剂量的治疗有效量的L-4-Cl-KYN与药物上可接受的载体和赋形剂一起配制用于口服施用。
应该设想到，本发明描述的范围内的待施用的L-4-Cl-KYN的精确剂量是安全和有效的，并且如美国专利号9,993,453中所描述的，它们产生施用L-4-Cl-KYN所获得的血浆水平的7-氯犬尿喹啉酸。因此，7-氯犬尿喹啉酸在血浆中的范围为约15ng/ml至约65ng/ml，约65ng/ml至约300ng/ml，和约300ng/ml至约550ng/ml是可以清楚地设想到的。也应该设想到，可以每天一次或多次施用单位剂量制剂，以延长L-4-CI-KYN水平升高至7-氯犬尿喹啉酸的治疗有效量的时间。
应该设想到，本发明中的组合物的给药方案是治疗有效的。同时，可以设想每天的给药方案，这将优选地为约5天至约30天，包括由患者的医生确定的更短和更长的给药方案。特别地，也可以清楚地设想到，约7天至约24天和约12天至约16天的给药方案。每日的给药方案可以包括每天施用一个或多个单位剂量。在优选的实施方式中，每日剂量不超过2900mg/天。
“治疗有效”是施用并且转化为7-氯犬尿喹啉酸以用于下调NMDA-R介导的信号传递或神经递质失衡的L-4-Cl-KYN的量，该量在神经系统功能中足以产生临床改善，例如，降低神经性疼痛或增加幸福的感受或减少抑郁的情绪或感觉。
本发明还涉及基于受试者的基因型预测受试者对于治疗的潜在响应性的方法。本发明的用于预测患有抑郁症、重度抑郁症和/或自杀意念的受试者对于施用L-4-Cl-KYN治疗的潜在响应性的方法包括：a)从患有抑郁症、重度抑郁症和/或自杀意念的受试者获取样本；b)化验样品以检测KMO基因变异(其中基因变异是KMO基因变异，其中基因变异是SNP的rs61825638的T等位基因)、SLC7A5中性氨基酸转运体基因变异(其中基因变异是SNP的rs28582913的T等位基因)、BDNF基因变异(其中基因变异是rs6265位点的普通G等位基因)或ACMSD基因变异(其中基因变异是rs2121337的C等位基因)中的至少一种；并且其中至少一种基因变异的缺失或存在表明对于治疗的潜在响应性。
所述方法也基于受试者的基因型预测对于治疗的潜在响应性水平。例如，相比于不存在基因变异的受试者，至少一种基因变异的存在表明受试者将是相对较高的响应者，例如，需要较少的药物或较短的施用时间。与仅有一个基因变异的受试者相比，多基因变异的存在，例如，SNP的rs61825638的T等位基因、SNP的rs28582913的T等位基因和rs2121337的C等位基因表明该受试者将是相对非常高的响应者，例如，需要甚至更少的药物或甚至更短的施用时间或者兼具两者。另一方面，与没有该基因变异的受试者相比，rs6265位点的普通G等位基因的存在表明该受试者是低响应者，例如，需要更多的药物或更长的施用时间。
实施例
实施例1：KMO基因变异的检测
从受试者的血液样本提取DNA。通过T等位基因特异性引物延伸法检测基因变异。含有多态性位点的PCR产物用作模板，引物延伸探针的3'端由等位基因碱基组成。只有当3'-碱基与目标DNA存在的等位基因互补时，引物才会延伸。因此，通过监测引物延伸的情况可以推断DNA样本中存在的等位基因(Pastinen et al.(2000)Genome Res.10:1031-1042.)。
实施例2：SLC7A5基因变异的检测
从受试者的血液样本提取DNA，采用上述T等位基因特异性方法，利用针对该变异的特异性引物，通过PCR检测该基因变异。
实施例3：BDNF基因变异的检测
从受试者的血液样本提取DNA，采用上述A等位基因特异性方法，利用针对该变异的特异性引物，通过PCR检测该基因变异。
实施例4：ACMSD基因变异的检测
从受试者的血液样本提取DNA，采用上述C等位基因特异性方法，利用针对该变异的特异性引物，通过PCR检测该基因变异。
实施例5：抑郁症的治疗
在不拘泥于特定的作用机制的情况下，人们认为由于7-氯犬尿喹啉酸具有靶向性，也就是说它可以阻断或拮抗NMDA受体的甘氨酸共激动剂(co-agonist)位点，4-Cl-KYN的治疗性施用可避免氯胺酮引起的潜在的拟精神病副作用同时可以维持疗效，这些拟精神病副作用通过药物辨别试验、条件性位置偏爱和前脉冲抑制试验所确定。然后，施用4-Cl-KYN可能导致“谷氨酸激增”，导致AMPA受体依赖性突触形成，这与氯胺酮的快速抗抑郁作用有关。
应该设想到，L-4-Cl-KYN对治疗自杀受试者有效，或对例如在医院急诊室等急性紧急情况下癫痫发作的受试者同样有效。对于本发明的此用途，对于那些不能口服施用的受试者，L-4-Cl-KYN作为可注射剂型或栓剂剂型是优选的施用方式。正如上文所描述，合适的制剂对本领域的技术人员来说是已知的。
抑郁症治疗的优选剂量范围为约20mg/天至约2900mg/天，优选为150mg/天至1000mg/天，更优选为约300mg/天至约1500mg/天，甚至更优选为约700mg/天至1200mg/天。在这些优选的剂量范围内，340mg/天、1080mg/天和1440mg/天也是优选的。
存在KMO基因变异(其中，该基因变异是SNP的rs61825638的T等位基因)、SLC7A5中性氨基酸转运蛋白基因变异(其中，该基因变异体是SNP的rs28582913的T等位基因)以及ACMSD基因变异(其中，该基因变异体是SNP的rs2121337的C等位基因)中的至少一者的情况下，观察到L-4-Cl-KYN对较大量受试者或相同数量的但剂量较低的患者的情绪增强或抗抑郁活性。在没有BDNF变异(其中BDNF变异是rs6265的普通G等位基因)的情况下，观察到L-4-Cl-KYN对较大量受试者或相同数量的但剂量较低的患者的情绪增强或抗抑郁活性。在具有BDNF变异(SNP的rs6265的A等位基因)的受试者中，更高剂量的L-4-Cl-KYN可导致情绪增强或抗抑郁响应。受试者肯定地报告了幸福的感觉。这与谷氨酸能系统有助于抑郁的病理生理学以及压力可引起NMDA受体的变化的报道一致。参见例如Calabrese et al.,PloS onevol.7,5(2012):e37916。
实施例6：MDD的治疗
25名18至65岁诊断为MDD的男性和女性受试者接受L-4-Cl-KYN(1080或1440mg/天口服)治疗2周，在设计上与相似的研究相似。例如参见Ibrahim et al.J ClinPsychopharmacol，2012Aug；32(4):551-557；Zarate et al.Biol Psychiatry.2013Aug15；74(4):257-64；Zarate et al.Arch Gen Psychiatry.2006Aug；63(8):856-64；Zarateet al.2005Biological psychiatry，57(4),430-432。预筛选对至少以下一种SNP变异呈阳性的受试者：SNP的rs61825638的T等位基因，SNP的rs28582913的T等位基因，或rs2121337的C基因，或对rs6265位点的G等位基因呈阳性。此外，由25名受试者组成的对照组被预筛选为缺少以下任意一种：SNP的rs61825638的T等位基因、SNP的rs28582913的T等位基因或rs2121337的C等位基因，或缺少SNP的rs6265的G等位基因。总体抑郁症状的改善显示为汉密尔顿抑郁评定量表(HORS)(Hamilton,M.(1959)J.Med.Psychol.32:50-5)和蒙哥马利阿斯伯格抑郁量表(MADRS)总分中一者或两者显著下降。Montgomery et al.1979,Brit.J.Psych.,134:382-389。
正如本领域的技术人员所理解的，对于特定受试者的治疗效果的其他指标包括受试者得到缓解(HDRS≤7)和治疗响应(HORS总分比刚治疗时的基线降低≥50％)；汉密尔顿焦虑量表(HAM-A)、哥伦比亚自杀严重程度量表(C-SSRS)总分(Posner et al.2011,Am JPsychiatry.2011；168:1266-1277)基线的改变，以及其他改善情绪或心理状态的措施，例如，例如贝克抑郁量表(BDI)(Beck et al.1974,Journal of Consulting and ClinicalPsychology,42(6),861-865)、视觉模拟量表(VAS)(Aitken RC,Proc R Soc Med.1969；62(10):989-93)、简明精神病评定量表(BPRS)(Overall et al.1962,Psych.Rep.10:799-812)、临床医生管理的分离量表(CADSS)(Bremner et al.1998,Journal of TraumaticStress,11:125-136)和青年躁狂评定量表(YMRS)(Young et al.1978,British Journalof Psychiatry,133(5),429-435)。
虽然已经在上文详细描述了某些示例性实施例，但应当理解，这些实施例仅仅是对本发明范围的说明而不是限制。应该认识到，本发明的教导作用适用于由所述制剂和组合物产生的各种各样的组合物和装置。本领域的技术人员应该理解，在不违背其广泛的发明范围的情况下，可以对本发明的上述实施例进行各种修改。因此，应当理解的是，本发明不限于所公开的实施例或部署，而是旨在涵盖在所附权利要求所定义的本发明的范围和精神内的任何变更、改编或修改。本说明书中所讨论或引用的所有文件通过引用整体并入。
Claims (13)
1.一种通过检测犬尿氨酸3-单加氧酶(KMO)基因变异、SLC7A5中性氨基酸转运体基因变异、脑源性神经营养因子(BDNF)基因变异和氨基羧基粘康酸半醛脱羧酶(ACMSD)基因变异中的至少一种来预测患有抑郁症、重度抑郁症和/或自杀意念的受试者对L-4-Cl-KYN治疗的响应性的方法，所述方法包括：
从所述受试者获得样本；和
化验所述样本以检测一种或多种：
(i)单核苷酸多态性(SNP)的rs61825638的T等位基因；
(ii)SNP的rs28582913的T等位基因；
(iii)SNP的rs6265的G等位基因；和
(iv)SNP的rs2121337的C等位基因。
2.根据权利要求1所述的方法，其中所述样本为基因组DNA样本。
3.根据权利要求1所述的方法，其中所述样本为RNA样本。
4.根据权利要求1所述的方法，其中，所述样本从受试者的血液或者唾液获得。
5.根据权利要求1所述的方法，其中通过DNA测序、限制性内切酶消化、聚合酶链反应(PCR)、杂交、实时PCR、逆转录酶PCR或连接酶链反应执行化验的步骤。
6.一种治疗受试者的抑郁症、重度抑郁症和/或自杀意念的方法，所述方法包括：
a)从所述受试者获得样本；
b)化验所述样本以检测至少一种：
KMO基因变异，其中所述基因变异是单核苷酸多态性(SNP)的rs61825638的T等位基因；
SLC7A5中性氨基酸转运体基因变异，其中所述基因变异是SNP的rs28582913的T等位基因；
RDNF基因变异，其中所述基因变异是rs6265位点的G等位基因；和
ACMSD基因变异，其中所述基因变异是SNP的rs2121337的C等位基因；和
c)基于在样本中检测到的至少一种变异的存在，向受试者施用治疗有效量的L-4-Cl-KYN来治疗受试者的抑郁症、重度抑郁症或自杀意念。
7.根据权利要求6所述的方法，其中，所述方法用于治疗抑郁症。
8.根据权利要求7所述的方法，其中，所述抑郁症是难治性抑郁症。
9.根据权利要求6所述的方法，其中，所述方法用于治疗重度抑郁症。
10.根据权利要求9所述的方法，其中，所述重度抑郁症是难治性重度抑郁症。
11.根据权利要求10所述的方法，其中，所述方法用于治疗自杀意念。
12.根据权利要求10所述的方法，其中，所述受试者是自杀受试者。
13.一种预测患有抑郁症、重度抑郁症和/或自杀意念的受试者对于施用L-4-Cl-KYN治疗的受试者潜在响应性的方法，该方法包括：
a)从患有抑郁症、重度抑郁症和/或自杀意念的受试者获取样本；
b)化验所述样本以检测至少一种：
KMO基因变异，其中所述基因变异是单核苷酸多态性(SNP)的rs61825638的T等位基因；
SLC7A5中性氨基酸转运体基因变异，其中所述基因变异是SNP的rs28582913的T等位基因；
RDNF基因变异，其中所述基因变异是SNP的rs6265的G等位基因；和
ACMSD基因变异，其中所述基因变异是SNP的rs2121337的C等位基因；
其中，至少一种基因变异的缺失或存在表明受试者对于治疗的响应性。
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| CA3136418A1 (en) | 2020-10-15 |
| EP3952856A1 (en) | 2022-02-16 |
| IL287098A (en) | 2021-12-01 |
| JP2022526427A (ja) | 2022-05-24 |
| KR20220045929A (ko) | 2022-04-13 |
| US20220202756A1 (en) | 2022-06-30 |
| AU2020271853A1 (en) | 2021-11-25 |
| MX2021012383A (es) | 2022-01-04 |
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