CN113811359A - 用于溶酶体贮积症的经鼻基因递送和口服肉桂酸、油酰胺或吉非贝齐的组合 - Google Patents
用于溶酶体贮积症的经鼻基因递送和口服肉桂酸、油酰胺或吉非贝齐的组合 Download PDFInfo
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Abstract
本文提供了用于治疗溶酶体贮积症的方法，包括给药编码溶酶体酶的基因和药剂。通过共同给药将基因疗法与药物组合物组合，不仅进一步增强了每种单独疗法的效果，而且由于每种单独组合物的作用机制不同，还提供了多方面的治疗方法。
Description
相关申请的交叉引用
本申请要求2019年3月22日提交的美国临时专利申请第62/822,310号的优先权，其通过引用全文纳入本文。
技术领域
本发明涉及将编码溶酶体酶的基因与用于治疗溶酶体贮积症(例如晚期婴儿巴顿病和克拉伯病)的药剂组合给药的方法。
背景
溶酶体是包含多种酶的膜结合细胞器，这些酶负责脂质、蛋白质、碳水化合物和核酸的降解(De Duve和Wattiaux，1966)。几乎任何这些成分的缺陷和缺损都会导致未消化和/或部分消化的物质在溶酶体中积累，从而形成许多溶酶体贮积症(LSD)的基础(De Duve和Wattiaux，1966，Perez-Sala等，2009)，包括巴顿病(婴儿、晚期婴儿和青少年神经元蜡样脂褐质沉积症)，克拉伯病和泰-萨二氏病。
神经元蜡样脂褐质沉积症(NCL)是一组神经退行性疾病，主要由典型的常染色体隐性遗传溶酶体贮积症组成。NCL的特征可包括临床表现，如进行性精神衰退、认知障碍、视力障碍、癫痫发作和运动功能恶化，并伴有组织学发现，如神经元或其他细胞类型中自发荧光贮积材料的积累(Hachiya等，2006)。根据发病年龄、累积贮积材料中的超微结构变化和每种特定疾病类型特有的遗传改变，NCL被细分为几组(1类-10类)(Lane等，1996和Mole等，2005)。
婴儿神经元蜡样脂褐质沉积症(INCL)在大约18个月大的儿童中出现，其症状包括失明、认知缺陷、癫痫发作和早夭(Hawkins-Salsbury等，2013)。编码溶酶体酶棕榈酰蛋白硫酯酶-1(PPT1)的clnl基因的缺陷导致各种自发荧光材料基质(例如脂褐质)在中枢神经系统和组织中积累(同上)。随后发生的神经元变性、皮质变薄和脑萎缩导致与未受影响的儿童相比脑质量减少约50％(同上)。目前没有可用的治疗方法。
晚期婴儿神经元蜡样脂褐质沉积症(詹-比二氏病(Jansky-Bielschowskydisease)，LINCL，2型)通常在2-4岁出现症状，进展迅速并在8-15岁死亡，这是由于神经元和其他细胞数目急剧减少(Lane等，1996和Sleat等，1997)。LINCL与cln2基因突变有关，该基因总长度为6.65kb，13个外显子和12个内含子，定位到染色体1 1p15.5。cln2基因编码溶酶体三肽基三肽酶I(TPP-I或胃蛋白酶不敏感蛋白酶)，一种46KD的蛋白质，其在溶酶体隔室的酸性环境中发挥作用，以从蛋白质的氨基末端去除三肽(Goebel 1995和Vines等，1999)。在cln2基因的该突变导致TPP1蛋白质的功能缺陷和/或丧失，这导致溶酶体内积累称为蜡样-脂褐质的自发荧光脂色素(Goebel，1995)。目前没有针对这种疾病的可用既定治疗或药物，所有方法只是支持性的或对症的，表明需要新的治疗方法(Chang et al.，2008)。然而，cln2突变有不同变体，且有报道称在LINCL患者中发现了残余TPP-I活性，这表明在患有LINCL的患者中一定有一些剩余的正常cln2基因的拷贝(Viglio等，2001和Walus等，2010)。
另一种NCL是青少年巴顿病(青少年婴儿神经元蜡样脂褐质沉积症(JINCL))。cln3基因编码可能与突触功能或退化有关的溶酶体跨膜蛋白(Dolisca等，2013)。与JINCL相关的cln3的突变特征为1.01kb缺失。与其他NCL的(特征)一样，JINCL的发病发生在4-7岁的儿童中，症状包括逐渐失明、运动和认知退化、癫痫发作和早天。
克拉伯病是罕见的溶酶体贮积疾病，是基于髓鞘退化的鞘脂沉积病的结果。该疾病是由β-半乳糖脑苷酯酶溶酶体贮积酶的突变导致的，从而积累细胞毒性代谢产物并破坏多种代谢途径，导致脱髓鞘。克拉伯病可以是婴儿型、晚期婴儿型、青少年型甚至成人型(Pavuluri等，2017)。
泰-萨二氏病是hexa基因突变的结果，该基因编码β-己糖胺酶，该酶负责将GM2神经节苷脂加工成GM3神经节苷脂(Dersh等，2016)。该酶由两个亚基构成，突变导致酶缺失或失活，导致GM2积累。在hexa基因中已经鉴定出超过100个与泰-萨二氏病(同上)相关的突变。
由于各种基因突变与导致溶酶体贮积症的多种酶有关，基因治疗是一种潜在的治疗选择。然而，基因递送(特别是用于治疗神经退行性疾病的)存在将治疗基因递送到大脑的问题。基于病毒的基因递送机制是众所周知的，由于病毒的免疫原性差，可以通过使用腺相关病毒载体特异性地实现基因递送(Shaw等，2013)。此外，这些包含治疗基因的病毒载体的经鼻给药允许递送至大脑。经鼻递送被认为利用了“鼻-脑”(N2B)运输系统(Djupesland，2013)，其中存在绕过血脑屏障直接递送到大脑的几种可能性。其包括被鼻粘膜吸收的药物排入鼻窦并最终排入颈动脉，在那里可能发生从静脉血到大脑的“逆流转移”。从嗅觉三叉神经和中枢神经系统(CNS)之间进入血管周围空间的淋巴引流也被假定为N2B运输的机制。
此外，基因治疗和口服药物治疗组合提供了另一种强大的治疗方法，可以增强单一疗法的作用。用于与基因治疗组合的两种候选药剂包括肉桂酸和油酰胺。肉桂酸是天然存在于植物中的具有神经保护作用的脂肪酸(Prorok等，2019)。已发现它参与过氧化物酶体增殖物激活受体(PPARa)的激活以保护帕金森病(Id)中的多巴胺能神经元。肉桂酸的各种衍生物也因其抗氧化特性和穿过血脑屏障的能力而闻名，这使得这些药物成为治疗神经退行性病症的理想选择(Roleira等，2010)。油酰胺是另一种具有广泛神经药理作用的脂肪酸。已知的内源性的脂肪酸油酰胺在脑脊液中首次发现(Nam等，2017)。它组成型存在于海马体中，在那里它作为PPARa配体并参与诱导睡眠(Pahan，2017)。因此，将肉桂酸作为天然药剂和油酰胺作为内源性脑配体与基因治疗组合的潜在用途是有益的。
此外，几项研究已经得出结论，神经炎症和细胞凋亡通路的诱导可归因于在大多数形式的NCL(包括LINCL)中的神经元损伤(Geraets等2016，Dhar等2002，Puranam等1997，Kohan等2011)。尽管炎症不是LINCL的起始因素，据信胶质细胞介导的持续炎症反应会导致疾病进展(Cooper等2015，Macauley等2014)。吉非贝齐(gemfibrozil)，FDA-批准的降脂药物，已知可减少血液循环中甘油三酯水平，并降低高脂血症的风险(Robins等2001，Rubins和Robins1992，Rubins等1999)。然而，最近的多项研究表明除了其降脂作用外，吉非贝齐还可以调节负责炎症、T-辅助细胞转换、细胞间接触、迁移、氧化应激和溶酶体生物发生的许多其他信号通路(Ghosh和Pahan 2012a，Corbett等2012，Ghosh等2012，Jana等2007，Jana和Pahan 2012，Dasgupta等2007，Pahan等2002，Roy和Pahan 2009，Ghosh等2015)。因此，基因治疗与吉非贝齐组合也具有巨大潜力。
发明概述
本文所述的一个实施方式是用于治疗溶酶体贮积症的方法，包括将包含治疗有效量的编码溶酶体酶的基因的第一组合物，和包含治疗有效量的药剂的第二组合物给予有需要的对象。
一方面，第一组合物是鼻内给药。
另一方面中，基因被递送穿过血脑屏障。
另一方面中，第一组合物大约每7-30天给药一次。
又一方面中，第一组合物包括病毒载体，其包含编码溶酶体酶的基因。
一方面，病毒载体是腺相关病毒载体。
另一方面中，基因包括pptl、cln2、cln3、gale或hexa。
另一方面中，溶酶体酶包括棕榈酰-蛋白硫酯酶-1、三肽基肽酶1、半乳糖基神经酰胺、巴顿病蛋白(battenin)或已糖胺酶A。
又一方面中，所述方法包括给药包含pptl基因的第一组合物以用于治疗包括婴儿神经元蜡样脂褐质沉积症的溶酶体贮积症。
一方面，所述方法包括给药包含cln2基因的第一组合物以用于治疗包括晚期婴儿神经元蜡样脂褐质沉积症的溶酶体贮积症。
另一方面中，所述方法包括给药包含cln3基因的第一组合物以用于治疗包括青少年神经元蜡样脂褐质沉积症的溶酶体贮积症。
另一方面中，所述方法包括给药包含gale基因的第一组合物以用于治疗包括克拉伯病的溶酶体贮积症。
又一方面中，所述方法包括给药包含hexa基因的第一组合物以用于治疗包括泰-萨二氏病的溶酶体贮积症。
一方面，药剂包括肉桂酸、油酰胺或贝特类。
另一方面中，贝特类为吉非贝齐或非诺贝特(fenofibrate)。
另一方面中，第二组合物进一步包含治疗有效量的全-反式视黄酸。
又一方面中，当药剂与全-反式视黄酸组合给药时，药剂的治疗有效量比所述药剂不伴随全-反式视黄酸递送时的药剂的治疗有效量低。
一方面，第二组合物是口服给药。
另一方面中，第二组合物每天给药一次。
另一方面中，给药第一组合物和第二组合物比单独给药第一组合物或第二组合物向对象提供了更强的治疗作用。
又一方面中，溶酶体贮积症选自下组：晚期婴儿巴顿病、青少年巴顿病、克拉伯病、泰-萨二氏病、尼-皮二氏病、法布瑞氏病、法伯病和戈谢病。
一方面，第一组合物是鼻内给药且第二组合物是口服给药。
另一方面中，第一组合物是每7天至少给药一次，第二组合物是每天给药一次。
另一方面中，病毒载体是腺相关病毒载体。
另一方面中，基因包含cln2。
另一方面中，第二组合物包含吉非贝齐。
另一方面中，第一组合物的给药增加了约100天的预期寿命。
附图简要说明
图1：腺病毒人Cln2基因(Ad-Cln2)的鼻内递送延长了Cln2(-/_)小鼠的寿命，其为晚期婴儿巴顿病的动物模型。为了鼻内基因递送，Cln2(-/_)小鼠从两周龄开始每周两次鼻内接受体积为51的5x106基因组拷贝的(
/鼻孔)Ad-Cln2，持续4周。为了吉非贝齐(gem)治疗，小鼠从六周龄开始以7.5mg/kg体重/天的剂量接受口服gem(溶于0.1％MeC)。图1描述了由Kaplan-Meier图展示的存活百分比。
图2：腺病毒人Cln2基因(Ad-Cln2)的鼻内递送延长了Cln2(-/_)小鼠的寿命，其为晚期婴儿巴顿病的动物模型。为了鼻内基因递送，Cln2(-/_)小鼠从两周龄开始每周两次鼻内接受体积为51的5x106基因组拷贝的(
/鼻孔)Ad-Cln2，持续4周。为了吉非贝齐(gem)治疗，小鼠从六周龄开始以7.5mg/kg体重/天的剂量接受口服gem(溶于0.1％MeC)。图2描述了平均存活天数。每组中六只小鼠(n＝6)包括3只雄鼠和3只雌鼠。***p＜0.001；NS，不显著。
发明详述
本文公开的实施方式无意于穷举或将本公开的范围限制在以下描述的确切形式。而是在本文中选择并描述实施方式作为示例，以便本领域其他技术人员能够利用其教导。
本公开涉及将编码溶酶体酶的基因与用于治疗溶酶体贮积症(例如晚期婴儿巴顿病和克拉伯病)的药剂组合共同给药的方法。
定义
除非另有定义，本文中所使用的所有术语(包括技术和科学术语)的含意与本领域普通技术人员通常所理解的相同。若有抵触，以本文件(包括定义)为准。虽然也可采用与本文所述类似或等同的方法和材料实施或测试本发明，但在此描述一些优选的方法和材料。本文提及的所有出版物、专利申请和其他参考文献通过引用全文纳入本文。
本文所述材料、方法和实施例都仅是说明性的，不构成限制。
本文所用术语“包括”、“包含”、“具有”、“有”、“可以”、“含有”及其变体旨在成为开放式过渡短语、术语或词，其不排除其他作用或结构的可能性。除非上下文另有明确规定，否则单数形式的“一个”、“一种”和“该”包括复数指代物。本公开还涵盖了其他实施方式“包括”“由......组成”和“基本由......组成”本文提出的实施方式或要素，无论是否明确提出。
本文所用术语“鼻内”是指包括与鼻粘膜表面接触或吸入以在肺部支气管通道中吸收的给药方式。
本文所用的术语“口服”是指包括口服、肠道、口腔、唇下和舌下胃肠道给药的给药方式。
本文所用的“治疗”、“处理”或“疗法”是指缓解与病症或疾病相关的症状，或阻止这些症状的进一步发展或恶化，或预防或防止疾病或病症。例如，在本公开的范围内，成功的治疗可以包括预防神经退行性疾病，缓解与神经退行性疾病有关的症状，或停止疾病(例如神经退行性疾病)的进展。如本文所用，用于测量相对于它的治疗的对照是指未接受治疗药剂的对象。
对于本文中数字范围的叙述，明确考虑了其间具有相同精度的每个间隔数字。例如，对于6-9的范围，除了6和9之外，还考虑了7和8，对于6.0-7.0的范围，明确考虑了6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0。
本文提供的是将编码溶酶体酶的基因和药物组合物共同给予对象的方法，包括给药治疗有效量的基因和药剂用以治疗溶酶体贮积症。
基因组合物
在一个本文所述的实施方式中，基因组合物含有“治疗有效量”的关注的治疗基因。“治疗有效量”指的是以必要的剂量和持续时间段实现所需治疗结果的有效的量。治疗基因的治疗有效量可以由本领域技术人员确定，并可根据因素例如疾病状态、年龄、性别和个人体重以及该组合物在个体中引起所需反应的能力而变化。治疗有效量也是基因的毒性或不良影响被治疗有益效果抵消的量。
在本文所述的一个方面，递送包含治疗基因的组合物的方法为通过鼻内给药。递送包含治疗基因的组合物的方法包括向鼻给药的许多模式，包括通过被动或主动递送机制递送用于鼻腔给药的组合物的液体或粉末制剂。在一个实施方式中，液体制剂可以通过多种机制递送，包括汽化通过鼻腔吸入，手动驱动鼻腔装置和机械喷雾泵。在另一个实施方式中，用于这种递送机制的制剂可以是以含有气雾剂的推进剂形式或无推进剂可吸入溶液形式。在另一个实施方式中，机械喷雾泵可以是手动驱动的、气体驱动的或电动的，如电动喷雾器或雾化器的情况下。在进一步的实施方式中，粉末制剂可以通过机械动力喷雾器、鼻吸入器和喷雾器/雾化器递送。
鼻内给药的目的是为了使治疗基因穿过血脑屏障最终递送到大脑。不希望囿于理论，基因治疗的经鼻递送可以利用“鼻-脑”(N2B)运输系统(Djupesland，2013)，其中存在绕过血脑屏障直接递送到大脑的几种可能性。其包括被鼻粘膜吸收的药物排入鼻窦并最终排入颈动脉，在那里可能发生从静脉血到大脑的“逆流转移”。因此，在本文所述的一方面中，基因被递送穿过血脑屏障。
在本文所述的一个实施方式中，约每1天至约每100天、约每2天至约每90天、约每3天至约每80天、约每4天至约每70天、约每5天至约60天、约每6天至约50天、每7天至约40天、约每8天至约每30天或约每9天至约20天给药一次包含治疗有效量的基因的基因组合物。一方面，基因组合物大约每7至约每30天给药一次。在另一方面中，基因组合物大约每7天给药一次。
在本文所述的一个实施方式中，通过使用病毒载体递送治疗基因。用于基因治疗的理想的病毒载体可以成功感染目标细胞，转移到细胞核并维持表达水平而不会引起毒性。病毒载体可以由任何适合基因治疗的病毒构成，包括逆转录病毒或腺病毒。适合作病毒载体的其他病毒包括腺相关病毒、慢病毒、痘病毒、甲病毒和疱疹病毒。腺相关病毒载体是理想的载体，由于它具有相对较低的致病性和持续表达。因此，在本文所述的一方面，病毒载体包括腺相关病毒载体。
在本文所述的另一个实施方式，病毒载体包括编码溶酶体酶的治疗基因。编码溶酶体酶和相关蛋白质的基因包括：天冬氨酰基氨基葡萄糖苷酶(ago)、芳基硫酸酯酶A(arsa)、芳基硫酸酯酶B(arsb)、酸性神经酰胺酶(asahl)、自噬蛋白5(atg5)、自噬蛋白7(atg7)、棕榈酰蛋白硫酯酶1或PPT1(clnl)、三肽基肽酶1(cln2)、巴顿病蛋白(battenin)(cln3)、跨膜内质网蛋白(cln6)、内质网载物受体(cln8)、溶酶体胱氨酸转运蛋白(cystinosin)(ctns)、组织蛋白酶A(ctsa)、组织蛋白酶K(ctsk)、磷酸肌醇磷酸酶(fig4)、a-L-岩藻糖苷酶1(fucal)、酸性α-葡萄糖苷酶{gad)、半乳糖神经酰胺酶(gale)、半乳糖胺(N-乙酰基)-6-硫酸酯酶(gains)、β-葡萄糖脑苷酯酶(gba)、α-半乳糖苷酶A(gld)、β-半乳糖苷酶1(glbl)、GM2神经节苷脂活化子(gm2a)、glcNAc-1-磷酸转移酶(gnptab)、N-乙酰葡萄糖胺-1-磷酸转移酶(gnptg)、N-乙酰葡萄糖胺-6-硫酸酯酶(gns)、β-葡萄糖醛酸酶(gush)、β-己糖胺酶A(hexa)、β-己糖胺酶B(hexb)、乙酰肝素-α-氨基葡萄糖苷N-乙酰转移酶(hgsnat)、透明质酸酶-1(hyall)、艾杜糖醛酸2-硫酸酯酶{ids)、α-L-艾杜糖醛酸酶(idua)、溶酶体相关膜蛋白2(1amp2)、溶酶体酸性脂肪酶(///3/4/)、α-甘露糖苷酶(iman2bl)、β-甘露糖苷酶(manba)、粘脂蛋白-1(mcolnl)、哺乳动物雷帕霉素靶标复合物1或机理雷帕霉素靶标复合物1(mtorcl)、a-N-乙酰半乳糖苷酶(naga)、a-N-乙酰葡萄糖胺糖苷酶(naglu)、神经氨酸酶1(neul)、尼-皮二氏Cl(i npcl)、尼-皮二氏Cl(npc2)、含有patatin-样磷脂酶结构域的蛋白质1(pnpla2)、棕榈酰-蛋白硫酯酶1(pptl)、激活蛋白原(psap)、N-磺氨基葡糖磺基水解酶(sgsh)、唾液酸蛋白(sialin protein)(slc！7a5)、TOR调控蛋白(slc389)、钠/氢交换体6(slc9A6)、酸性鞘磷脂酶(smpdl)、甲酰基甘氨酸-生成酶(.sumfl)或三肽基肽酶1(itppT)。在本文所述的一个方面中，治疗基因包括pptl、c/＜＜2、cln3、gale或hexa。
导致溶酶体贮积症的溶酶体酶种类繁多。与溶酶体贮积症有关的溶酶体酶的示例包括：a-N-乙酰半乳糖苷酶、酸性神经酰胺酶、酸性麦芽糖酶、酸性鞘磷脂酶、酸性鞘磷脂酶、酸性b-葡萄糖苷酶、脂肪甘油三酯脂肪酶、芳基硫酸酯酶A、芳基硫酸酯酶B、ATG5、ATG7、巴顿病蛋白(battenin)、组织蛋白酶K、溶酶体胱氨酸转运蛋白(cystinosin)、附睾分泌蛋白HE1、半乳糖胺-6-硫酸酯酶、半乳糖神经酰胺、N-乙酰葡萄糖胺-1-磷酸转移酶的γ亚基、糖基天冬酰胺酶、GM2-活化蛋白、乙酰肝素N-硫酸酯酶、己糖胺酶A和B、透明质酸酶、艾杜糖醛酸2-硫酸酯酶、溶酶体酸性脂肪酶、溶酶体b-甘露糖苷酶、溶酶体-相关-膜蛋白-2、单价钠-选择性钠/氢交换剂体(NHE)、mTORCl、粘脂蛋白-1、N-a-乙酰葡萄糖胺糖苷酶、神经氨酸苷酶、棕榈酰-蛋白硫酯酶-1、PIP(2)5-磷酸酶、保护蛋白/组织蛋白酶A.结脂蛋白(saposin)B、结脂蛋白(saposin)C、唾液酸蛋白、SLC38A9、硫酸酯酶-修饰因子-1、三肽基肽霉1、a-半乳糖苷酶、a-L-岩藻糖苷酶、a-L-艾杜糖醛酸酶、a-甘露糖苷酶或β-葡萄糖苷酶。在本文所述的一个方面中，溶酶体酶包括棕榈酰-蛋白质硫酯酶-1、三肽基肽酶1、半乳糖基神经酰胺、巴顿病蛋白(battenin)或己糖胺酶A。
用于靶向大脑的治疗基因的鼻内递送是治疗神经退行性疾病和溶酶体贮积症的理想选择。神经退行性病症可包括阿尔茨海默病(AD)，亨廷顿病，肌萎缩性侧索硬化症(ALS)，帕金森病，包括帕金森加疾病，例如多系统萎缩(MSA)，多发性硬化症(MS)，进行性核上性麻痹(PSP)，皮质基底节变性(CBD)或路易体痴呆(DLB)。神经退行性疾病可由溶酶体贮积症引起。巴顿病是称为神经元蜡样脂褐质沉积症(NCL)的一组病症中最常见的形式，该组病症包括婴儿神经元蜡样脂褐质沉积症(INCL)、晚期婴儿神经元蜡样脂褐质沉积症(LINCL)和青少年神经元蜡样脂褐质沉积症(JINCL)。溶酶体贮积症也可以是，例如，泰-萨二氏病、法布瑞氏病、尼-皮二氏病、克拉伯病、戈谢病、亨特氏综合征、α-甘露糖苷贮积症、天冬氨酰基葡萄糖胺尿症、胆固醇酯贮积病、慢性己糖苷酶A缺乏症、胱氨酸病、达农病(Danon disease)、法伯病、岩藻糖苷贮积症或半乳糖唾液酸贮积症。一方面，溶酶体贮积症包括婴儿神经元蜡样脂褐质沉积症(INCL)、晚期婴儿神经元蜡样脂褐质沉积症(LINCL)和青少年神经元蜡样脂褐质沉积症(JINCL)或克拉伯病。在本文所述的一方面中，溶酶体贮积症包括晚期婴儿巴顿病、青少年巴顿病、克拉伯病、泰-萨二氏病、尼-皮二氏病、法布瑞氏病、法伯病和戈谢病。
在本文所述的另一方面中，pptl基因编码涉及婴儿神经元蜡样脂褐质沉积症的酶。另一方面，cln2基因编码涉及晚期婴儿神经元蜡样脂褐质沉积症的酶。另一方面，cln3基因编码涉及青少年神经元蜡样脂褐质沉积症的酶。又一方面，gale基因编码涉及克拉伯病的酶。另一方面，hexa基因编码涉及泰-萨二氏病的酶。
药物组合物
药物组合物可包含“治疗有效量”或“预防有效量”的药剂。“治疗有效量”指的是以必要的剂量和持续时间段实现所需治疗结果的有效的量。组合物的治疗有效量可以由本领域技术人员确定，并可根据因素例如疾病状态、年龄、性别和个人体重以及该组合物在个体中引起所需反应的能力而变化。治疗有效量也是药剂毒性或不良影响被治疗有益效果抵消的量。“预防有效量”指的是以必要的剂量和持续时间段实现所需预防结果的有效的量。通常，由于在疾病的早期阶段或之前在对象中使用预防剂量，预防有效量会比治疗有效量低。
药剂可以是诱导用于治疗溶酶体贮积症的治疗效果的任何活性成分。药剂可以是天然存在的或合成的。天然存在的药剂的实例包括天然饱和脂肪酸及其衍生物，例如硬脂酸、棕榈酸、肉桂酸、月桂酸、癸酸等。天然存在的不饱和脂肪酸及其衍生物的实例包括油酸、油酰胺、亚油酸、亚麻酸和蓖麻油酸。本文所述的一方面中，药剂为肉桂酸或油酰胺。
作为药剂的合成药剂的实例包括，例如，降脂药物例如贝特类。贝特类的非限制性实例包括吉非贝齐、非诺贝特、氯贝特、苯扎贝特、环丙贝特和克利贝特(clinofibrate)。吉非贝齐(5-(2，5-二甲基苯氧基)-2，2-二甲基戊酸)可以商标名
从辉瑞公司(Pfizer)商购获得。非诺贝特(2-(4-(4-氯苯甲酰基)苯氧基)-2-甲基-丙酸1-甲基乙酯)可以
从艾伯维(Abbvie)商购获得.其他贝特类包括氯贝特(2-(4-氯苯氧基)-2-甲基-丙酸乙酯)、苯扎贝特(2-(4-(2-(4-氯-苯甲酰胺基)-乙基)苯氧基)-2-甲基-丙酸)、环丙贝特(2-(4-(2，2-二氯环丙基)苯氧基)-2-甲基丙酸)和克利贝特(2-[4-[1-[4-(2-羧基丁-2-基氧基)苯基]环己基]苯氧基]-2-甲基丁酸)。本文所述的一方面中，药剂为贝特类。本文所述的另一方面中，药剂为吉非贝齐或非诺贝特。
药剂可以被纳入适合向对象(例如患者，其可以是人或非人)给药的药物组合物中。
药物组合物还可进一步包含其他治疗有效的药剂。在本文所述的一方面中，药物组合物进一步包含治疗有效量的全-反式视黄酸。全-反式视黄酸与认知活动有关，并被认为减少与阿尔茨海默病相关的氧化应激(Lee等，2009)。因此，与单独给药全反式视黄酸、药剂或治疗基因相比，将全反式视黄酸与药剂和治疗基因一起给药可以在对象中提供进一步增强的治疗效果。在本文所述的另一个方面中，当药剂与全-反式视黄酸组合给药时，药剂的治疗有效量比所述药剂不伴随全-反式视黄酸递送时的药剂的治疗有效量低。
药物组合物可包括药学上可接受的运载体。如本文所用，术语“药学上可接受的运载体”是指任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。可用作药学上可接受的运载体的材料的一些示例：糖，例如但不限于乳糖、葡萄糖和蔗糖；淀粉，例如但不限于玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如但不限于羧甲基纤维素钠、乙基纤维素和乙酸纤维素；粉末状黄蓍胶；麦芽；明胶；滑石；赋形剂例如但不限于可可脂和栓剂蜡；油，例如但不限于花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇；例如丙二醇；酯例如但不限于油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，例如但不限于氢氧化镁和氢氧化铝；海藻酸；无热原水；等渗盐水；林格氏溶液；乙醇和磷酸盐缓冲溶液，以及其他无毒相容性润滑剂，例如但不限于十二烷基硫酸钠和硬脂酸镁，以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂，防腐剂和抗氧化剂也可以存在于组合物中，根据配方师的判断。
治疗神经系统疾病例如晚期婴儿神经元蜡样脂褐质沉积症的方法可包括多种给予药剂或药剂的药物组合物的模式。本文所述的一方面中，药物组合物与基因组合物一起给药。
本文所述的另一方面中，药物组合物为口服给药。口服给药可包括片剂、丸剂、糖衣丸、硬和软凝胶胶囊、颗粒剂、丸粒、水性、脂质、油性或其他溶液、乳液例如水包油乳液、脂质体、水性或油性悬浮液、糖浆、酏剂、固体乳液、固体分散体或可分散粉末。为了制备用于口服给药的药物组合物，可以将药剂与公知和使用的佐剂和赋形剂混合，例如阿拉伯树胶、滑石粉、淀粉、糖类(例如甘露糖、甲基纤维素、乳糖)、明胶、表面活性剂、硬脂酸镁、水性或非水性溶剂、石蜡衍生物、交联剂、分散剂、乳化剂、润滑剂、防腐剂、调味剂(例如醚油)、溶解度增强剂(例如苯甲酸苄酯或苯甲醇)或生物利用度增强剂(例如Gelucire.TM.)。在药物组合物中，药剂也可以分散于微粒例如纳米颗粒组合物中。
在一个实施方式中，治疗有效量的药物组合物给药按约每1至约100天每天一次、约每2至约每90天每天一次、约每3至约每80天每天一次、约每4至约每70天每天一次、约每5至约60天每天一次、约每6至约50天一次、每7至约40天一次、约每8至约每30天一次或约每9至约20天一次。在本文所述另一个实施方式中，药物组合物约每1至约100天给药两次、约每2至约每90天给药两次、约每3至约每80天一次、约每4至约每70天一次、约每5至约60天一次、约每6至约50天一次、每7至约40天一次、约每8至约每30天一次或约每9至约20天一次。本文所述的一方面中，药物组合物为每日给药。
组合疗法
通过共同给药将基因疗法与药物组合物组合，不仅进一步增强了每种单独疗法的作用，而且由于每种单独组合物的作用机制不同，还提供了多方面的治疗方法。通过这种方式，不仅酶功能被恢复，而且功能性酶的数量增加。因此，本文所述的一个方面中，基因递送恢复溶酶体功能，药剂增加溶酶体数量。本文所述的另一方面中，共同给药第一组合物和第二组合物比单独给药第一组合物或第二组合物向对象提供了更强的治疗作用。在一些方面中，基因组合物可以以一个间隔递送，药物组合物可以以不同的第二间隔递送。在一些方面中，基因组合物的递送频率可以低于药物组合物。作为非限制性实例，基因组合物可以每周递送，药物组合物可以每天递送。其他组合给药方案也可以用于递送组合疗法。
本公开具有多个方面，由以下非限制性实施例说明。
实施例
进行研究以评估鼻内基因治疗和药物组合物组合在神经退行性病状的动物模型中的效果。
基因和药物组合物。基因组合物将使用包含pptl、cln2、cln3、gale或hexa基因的腺相关病毒载体制备。将使用口服吉非贝齐、肉桂酸或油酰胺组合物。
雾化。在一些方面中，雾化将用于鼻内递送，但也可使用其他鼻内方法，例如但不限于滴鼻剂、软膏、雾化泵和加压气雾剂。将使用DSITM的Buxco吸入塔一体式控制器用于雾化空气供应(图1A)。全身腔室将配备
超声雾化器(图1B)，由Buxco偏流泵提供空气。小鼠将以恰当的剂量(溶于100pi双蒸水/小鼠的体积中)雾化基因组合物3分钟。对照组小鼠也通过雾化接受
水。
实施例1：婴儿神经元蜡样脂褐质沉积症
用鼻内基因疗法和口服吉非贝齐、肉桂酸或油酰胺治疗患有INCL的pptl(-/_)小鼠：来自相同背景的年龄-和性别-匹配的pptl(+/+)小鼠将会被用作野生型(WT)对照，pptl(-/_)动物将被用于不同的治疗组。将会用基因疗法组合物和选自吉非贝齐、肉桂酸和油酰胺的药物组合物治疗小鼠，将会仅使用运载体治疗对照组。
pptl(-/-)小鼠和对照将接受每周经鼻AAV1-PPT1(每只小鼠2ml含有2x106基因组拷贝)+每日口服肉桂酸(25mg/kg体重/d)、油酰胺(5mg/kg体重/d)或吉非贝齐(8mg/kg体重/d)治疗，随后记录寿命并监测脑内贮积物质。
实施例2：青少年巴顿病
Cln3^小鼠将接受每周经鼻AAV1-CLN3(每只小鼠2m1含有2x106基因组拷贝)+每日口服肉桂酸(25mg/kg体重/d)、油酰胺(5mg/kg体重/d)或吉非贝齐(8mg/kg体重/d)治疗，随后记录寿命并监测脑内贮积物质。
实施例3：克拉伯病
Galc^小鼠将接受每周经鼻AAV1-GALC(每只小鼠2m1含有2x106基因组拷贝)+每日口服肉桂酸(25mg/kg体重/d)、油酰胺(5mg/kg体重/d)或吉非贝齐(8mg/kg体重/d)治疗，随后记录寿命并监测脑内贮积物质。
实施例4：泰-萨二氏病
Hexa^小鼠将接受每周经鼻AAV1-HEXA(每只小鼠2m1含有2x106基因组拷贝)+每日口服肉桂酸(25mg/kg体重/d)、油酰胺(5mg/kg体重/d)或吉非贝齐(8mg/kg体重/d)治疗，随后记录寿命并监测脑内贮积物质。
实施例5：晚期婴儿神经元蜡样脂褐质沉积症(LINCL)
检验鼻内基因递送作为致命溶酶体贮积症的有效选择。使用晚期婴儿神经元蜡样脂褐质沉积症(LINCL)的小鼠模型，这是由Cln2基因突变引起的罕见神经退行性疾病，该突变导致三肽基肽酶1(TPP1)酶的功能缺陷或丧失。
通过鼻内途径向两周龄的Cln2-/-小鼠递送人Cln2基因腺病毒载体(Ad-Cln2)(每周两次，体积为
的5xl06基因组拷贝的Ad-Cln2；
/鼻孔)。鼻内基因治疗4周后，一组小鼠(n＝6)不再治疗，另一组小鼠(n＝6)用口服吉非贝齐治疗，剂量为7.5mg/kg体重/天。因此，一组未接受Ad-Cln2的Cln2-/-小鼠也用口服吉非贝齐治疗。
发现吉非贝齐治疗显著增加了Cln2-/-小鼠的寿命(图1-2)。然而，每两周一次单独鼻内基因递送持续四周比吉非贝齐显著更有效地增加了Cln2-/-小鼠的寿命(图1-2)。然而，每两周一次单独鼻内基因递送持续四周比吉非贝齐显著更有效地增加了Cln2_/-小鼠的寿命(图1-2)。相比之下，口服吉非贝齐治疗没有进一步增加接受了鼻内Ad-Cln2的Cln2-/-小鼠的寿命(图1-2)。
本说明书中引用的所有出版物、专利和专利申请均通过引用纳入本文，以用于使用此类引用的教导。
所观察到的具体反应可根据并取决于所采用的制剂的具体类型和给药模式而变化，并且根据本发明的实践，结果中的这些预期变化或差异被考虑在内。
尽管本文中详细说明和描述了本发明的具体实施方式，但本发明不限于此。以上详细描述是作为本发明的示例提供的，不应被理解为构成对本发明的任何限制。修改对于本领域技术人员来说是显而易见的，并且所有不脱离本发明精神的修改都旨在包括在所附权利要求的范围内。
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Claims (27)
1.一种用于治疗溶酶体贮积症的方法，包括将包含治疗有效量的编码溶酶体酶的基因的第一组合物，和包含治疗有效量的药剂的第二组合物给予有需要的对象。
2.如权利要求1所述方法，其中所述第一组合物是鼻内给药。
3.如权利要求1所述方法，其中所述基因被递送穿过血脑屏障。
4.如权利要求1所述方法，其中所述第一组合物约每7-30天给药一次。
5.如权利要求1所述方法，其中所述第一组合物包括病毒载体，其包含所述编码溶酶体酶的基因。
6.如权利要求6所述方法，其中所述病毒载体是腺相关病毒载体。
7.如权利要求1所述方法，其中所述基因包括pptl、cln2、cln3、gale或hexa。
8.如权利要求1所述方法，其中所述溶酶体酶包括棕榈酰-蛋白质硫酯酶-1、三肽基肽酶1、半乳糖基神经酰胺、巴顿病蛋白或己糖胺酶A。
9.如权利要求7所述方法，其包括给药包含所述pptl基因的所述第一组合物，用于治疗包括婴儿神经元蜡样脂褐质沉积症的所述溶酶体贮积症。
10.如权利要求7所述方法，其包括给药包含所述cln2基因的所述第一组合物，用于治疗包括晚期婴儿神经元蜡样脂褐质沉积症的所述溶酶体贮积症。
11.如权利要求7所述方法，其包括给药包含所述cln3基因的所述第一组合物，用于治疗包括青少年神经元蜡样脂褐质沉积症的所述溶酶体贮积症。
12.如权利要求7所述方法，其包括给药包含所述gale基因的所述第一组合物，用于治疗包括克拉伯病的所述溶酶体贮积症。
13.如权利要求7所述方法，其包括给药包含所述hexa基因的所述第一组合物，用于治疗包括泰-萨二氏病的所述溶酶体贮积症。
14.如权利要求1所述方法，其中所述药剂包括肉桂酸、油酰胺或贝特类。
15.如权利要求14所述方法，其中所述贝特类是吉非贝齐或非诺贝特。
16.如权利要求1所述方法，其中所述第二组合物进一步包含治疗有效量的全-反式视黄酸。
17.如权利要求1所述方法，其中当所述药剂与全-反式视黄酸组合给药时，所述药剂的治疗有效量比所述药剂不随全-反式视黄酸递送时的所述药剂的治疗有效量低。
18.如权利要求1所述的方法，其中所述第二组合物是口服给药。
19.如权利要求1所述的方法，其中所述第二组合物每天给药一次。
20.如权利要求1所述方法，其中给药所述第一组合物和所述第二组合物比单独给药所述第一组合物或所述第二组合物在所述对象中提供了更强的治疗作用。
21.如权利要求1所述方法，其中所述溶酶体贮积症选自下组：晚期婴儿巴顿病、青少年巴顿病、克拉伯病、泰-萨二氏病、尼-皮二氏病、法布瑞氏病、法伯病和戈谢病。
22.如权利要求1所述方法，其中所述第一组合物是鼻内给药且所述第二组合物是口服给药。
23.如权利要求1或权利要求22所述方法，其中所述第一组合物是每7天至少给药一次，所述第二组合物是每天给药一次。
24.如权利要求23所述方法，其中所述病毒载体是腺相关病毒载体。
25.如权利要求23所述方法，其中所述基因包括cln2。
26.如权利要求23所述方法，其中所述第二组合物包括吉非贝齐。
27.如权利要求25所述方法，其中所述第一组合物的给药增加约100天的寿命。
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| EP3941584A1 (en) | 2022-01-26 |
| CA3132379A1 (en) | 2020-10-01 |
| WO2020197967A1 (en) | 2020-10-01 |
| AU2020245415A1 (en) | 2021-09-16 |
| JP2022525888A (ja) | 2022-05-20 |
| EP3941584A4 (en) | 2022-11-30 |
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