CN111671918A - Mrna递送的脂质纳米颗粒组合物和方法 - Google Patents
Mrna递送的脂质纳米颗粒组合物和方法 Download PDFInfo
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Abstract
本文公开在靶细胞中调节蛋白的产生的组合物和方法。本文公开的组合物和方法能够减轻与蛋白或酶缺乏相关的疾病。
Description
本申请是申请号为201280036309.5、申请日为2012年6月8日、发明名称为“MRNA递送的脂质纳米颗粒组合物和方法”的中国发明专利申请的分案申请,原申请为国际申请号为PCT/US2012/041724的国家阶段申请,该国际申请要求申请日为2011年6月8日,申请号为61/494,881的美国临时专利申请的优先权。
治疗蛋白和酶缺乏仍然需要新的途径和治疗方法。例如,溶酶体沉积病是由溶酶体功能缺乏导致的约50种的一组稀有遗传性代谢疾病,通常由于代谢所需酶缺乏导致。法布里病(Fabry disease)是酶α半乳糖苷酶(GLA)缺乏导致的溶酶体沉积病,其导致称为神经酰胺三己糖苷(globotriaosylceramide)的糖脂在血管和其他组织中积累,从而引起各种令人痛苦的临床症状。对于某些疾病,类似于法布里病,有需求代替蛋白或酶,该蛋白或酶通常通过细胞分泌至血流内。增加受影响的蛋白或酶的水平或产量的治疗,例如基因治疗,能够提供这些疾病的治疗或者甚至治愈这些疾病。然而,为了该目的使用常规基因治疗一直有多处限制。
常见基因治疗包括使用DNA插入所需遗传信息至宿主细胞内。引入DNA内的细胞通常被一定程度整合至一种或多种转染的细胞的基因组内,使得引入的遗传物质可在宿主中长期作用。尽管这种持续的作用可以有巨大益处,但外源性DNA整合至宿主基因组内也可具有许多不利作用。例如,将引入的DNA插入完整基因内,可能导致妨碍或者甚至完全消除内源基因的作用的突变。因此,使用DNA的基因治疗可导致对治疗的宿主中关键遗传功能的损害,例如,消除或者有害地降低关键酶的产生或者中断调解细胞生长的关键基因,这导致未调节或癌性细胞增殖。此外,使用常见的基于DNA的基因治疗,所需基因产品的有效表达是必须的,从而包含强的启动子序列,这也可导致在细胞中常见基因表达调节的非期望改变。也可能,基于DNA的遗传物质导致引入非所需抗-DNA抗体,反过来,这可触发可能的致命免疫应答。使用病毒载体的基因治疗途径也能够导致不利的免疫应答。在一些情况下,病毒载体甚至可整合至宿主基因组内。此外,制备临床级别病毒载体也昂贵和耗时。使用病毒载体对引入的遗传物质的靶向递送也难于控制。因此,尽管已经评估使用病毒载体递送分泌的蛋白的基于DNA的基因治疗(美国专利No.6,066,626;US2004/0110709),但由于这些各种原因这些途径受到限制。
递送编码分泌的蛋白的核酸的这些现有途径的另一障碍是最终产生的蛋白的水平。在血液中难以达到所需蛋白的显著水平,并且量维持时间不长。例如,通过核酸递送产生的蛋白量未达到正常生理水平。参见,例如,US2004/0110709。
与DNA相比,使用RNA作为基因治疗剂则基本上更加安全,因为:(1)RNA未涉及稳定地整合至转染的细胞的基因组内,从而消除以下忧虑:引入的遗传物质破坏必需基因的正常功能,或者导致引起有害或致癌作用的突变;(2)有效地翻译编码的蛋白无需外源性启动子序列,从而也避免有害的副作用;(3)与质粒DNA(pDNA)相比,信使RNA(mRNA)缺乏免疫CpG基序,从而不会产生抗-RNA抗体;以及(4)由于RNA的相对较短的半衰期,由于基于mRNA的基因治疗导致的任何有害作用具有有限的持续时间。此外,mRNA不需要进入细胞核内执行它的功能,但DNA必须克服该主要障碍。
基于mRNA的基因治疗过去使用不多的一个原因是mRNA远远不如DNA稳定,特别是当它达到细胞的细胞质处以及将它暴露于降解的酶时。在mRNA中糖部分的第二个碳上羟基的存在导致空间位阻,该空间位阻妨碍mRNA形成DNA的更加稳定的双螺旋结构,因而使得mRNA更加容易水解降解。因此,直至最近,普遍认为mRNA对于抵抗转染方案太不稳定。RNA稳定修饰上的进展激起对在基因治疗中使用mRNA替代质粒DNA的更多兴趣。诸如阳离子脂质或高分子递送媒介物的某些递送媒介物也可帮助保护转染的mRNA远离内源性RNA酶。然而,尽管增加了修饰的mRNA的稳定性,但将mRNA以使得可达蛋白产生的治疗水平的方式体内递送至细胞内仍然是个挑战,特别是对于编码全长蛋白的mRNA。尽管对编码分泌的蛋白的mRNA的递送已经有预估(US2009/0286852),但是通过体内mRNA递送实际产生的全长分泌的蛋白的水平尚不得而知,并且也没有理由期望其水平超出由基于DNA的基因治疗的水平更高。
迄今为止,使用mRNA基因治疗的显著进展仅在低水平的翻译不是限制因素的申请中出现,例如使用编码抗原的mRNA免疫。涉及通过皮内注射裸露或鱼精蛋白复合的mRNA针对肿瘤抗原的接种的临床试验已经表明其可行性、没有毒性和有前景的结果。X.Su等人,Mol.Pharmaceutics 8:774-787(2011)。遗憾的是,在其他申请中低水平的翻译极大地限制基于mRNA的基因治疗的探索,其需要较高水平的编码蛋白的mRNA持续表达以发挥生理或治疗作用。
本发明提供递送通过“储库效应”导致治疗有效水平的分泌的蛋白产生的mRNA基因治疗剂的方法。在本发明的实施方案中,编码分泌的蛋白的mRNA承载在脂质纳米颗粒中以及体内递送至靶细胞。然后靶细胞用作产生治疗水平的可溶、分泌的蛋白至循环系统内的储存来源。在一些实施方案中,产生的分泌的蛋白的水平在正常生理水平上。
本发明提供将在脂质体转移媒介物中mRNA细胞内递送至一种或多种靶细胞以产生分泌的功能性蛋白的治疗水平的组合物和方法。
本发明的组合物和方法用于控制和治疗大量疾病,特别是由蛋白和/或酶缺乏引起的疾病,其中蛋白或酶通常由分泌产生。患有这些疾病的个体可具有潜在遗传缺陷,其导致蛋白或酶表达受损,包括例如分泌的蛋白未合成、分泌的蛋白减少合成,或者合成缺乏或具有减弱生理活性的分泌的蛋白。特别地,本发明的方法和组合物用于治疗溶酶体沉积病和/或尿素循环代谢障碍,这些疾病由于在尿素循环中涉及的分泌酶的生物合成中一种或多种缺陷发生。
本发明的组合物包含mRNA、转移媒介物以及促进与它们接触和随后靶细胞的转染的试剂。mRNA能够编码临床使用的分泌的蛋白。例如,mRNA可编码功能性分泌的尿素循环酶或者在溶酶体沉积病中牵涉的分泌的酶。mRNA能够编码例如红细胞生成素(例如,人EPO)或者α-半乳糖苷酶(例如,人α-半乳糖苷酶(人GLA))。
在一些实施方案中,mRNA能够包含赋予mRNA稳定性(例如,与mRNA的野生型或天然形式相比)的一种或多种修饰以及也可包含相对于野生型的一种或多种修饰,这些修饰修正在蛋白的相关异常表达中牵涉的缺陷。例如,本发明的核酸可包含对5'和3'非翻译区的一者或两者的修饰。这些修饰可包括但不限于包含巨细胞病毒(CMV)即刻早期1(IE1)基因的部分序列、聚A尾巴(poly A tail)、Cap1结构或者编码人生长激素(hGH)的序列。在一些实施方案中,将mRNA修饰以降低mRNA免疫原性。
也涵盖包括施用本发明的组合物的治疗受试者的方法。例如,提供治疗或预防病症的方法,其中特定分泌的蛋白的产生和/或特定分泌的蛋白的利用不充足。在一个实施方案中,本文提供的方法能够用于治疗患有一种或多种尿素循环酶的缺乏或者在溶酶体沉积病中缺乏的一种或多种酶的受试者。
在优选的实施方案中,将在本发明的组合物中mRNA配制在脂质体转移媒介物中以促进递送至靶细胞。涵盖的转移媒介物可包含一种或多种阳离子脂质、非阳离子脂质和/或PEG-修饰的脂质。例如,转移媒介物可包含以下阳离子脂质的至少一种:C12-200、DLin-KC2-DMA、DODAP、HGT4003、ICE、HGT5000或HGT5001。在实施方案中,转移媒介物包含胆固醇(chol)和/或PEG-修饰的脂质。在一些实施方案中,转移媒介物包含DMG-PEG2K。在某些实施方案中,转移媒介物包含以下脂质制剂之一:C12-200、DOPE、chol、DMG-PEG2K;DODAP、DOPE、胆固醇、DMG-PEG2K;HGT5000、DOPE、chol、DMG-PEG2K;HGT5001、DOPE、chol、DMG-PEG2K。
本发明也提供用于促进一种或多种mRNA分子转染和递送至能够表现出“储库效应”的靶细胞的组合物和方法。例如,本发明的组合物和方法涵盖能够增强组合物与一种或多种靶细胞的亲和力的靶向脂质的使用。在一个实施方案中,靶向脂质是载脂蛋白-B或载脂蛋白-E以及相关靶细胞表达低密度脂蛋白受体,从而促进靶向脂质的识别。本发明的方法和组合物可用于优选地靶向大量靶细胞。例如,所涵盖的靶细胞包括但不限于:肝细胞、上皮细胞、造血细胞、上皮细胞、内皮细胞、肺细胞、骨细胞、干细胞、间质细胞、神经细胞、心脏细胞、脂肪细胞、血管平滑肌细胞、心肌细胞、骨骼肌细胞、β细胞、脑垂体细胞、滑膜衬里细胞、卵巢细胞、睾丸细胞、成纤维细胞、B细胞、T细胞、网状细胞、白细胞、粒细胞和肿瘤细胞。
在实施方案中,分泌的蛋白通过靶细胞产生维持量的时间。例如,在施用之后,分泌的蛋白可产生大于1小时、大于4小时、大于6小时、大于12小时、大于24小时、大于48小时,或者大于72小时。在一些实施方案中,在施用之后,多肽在约6小时达峰值水平。在一些实施方案中,多肽的表达维持至少治疗水平。在一些实施方案中,在施用之后,多肽表达在至少治疗水平下大于1小时、大于4小时、大于6小时、大于12小时、大于24小时、大于48小时,或者大于72小时。在一些实施方案中,多肽为在患者血清或组织(例如,肝或肺)可检测水平。在一些实施方案中,可检测水平的多肽来自在施用之后大于1小时、大于4小时、大于6小时、大于12小时、大于24小时、大于48小时,或者大于72小时的时间段内mRNA组合物的连续表达。
在某些实施方案中,分泌的蛋白以超过正常生理水平的水平产生。与对照比较,分泌的蛋白的水平可增加。
在一些实施方案中,对照是在正常个体中或者在正常个体的群体中多肽的基线生理水平。在其他实施方案中,对照是在具有相关蛋白或多肽缺乏的个体中或者在具有相关蛋白或多肽缺乏的个体的群体中多肽的基线生理水平。在一些实施方案中,对照可以是在向其施用组合物的个体中相关蛋白或多肽的正常水平。在其他实施方案中,对照是在其他治疗干预之上多肽的表达水平,例如,通过在一个或多个可比较时间点下直接注射相应多肽。
在某些实施方案中,通过靶细胞表达为对照的至少1.5倍、至少2倍、至少5倍、至少10倍、至少20倍、30倍、至少100倍、至少500倍、至少5000倍、至少50,000倍或至少100,000倍的水平的多肽。在一些实施方案中,在施用之后,相对对照的表达增加倍数持续大于1小时、大于4小时、大于6小时、大于12小时、大于24小时,或大于48小时,或者大于72小时。例如,在一个实施方案中,在血清中检测的分泌的蛋白水平为对照的至少1.5倍、至少2倍、至少5倍、至少10倍、至少20倍、30倍、至少100倍、至少500倍、至少5000倍、至少50,000倍或者至少100,000倍至少48小时或者2天。在某些实施方案中,在施用之后,分泌的蛋白水平可检测3天、4天、5天,或者1周或更久。在血清中和/或在组织(例如,肝、肺)中可观察到分泌的蛋白水平增加。
在一些实施方案中,本方法产生所需分泌的蛋白的持续循环半衰期。例如,分泌的蛋白可检测比通过分泌的蛋白的皮下注射观察的半衰期长数小时或数天。在实施方案中,分泌的蛋白的半衰期维持大于1天、2天、3天、4天、5天,或1周或者更久。
在一些实施方案中,施用包括单一或重复给药。在某些实施方案中,静脉内,或通过肺部递送来实施给药。
多肽可以是例如红细胞生成素、α-半乳糖苷酶、LDL受体、因子VIII、因子IX、α-L-艾杜糖苷酸酶(对于MPS I)、艾杜糖醛酸硫酸酯酶(对于MPS II)、肝素-N-硫酸酯酶(对于MPS IIIA)、α-N-乙酰葡糖胺糖苷酶(对于MPS IIIB)、半乳糖6-硫酸酯酶(对于MPS IV A)溶酶体酸酯酶或者芳香基硫酸酯酶-A中的一种或多种。
某些实施方案涉及提供细胞或受试者mRNA的组合物和方法,其至少一部分以基本上小于由mRNA产生的对应功能性蛋白的量编码功能性蛋白。换而言之,在某些实施方案中,递送至细胞的mRNA能够产生一定量的蛋白,该量基本上大于递送至细胞的mRNA的量。例如,在给定量时间内,例如向细胞或受试者施用mRNA开始1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、12小时、15小时、20小时或24小时,通过该mRNA生成的对应蛋白的量可以是实际向细胞或受试者施用的mRNA的量的至少1.5倍、2倍、3倍、5倍、10倍、15倍、20倍、25倍、50倍、100倍、150倍、200倍、250倍、300倍、400倍、500倍,或者更多倍。这能够通过质量比质量计、摩尔比摩尔计和/或分子比分子计来测定。能够以各种方式测定蛋白。例如,对于细胞,测定的蛋白能够作为细胞内蛋白、细胞外蛋白,或者两者的组合来测定。对于受试者,测定的蛋白可以是在血清中;在具体一种或多种组织中,例如肝、肾、心脏或脑;在具体细胞类型中,例如肝或脑的各种细胞类型之一;或者在血清、组织和/或细胞类型的任意组合中测定的蛋白。而且,能够测定在施用mRNA之前在细胞或受试者中内源性蛋白的基线量,然后由在施用mRNA之后测定的蛋白减去该基线量,得到由mRNA生成的对应蛋白的量。以这种方式,mRNA能够向细胞或受试者提供大量治疗物质的储藏或储存来源,例如,如与递送至细胞或受试者的mRNA相比。储存来源能够用作由mRNA的多肽表达的连续来源持续一段时间。
当连同所附实施例参照本发明的以下详细描述时,能更好地理解本发明的以上讨论和许多其他特征和附加优势。本文描述的各实施方案是附带的,并且鉴于本文包含的技术通过本领域技术人员理解的方式能够合并或者一起使用。
附图简述
图1显示5'CMV的核苷酸序列(SEQ ID NO:l),其中如果存在,X是GGA。
图2显示3'hGH序列的核苷酸序列(SEQ ID NO:2)。
图3显示人红细胞生成(EPO)mRNA的核苷酸序列(SEQ ID NO:3)。该序列能够在5'端上与SEQ ID NO:l旁侧连接以及在3'端上与SEQ ID NO:2旁侧连接。
图4显示人α-半乳糖苷酶(GLA)mRNA的核苷酸序列(SEQ ID NO:4)。该序列能够在5'端上与SEQ ID NO:l旁侧连接以及在3'端上与SEQ ID NO:2旁侧连接。
图5显示人α-1抗胰蛋白酶(A1AT)mRNA的核苷酸序列(SEQ ID NO:5)。该序列能够在5’端上与SEQ ID NO:l旁侧连接以及在3’端上与SEQ ID NO:2旁侧连接。
图6显示人因子IX(FIX)mRNA的核苷酸序列(SEQ ID NO:6)。该序列能够在5’端上与SEQ ID NO:l旁侧连接以及在3’端上与SEQ ID NO:2旁侧连接。
图7显示如通过ELISA测定的分泌的hEPO蛋白水平的定量。检测的蛋白是由通过单次给药的各种脂质纳米颗粒制剂静脉内递送的hEPO mRNA产生的结果。制剂C12-200(30ug)、HGT4003(150ug)、ICE(100ug)、DODAP(200ug)呈现为各检品(制剂1-4)的阳离子/离子脂质组分。数值基于施用四小时之后血液样品。
图8显示经单次IV给药的人EPO mRNA-承载的脂质纳米颗粒(制剂1-4)处理的小鼠的血细胞比容测定值。在施用之后4h(第1天)、24h(第2天)、第4天、第7天和第10天取得所有血液样品。
图9显示经单次IV给药或者三次注射(第1天、第3天、第5天)的人EPO-mRNA-承载的脂质纳米颗粒处理的小鼠的血细胞比容测定值。在注射之前(第-4天)、第7天和第15天取得全部血液样品。以(30ug,单次给药)或者(3x 10ug,第1天、第3天、第5天给药)施用制剂1;以(3x 50ug,第1天、第3天、第5天给药)施用制剂2。
图10显示如通过ELISA测定的分泌的人α-半乳糖苷酶(hGLA)蛋白水平的定量。检测的蛋白是由通过脂质纳米颗粒(制剂1;30ug单次静脉内给药,基于包封的mRNA)递送的hGLA mRNA产生的结果。检测hGLA蛋白48小时。
图11显示在血清中hGLA活性。在37℃下使用基质4-甲基伞形酮基-α-D-乳酸吡喃糖苷甲酯(4-MU-α-gal)测定hGLA活性。数据为6至9名个体测定值的平均值。
图12显示如通过ELISA测定在血清中hGLA蛋白水平的定量。由通过C12-200-基脂质纳米颗粒(C12-200:DOPE:Chol:DMGPEG2K,40:30:25:5(制剂1);30ug基于包封的mRNA的mRNA,单次IV给药)递送的hGLA mRNA产生蛋白。根据包封的mRNA,每单次静脉给药下,监控hGLA蛋白72小时。监控hGLA蛋白72小时。
图13显示如通过ELISA测定在肝、肾和脾中hGLA蛋白水平的定量。由通过C12-200-基脂质纳米颗粒(制剂1;30ug基于包封的mRNA的mRNA,单次IV给药)递送的hGLA mRNA产生蛋白。监控hGLA蛋白72小时。
图14显示监控hGLA(如在血清(A)和肝(B)中如分泌的MRT-来源的人GLA蛋白)的蛋白产生的剂量反应研究。施用之后24小时测定样品(制剂1;单次给药,IV,N=4只小鼠/组),并通过ELISA定量。
图15显示在无胸腺裸小鼠(40ug/kg剂量)中ERT-基α-半乳糖苷酶和由MRT产生的hGLA蛋白(制剂1;1.0mg/kg mRNA剂量)的药物代谢动力学性质。
图16显示如使用ELISA测定在MRT-处理的法布里小鼠中分泌的hGLA蛋白水平的定量。由通过C12-200-基脂质纳米颗粒(制剂1;10ug mRNA/单次静脉内给药,基于包封的mRNA)递送的hGLA mRNA产生蛋白。监控血清72小时。
图17显示如通过ELISA测定在MRT-处理的法布里KO小鼠的肝、肾、脾和心脏中hGLA蛋白水平的定量。由通过C12-200-基脂质纳米颗粒(制剂1;30ug基于包封的mRNA的mRNA;单次IV给药)递送的hGLA mRNA产生蛋白。监控hGLA蛋白72小时。将表示正常生理水平的文献数值绘图为虚线。
图18显示如使用ELISA测定在MRT和α-半乳糖苷酶处理的法布里小鼠中分泌的hGLA蛋白水平的定量。两种疗法均为单次静脉内1.0mg/kg剂量给药。
图19显示如通过ELISA测定的在MRT和ERT(α-半乳糖苷酶)-处理的法布里KO小鼠的肝、肾、脾和心脏中hGLA蛋白水平的定量。由通过脂质纳米颗粒(制剂1;1.0mg/kg基于包封的mRNA的mRNA,单次IV给药)递送的hGLA mRNA产生蛋白。
图20显示在经处理和未经处理的小鼠的肾中神经酰胺三己糖苷(Gb3)和lyso-Gb3的相对定量。将雄性法布里KO小鼠经1.0mg/kg下GLA mRNA-承载的脂质纳米颗粒或者α-半乳糖苷酶单次给药。量反映施用一周之后Gb3/lyso-Gb3的量。
图21显示在经处理和未经处理的小鼠的心脏中神经酰胺三己糖苷(Gb3)和lyso-Gb3的相对定量。使用1.0mg/kg下GLA mRNA-承载的脂质纳米颗粒或者α-半乳糖苷酶的单次给药来处理雄性法布里KO小鼠。该量反映在施用一周之后Gb3/lyso-Gb3的定量。
图22显示监控GLA(如在血清中分泌的MRT-来源的人GLA蛋白)的产生的剂量反应研究。在施用HGT4003(制剂3)或者HGT5000-基脂质纳米颗粒(制剂5)24小时(单次给药,IV,N=4只小鼠/组)之后测定样品,并通过ELISA定量。
图23显示如在血清(A)中或者在肝、肾和脾(B)中测定的hGLA蛋白产生。在施用HGT5001-基脂质纳米颗粒(制剂6)之后6小时和24小时(单次给药,IV,N=4只小鼠/组)测定样品并通过ELISA定量。
图24显示使用ELISA测定的分泌人因子IX蛋白水平的定量(平均ng/mL±标准偏差)。由通过C12-200-基脂质纳米颗粒(C12-200:DOPE:Chol:DMGPEG2K,40:30:25:5(制剂1);30ug mRNA/单次静脉内给药,基于包封的mRNA)递送的FIX mRNA来产生FIX蛋白。监控FIX蛋白72小时(n=24只小鼠)。
图25显示使用ELISA测定的分泌人α-1-抗胰蛋白酶(A1AT)蛋白水平的定量。由通过C12-200-基脂质纳米颗粒(C12-200:DOPE:Chol:DMGPEG2K,40:30:25:5(制剂1);30ugmRNA/单次静脉内给药,基于包封的mRNA)递送的A1AT mRNA来产生A1AT蛋白。监控A1AT蛋白24小时。
图26显示在气管内施用hEPO mRNA-承载的纳米颗粒(测定的mIU)(C12-200、HGT5000或HGT5001-基脂质纳米颗粒;分别为制剂1、5、6)之后处理的小鼠的肺脏和血清中检测的hEPO蛋白的基于ELISA的定量。施用之后6小时处死动物(n=4只动物/组)。
示例性实施方案的描述
本发明提供将在脂质体转移媒介物中mRNA细胞内递送至一种或多种靶细胞以产生分泌的功能性蛋白的治疗水平的组合物和方法。
如本文所使用的定性蛋白或酶的术语“功能性”是指蛋白或酶具有生理活性,或者可选地能够进行如天然或者正常功能的蛋白或酶的相同或者类似的功能。本发明的mRNA组合物用于治疗各种代谢或遗传疾病,特别是包括蛋白或酶的未表达、错误表达或者缺陷的那些遗传或者代谢疾病。术语“治疗水平”是指在血液或组织中检测的高于对照水平的蛋白水平,其中对照可以为正常生理水平,或者在施用mRNA组合物之前受试者的水平。术语“分泌的”是指在靶细胞外(细胞外空间)检测的蛋白。在血液中或者在组织中可检测到蛋白。在本发明的上下文中,以最广意义使用的术语“产生的”是指至少一种mRNA翻译至蛋白或酶内。如本文所提供,组合物包括转移媒介物。如本文所使用,术语“转移媒介物”包括任意标准药物载体、稀释剂、赋形剂等,其通常旨在连同包括核酸的生物活性剂一起使用。组合物以及特别是本文描述的转移媒介物能够递送mRNA至靶细胞。在实施方案中,转移媒介物是脂质纳米颗粒。
mRNA
在本发明的组合物中mRNA可编码例如分泌的激素、酶、受体、多肽、肽或者正常分泌的其他目标蛋白。在本发明的一个实施方案中,mRNA可任选具有化学或生物修饰,例如,其改善这些mRNA的稳定性和/或半衰期或者其改善或者促进蛋白产生。
本发明的方法提供任选共同递送一种或多种独特mRNA至靶细胞,例如,通过联合两种独特mRNA至单独的转移媒介物内。在本发明的一个实施方案中,可将治疗性第一mRNA和治疗性第二mRNA配制在单独的转移媒介物内,并且施用。本发明也涵盖共同递送和/或共同施用治疗性第一mRNA和第二核酸以促进和/或增强治疗性第一mRNA的功能或递送。例如,这些第二核酸(例如,外源性或合成mRNA)可编码膜转运蛋白,所述膜转运蛋白一旦表达(例如,外源性或者合成mRNA)便可促进递送或者增强第一mRNA的生物活性。可选地,可将治疗性第一mRNA与用作“陪伴分子”的第二核酸一起施用,例如以引导治疗性第一mRNA的折叠。
本发明的方法也提供一种或多种治疗核酸的递送以治疗单一病症或者缺乏,其中这些治疗核酸各自通过不同作用机制作用。例如,本发明的组合物可包含治疗性第一mRNA和紧随其后的第二核酸,例如,施用该第一mRNA以矫正内源性蛋白或酶缺乏,施用该第二核酸以灭活或者“拆掉”功能不正常的内源性核酸和它的蛋白或者酶产品。这些“第二”核酸可编码诸如mRNA或者siRNA。
一旦转染,在本发明的组合物中天然mRNA可衰变,其具有介于30分钟和数天之间的半衰期。在本发明的组合物中mRNA优选保留至少一些待翻译的能力,从而产生功能性分泌的蛋白或者酶。因此,本发明提供包含稳定的mRNA的组合物和施用稳定的mRNA的方法。在本发明的一些实施方案中,mRNA的活性延长预期时间段。例如,mRNA的活性可延长,使得将本发明的组合物以半周一次或者每周两次向受试者施用,或者更优选为每月一次、每月两次、每季一次或者每年一次。本发明的mRNA的预期或延长的活性与由这些mRNA产生的分泌功能性蛋白或酶的量直接相关。类似地,通过改善或增强mRNA的翻译制备的修饰,本发明的组合物的活性可进一步延伸或者延长。而且,通过靶细胞产生的功能性蛋白或酶的量是递送至靶细胞的mRNA的量和这些mRNA的稳定性的函数。鉴于本发明的mRNA的稳定性可改善或增强的程度,产生的分泌的蛋白或者酶的活性和组合物的给药频率可进一步延长。
因此,在一些实施方案中,在本发明的组合物中mRNA包含至少一种修饰,其赋予对核酸的增加或者增强的稳定性,包括例如,改善的对体内核酸酶消化的抵抗。如本文所使用,如与本文提供的核酸相关的这些定义的术语“修饰”和“经修饰”包括至少一种改变,其优选增强稳定性和导致mRNA比mRNA的野生型或者天然存在版本更加稳定(例如,对核酸酶消化抵抗)。如本文所使用,如与本发明的核酸相关(并且特别是与mRNA相关)的这些定义的术语“稳定的”和“稳定性”是指增加或者增强对通过通常能够降解这些mRNA的诸如核酸酶(即,核酸内切酶或者核酸外切酶)的降解的抵抗。增加的稳定性能够包括例如对通过内源性酶(例如,核酸内切酶或者核酸外切酶)或在靶细胞或组织内条件的水解或其他破坏敏感性降低,从而增加或者增长在靶细胞、组织、受试者和/或细胞质中这些mRNA的停留时间。本文提供的稳定的mRNA分子证实相对于它们天然存在、未经修饰的对应物(例如,mRNA的野生型版本)具有更久的半衰期。通过如与本发明的mRNA相关的这些定义的术语“修饰”和“经修饰”也涵盖改善或者增强mRNA核酸的翻译的改变,包括例如,并入在蛋白翻译的起始中发挥作用的序列(例如,Kozac共有序列)(Kozak,M,Nucleic Acids Res 15(20):8125-48(1987))。
在一些实施方案中,对本发明的mRNA进行了化学或生物修饰以导致它们更加稳定。对mRNA的示例性修饰包括碱基的耗竭(depletion)(例如,通过缺失或者通过一种核苷酸取代另一种)或者碱基的修饰,例如,碱基的化学修饰。如本文所使用的短语“化学修饰”包括引入不同于在天然存在的mRNA中所见到那些的化学物质的修饰,例如,共价修饰,例如引入经修饰的核苷酸(例如,核苷酸类似物,或者引入在这些mRNA分子中未天然发现的侧基)。
此外,合适的修饰包括在密码子的一种或多种核苷酸中改变,使得密码子编码相同氨基酸,但比在mRNA的野生型版本中发现的密码子更加稳定。例如,已经证实RNA的稳定性与更多数目的胞苷(C)和/或尿苷(U)残基之间的相反关系,并且已经发现缺乏C和U残基的RNA对大部分RNA酶稳定(Heidenreich,等人J Biol Chem 269,2131-8(1994))。在一些实施方案中,在mRNA序列中C和/或U残基的数目减少。在另一实施方案中,C和/或U残基的数目通过编码特定氨基酸的一种密码子被编码相同或者相关氨基酸的另一种密码子取代来降低。
本发明的mRNA核酸涵盖的修饰也包括并入假尿苷。将假尿苷并入本发明的mRNA核酸内可增强稳定性和翻译能力、以及降低体内免疫原性。参见,例如,Karikó,K.,等人,Molecular Therapy 16(11):1833-1840(2008)。通过本领域普通技术人员容易得知的方法可进行对本发明的mRNA的取代和修饰。
与非翻译区相比,在mRNA的编码区内减少在序列中C和U残基的数目的限制可能更大,(即,可能无法消除信使中存在的所有C和U残基,但仍然保存信使编码所需氨基酸序列的能力)。然而,遗传密码的简并性呈现出使得在序列中存在的C和/或U残基的数目可减少的机会,但保持相同编码能力((即,取决于何种氨基酸通过密码子编码,可以有RNA序列的修饰的多种不同可能形式)。例如,Gly的密码子能够变为GGA或者GGG,而不是GGU或者GGC。
术语修饰也包括例如并入非核苷酸连接或经修饰的核苷酸至本发明的mRNA序列内(例如,对编码功能性分泌的蛋白或酶的mRNA分子的3'和5'端的一端或者两端的修饰)。这些修饰包括加入碱基至mRNA序列(例如,并入聚A尾巴或者更长的聚A尾巴)、3'UTR或5'UTR的改变、使mRNA与试剂(例如,蛋白或互补核酸分子)复合和并入改变mRNA分子的结构的元件(例如,其形成二级结构)。
据认为,聚A尾巴稳定天然信使。因此,在一个实施方案中,能够将长聚A尾巴加至mRNA分子,从而使得mRNA更加稳定。使用各种本领域已知技术能够加入聚A尾巴。例如,能够将长聚A尾巴加入以使用聚A聚合酶合成或者体外转录mRNA(Yokoe,等人NatureBiotechnology.1996;14:1252-1256)。转录载体也能够编码长聚A尾巴。此外,通过直接由PCR产品转录能够加入聚A尾巴。在一个实施方案中,聚A尾巴的长度为至少约90、200、300、400、至少500个核苷酸。在一个实施方案中,调整聚A尾巴的长度以控制本发明的修饰的mRNA分子的稳定性,因而转录蛋白。例如,因为聚A尾巴的长度能够影响mRNA分子的半衰期,所以能够调整聚A尾巴的长度以修饰mRNA抵抗核酸酶的水平,从而控制在细胞中蛋白表达的时程。在一个实施方案中,稳定的mRNA分子充分抵抗体内降解(例如,通过核酸酶),从而可在没有转移媒介物下将它们递送至靶细胞。
在一个实施方案中,通过合并在野生型mRNA中未天然发现的3'和/或5'未经翻译(UTR)序列能够修饰mRNA。在一个实施方案中,能够将天然旁侧连接mRNA和编码第二、不相关蛋白的3'和/或5'旁侧序列合并至编码治疗或功能性蛋白的mRNA分子的核苷酸序列内,从而对它进行修饰。例如,能够将稳定的来自mRNA分子的3'或5'序列(例如,珠蛋白、肌动蛋白、GAPDH、微管蛋白、组蛋白,或者柠檬酸循环酶)合并至正义mRNA核酸分子的3'和/或5'区,从而增加正义mRNA分子的稳定性。参见,例如,US2003/0083272。
在一些实施方案中,在本发明的组合物中mRNA包括mRNA的5'端修饰,从而包括CMV即刻早期1(IE1)基因的部分序列,或其片段(例如,SEQ ID NO:l)以改善核酸酶抗性和/或延长mRNA的半衰期。除了增加mRNA核酸序列的稳定性之外,令人惊讶地发现,包含CMV即刻早期1(IE1)基因的部分序列增强mRNA的翻译和功能性蛋白或酶的表达。也涵盖包含人生长激素(hGH)基因序列的内含物,或其片段(例如,SEQ ID NO:2)至核酸(例如,mRNA)的3'端,从而进一步稳定mRNA。通常,优选的修饰相对于它们未经修饰的对应物改善mRNA的稳定性和/或药物代谢动力学性质(例如,半衰期),以及包括改善这些mRNA对体内核酸酶消化抗性进行的修饰。
进一步涵盖SEQ ID NO:l和/或SEQ ID NO:2的核酸序列的变体,其中变体维持核酸的功能性质,包括稳定mRNA和/或药物动力学性质(例如,半衰期)。变体可与SEQ ID NO:l或者SEQ ID NO:2具有大于90%、大于95%、大于98%,或者大于99%序列同一性。
在一些实施方案中,组合物能够包含稳定试剂。组合物能够包括直接或间接结合、并稳定mRNA的一种或多种制剂试剂,从而增加在靶细胞中停留时间。这些试剂优选导致在靶细胞中mRNA的改善的半衰期。例如,通过合并“稳定试剂”可增加mRNA的稳定性和翻译的效率,该“稳定试剂”与在细胞中天然存在的mRNA形成复合物(参见,例如,美国专利No.5,677,124)。
例如,通过合并聚A和蛋白以及在转移媒介物内在承载或包封mRNA之前待体外稳定的mRNA能够完成稳定试剂的合并。示例性稳定试剂包括一种或多种蛋白、肽、适体、翻译辅助蛋白、mRNA结合蛋白和/或翻译起动因子。
通过使用调理作用抑制部分也可改善组合物的稳定,该调理作用抑制部分通常为与转移媒介物化学或物理结合的大的亲水聚合物(例如,通过脂溶性锚嵌入膜自身内,或者通过直接与膜脂质的活性基团直接结合)。这些调理作用抑制亲水聚合物形成保护表面层,其显著降低脂质体通过巨噬细胞-单核细胞系统和网状内皮系统的摄取(例如,如在美国专利No.4,920,016中所述,其全部公开通过引用方式并入本文)。转移媒介物经调理作用抑制部分修饰,因此比它们未经修饰的对应物在循环中保留更长些。
当RNA与互补核酸分子(例如,DNA或RNA)杂交时,可使它避免核酸酶而受到保护(Krieg,等人Melton.Methods in Enzymology.1987;155,397-415))。杂交的mRNA的稳定性是可能的,这是由于大部分RNA酶的固有单链特异性。在一些实施方案中,与mRNA复合选择的稳定试剂是真核蛋白(例如,哺乳动物蛋白)。在又一实施方案中,通过与第二核酸分子杂交能够修饰mRNA。如果全部mRNA分子与互补核酸分子杂交,则翻译起始可减少。在一些实施方案中,mRNA分子的5'非翻译区和AUG起始区可任选保留未被杂交。在翻译起始之后,即使在高亲和力双链体上核蛋白体复合物的解旋活性能够发挥作用,从而使得翻译能够进行。(Liebhaber.J.Mol.Biol.1992;226:2-13;Monia等人,J Biol Chem.1993;268:14514-22.)
应理解,用于增强mRNA的稳定性的任意以上描述的方法可单独使用或者联合一种或多种任意其他上述方法和/或组合物使用。
本发明的mRNA可任选与报道基因(例如,mRNA的编码区的上游或下游)结合,其例如促进确定mRNA递送至靶细胞或者组织。合适的报道基因可包括例如绿色荧光蛋白mRNA(GFP mRNA)、花虫型荧光素酶mRNA(荧光素酶mRNA)、萤火虫荧光素酶mRNA或其任意组合。例如,GFP mRNA可与编码可分泌蛋白的mRNA融合,从而便于证实mRNA位于用作蛋白产生储存库的靶细胞中。
如本文所使用,术语“使转染”或“转染”是指细胞内引入mRNA至细胞内,或者优选至靶细胞内。引入的mRNA可以稳定地或者暂时维持在靶细胞中。术语“转染效率”是指通过靶细胞吸收的经过转染的mRNA的量。在实践中,在转染之后,通过靶细胞表达的报道核酸产物的量来评估转染效率。优选实施方案包括具有高转染效率的组合物,特别是最小化通过非靶细胞的转染介导的副作用的那些组合物。证实高转染效率的本发明的组合物改善合适剂量的mRNA递送至靶细胞的可能性,同时最小化可能系统副作用。在本发明的一个实施方案中,本发明的转移媒介物能够递送大的mRNA序列(例如,至少1kDa、1.5kDa、2kDa、2.5kDa、5kDa、l0kDa、12kDa、15kDa、20kDa、25kDa、30kDa,或者更多的mRNA)。使用一种或多种可接受试剂能够配制mRNA,其提供递送这些mRNA至靶细胞的媒介物。通常根据大量因素来选择合适的试剂,其中,所述因素包括mRNA的生物或化学性质、预期施用途径、这些mRNA将暴露的期望生物环境以及预期靶细胞的具体性质。在一些实施方案中,诸如脂质体的转移媒介物在未损害生物活性下包封mRNA。在一些实施方案中,相对于非靶细胞,转移媒介物证实优选和/或大量结合靶细胞。在优选的实施方案中,转移媒介物递送它的内容物至靶细胞,使得将mRNA递送至合适的亚细胞区室,例如细胞质。
转移媒介物
在实施方案中,在本发明的组合物中转移媒介物是脂质体转移媒介物,例如,脂质纳米颗粒。在一个实施方案中,可选择和/或制备转移媒介物以最佳化mRNA递送至靶细胞。例如,如果靶细胞是肝细胞,则转移媒介物的性质(例如,尺寸、电荷和/或pH)可优选有效地递送这些转移媒介物至靶细胞、降低免疫清除和/或促进在该靶细胞中停留。可选地,如果靶细胞是中枢神经系统(例如,用于治疗神经变性疾病施用的mRNA可特异性靶向脑或者脊髓组织),则转移媒介物的选择和制备必须考虑到在血脑屏障内渗透和保留和/或直接递送这些转移媒介物至这些靶细胞的可替代方式的使用。在一个实施方案中,本发明的组合物可与促进外源性mRNA的转移的试剂联合使用(例如,干扰或改善血脑屏障的渗透性,从而增加外源性mRNA转移至靶细胞的试剂)。
通过本发明涵盖脂质体转移媒介物的使用以促进核酸递送至靶细胞。脂质体(例如,脂质体脂质纳米颗粒)通常用于研究、工业和医学的各种应用中,特别是它们用作体内诊断或治疗化合物的转移媒介物(Lasic,Trends Biotechnol.,16:307-321,1998;Drummond等人,Pharmacol.Rev.,51:691-743,1999),以及它的特征通常在于通过一个或多个双层的膜由外部介质隔离的具有内部水空间的极小囊泡。通常通过两性分子形成脂质体的双层膜,例如包含空间隔离的亲水性和疏水性结构域的合成或天然来源的脂质(Lasic,Trends Biotechnol.,16:307-321,1998)。通过两亲性聚合物和表面活性剂(例如,聚合囊(polymerosome)、微囊(niosome)等)也能够形成脂质体的双层膜。
在本发明的上下文中,脂质体转移媒介物通常用于转运mRNA至靶细胞。为了本发明的目的,制备含有所需核酸的脂质体转移媒介物。合并所需实体(例如,核酸)至脂质体内的过程通常称为“承载”(Lasic,等人,FEBS Lett.,312:255-258,1992)。脂质体合并的核酸可完全或者部分位于脂质体的内部空间中、在脂质体的双层膜内,或者与脂质体膜的外表面相缔合。将核酸合并至脂质体内在本文中也称为“包封”,其中核酸全部包含在脂质体的内部空间内。合并mRNA至诸如脂质体的转移媒介物内的目的通常是为了使核酸免受可含有酶或化学物质的环境,这些酶或化学物质降解核酸和/或系统或导致核酸快速排泄的受体。因此,在本发明的优选实施方案中,选择的转移媒介物能够增强其中包含的mRNA的稳定性。脂质体能够使得包封的mRNA到达靶细胞和/或可优选使得包封的mRNA到达靶细胞,或者可选地限制这些mRNA递送至其他位置或细胞,其中施用的mRNA的存在可无用或者为所需。而且,将mRNA并入诸如阳离子阳离子脂质体的转移媒介物也促进递送这些mRNA至靶细胞内。
理想地,制备脂质体转移媒介物以包封一个或多个所需mRNA,使得组合物证实具有高转染效率和增强的稳定性。尽管脂质体能够促进引入核酸至靶细胞内,但作为共聚物的多聚阳离子(例如,聚L-赖氨酸和鱼精蛋白)的加入能够促进、并在一些情况下体外和体内显著增加在大量细胞系中多种类型的阳离子脂质体的转染效率2-28倍(参见N.J.Caplen等人,Gene Ther.1995;2:603;S.Li,等人,Gene Ther.1997;4,891)。
脂质纳米颗粒
在本发明的优选实施方案中,配制作为脂质纳米颗粒的转移媒介物。如本文所使用,短语“脂质纳米颗粒”是指包含一种或多种脂质(例如,阳离子脂质、非阳离子脂质和PEG-修饰的脂质)的转移媒介物。优选地,配制脂质纳米颗粒以递送一个或多个mRNA至一种或多种靶细胞。合适的脂质的颗粒包括例如磷脂酰基化合物(例如,磷脂酰甘油、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、神经鞘脂类、脑苷脂类和神经节苷脂)。也涵盖使用作为转移媒介物的聚合物,无论单独或者与其他转移媒介物联合使用。合适的聚合物可包括例如聚丙烯酸酯、聚氰基丙烯酸酯、聚乳酸、聚乳酸-聚乙醇酸交酯共聚物、聚己内酯、右旋糖酐、白蛋白、明胶、海藻酸、胶原、壳聚糖、环糊精、树状高分子和聚乙烯亚胺。在一个实施方案中,基于它的能力来选择转移媒介物以便于mRNA转染至靶细胞。
本发明涵盖使用脂质纳米颗粒作为包含阳离子脂质的转移媒介物以包封和/或增加mRNA递送至用作蛋白产生储存库的靶细胞内。如本文所使用,短语“阳离子脂质”是指在诸如生理pH的选择的pH下携带净正电荷的任意数目的脂质类型。通过包括不同比率的采用一种或多种阳离子脂质、非阳离子脂质和PEG-修饰的脂质的多组分脂质混合物可制备涵盖的脂质纳米颗粒。已经在文献中描述多种阳离子脂质,其中许多均为市售。
在本发明的组合物和方法中使用的特别合适的阳离子脂质包括在通过引用方式并入本文的国际专利公开WO 2010/053572中描述的那些,以及最特别地,在WO 2010/053572的段落[00225]中描述的C12-200。在某些实施方案中,本发明的组合物和方法采用包括在2012年3月29日提出美国临时专利申请61/617,468(通过引用方式并入本文)中描述的可离子化阳离子脂质的脂质纳米颗粒,例如,(15Z,18Z)-N,N-二甲基-6-(9Z,12Z)-十八-9,12-二烯-1-基)二十四碳-15,18-二烯-1-胺(HGT5000)、(15Z,18Z)-N,N-二甲基-6-((9Z,12Z)-十八-9,12-二烯-1-基)二十四碳-4,15,18-三烯-1-胺(HGT5001)和(15Z,18Z)-N,N-二甲基-6-((9Z,12Z)-十八-9,12-二烯-1-基)二十四碳-5,15,18-三烯-1-胺(HGT5002)。
在一些实施方案中,使用阳离子脂质N-[1-(2,3-二油基氧基)丙基]-N,N,N-三甲基氯化铵或者"DOTMA"。(Feigner等人(Proc.Nat'l Acad.Sci.84,7413(1987);美国专利No.4,897,355)。能够单独配制DOTMA或者能够联合中性脂质、二油基磷脂酰基-乙醇胺或"DOPE"或者其他阳离子或非阳离子脂质配制至脂质体转移媒介物或脂质纳米颗粒内,并且这些脂质体能够用于增加核酸递送至靶细胞内。其他合适的阳离子脂质包括例如5-羧基精胺基甘氨酸双十八烷基酰胺或者"DOGS"2,3-二油基氧基-N-[2(精胺-氨甲酰基)乙基]-N,N-二甲基-1-丙铵或"DOSPA"(Behr等人Proc.Nat.'l Acad.Sci.86,6982(1989);美国专利No.5,171,678;美国专利No.5,334,761);1,2-二油酰基-3-二甲基铵-丙烷或"DODAP"、1,2-二油酰基-3-三甲基铵-丙烷或"DOTAP"。涵盖的阳离子脂质也包括1,2-二硬脂酰基氧基-N,N-二甲基-3-氨基丙烷或"DSDMA"、1,2-二油基氧基-N,N-二甲基-3-氨基丙烷或"DODMA"、1,2-二亚油基氧基-N,N-二甲基-3-氨基丙烷或"DLinDMA"、1,2-二亚油酰基氧基-N,N-二甲基-3-氨基丙烷或"DLenDMA"、N-二油烯基-N,N-二甲基氯化铵或"DODAC"、N,N-二硬脂酰基-N,N-二甲基溴化铵或"DDAB"、N-(1,2-双肉豆蔻基氧基丙-3-基)-N,N-二甲基-N-羟基乙基溴化铵或"DMRIE"、3-二甲基氨基-2-(胆甾-5-烯-3-β-氧基丁烷-4-氧基)-1-(顺式,顺式-9,12-十八二烯氧基)丙烷或"CLinDMA"、2-[5'-(胆甾-5-烯-3-β-氧基)-3'-氧杂戊氧基)-3-二甲基-1-(顺式,顺式-9',l-2'-十八二烯氧基)丙烷或"CpLinDMA"、N,N-二甲基-3,4-二油基氧基苄胺或"DMOBA"、1,2-N,N'-二油基氨甲酰基-3-二甲基氨基丙烷或"DOcarbDAP"、2,3-二亚麻酰基氧基-Ν,Ν-二甲基丙胺或"DLinDAP"、1,2-N,N'-二亚油基氨甲酰基-3-二甲基氨基丙烷或"DLincarbDAP"、1,2-二亚麻酰基氨甲酰基-3-二甲基氨基丙烷或"DLinCDAP"、2,2-二亚油基-4-二甲基氨基甲基-[1,3]-二氧戊烷或"DLin-K-DMA"、2,2-二亚油基-4-二甲基氨基乙基-[1,3]-二氧戊烷或"DLin-K-XTC2-DMA",和2-(2,2-二((9Z,12Z)-十八-9,12-二烯-1-基)-1,3-二氧戊环-4-基)-N,N-二甲基乙胺(DLin-KC2-DMA))(参见,WO2010/042877;Semple等人,Nature Biotech.28:172-176(2010)),或其混合物。(Heyes,J.,等人,J Controlled Release 107:276-287(2005);Morrissey,DV.,等人,Nat.Biotechnol.23(8):1003-1007(2005);PCT公开WO2005/121348A1)。
通过本发明也涵盖胆固醇基阳离子脂质的使用。能够单独或者联合其他阳离子或者非阳离子脂质使用这些胆固醇基阳离子脂质。合适的胆固醇基阳离子脂质包括例如,DC-Chol(N,N-二甲基-N-乙基氨甲酰基胆固醇)、1,4-双(3-N-油烯基氨基-丙基)哌嗪(Gao,等人Biochem.Biophys.Res.Comm.179,280(1991);Wolf等人BioTechniques 23,139(1997);美国专利No.5,744,335),或ICE。
此外,由市售得到多种试剂以增加转染效率。合适的例子包括LIPOFECTIN(DOTMA:DOPE)(Invitrogen,Carlsbad,Calif.)、LIPOFECTAMINE(DOSPA:DOPE)(Invitrogen)、LIPOFECTAMINE2000(Invitrogen)、FUGENE、TRANSFECTAM(DOGS)和EFFECTENE。
也涵盖阳离子脂质,例如二烷基氨基-基、咪唑基、和胍基脂质。例如,某些实施方案涉及包含一种或多种咪唑基阳离子脂质的组合物,例如,如通过以下结构(I)表示的咪唑胆固醇酯或"ICE"脂质(3S,10R,13R,17R)-10,13-二甲基-17-((R)-6-甲基庚烷-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-3-基3-(1H-咪唑-4-基)丙酸酯。在优选的实施方案中,递送mRNA的转移媒介物可包含一种或多种咪唑基阳离子脂质,例如,如通过结构(I)表示的咪唑胆固醇酯或"ICE"脂质(3S,10R,13R,17R)-10,13-二甲基-17-((R)-6-甲基庚烷-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊[a]菲-3-基3-(1H-咪唑-4-基)丙酸酯。
不受特定理论限制,据认为,咪唑基阳离子脂质ICE的融合性与通过咪唑基团促进的核内体破坏相关,其具有比常见阳离子脂质更低的pKa。结果,核内体破坏促进渗透膨胀和脂质体膜的破坏,随后为承载其中的核酸的转染或细胞内释放至靶细胞内。
咪唑基阳离子脂质的特征也在于它们相对于其他阳离子脂质毒性降低。咪唑基阳离子脂质(例如,ICE)可用作在脂质纳米颗粒中唯一阳离子脂质,或者可选地可与常见阳离子脂质、非阳离子脂质和PEG-修饰的脂质联合使用。阳离子脂质可包含约1%至约90%、约2%至约70%、约5%至约50%、约10%至约40%的摩尔比的存在于转移媒介物的总脂质,或者优选为约20%至约70%的存在于转移媒介物的总脂质。
类似地,某些实施方案涉及包含如通过以下结构(II)表示和如在2011年6月8日提出的美国临时申请No:61/494,745中进一步描述的HGT4003阳离子脂质2-((2,3-双((9Z,12Z)-十八-9,12-二烯-1-基氧基)丙基)二硫基)-N,N-二甲基乙胺的脂质纳米颗粒,该文献中全部技术通过引用整体并入本文:
在其他实施方案中,本文描述的组合物和方法涉及包含一种或多种可分裂的脂质的脂质纳米颗粒,例如,包含可分裂的二硫化物(S-S)官能团(例如,HGT4001、HGT4002、HGT4003、HGT4004和HGT4005)的一种或多种阳离子脂质或化合物,如在美国临时申请No:61/494,745中进一步描述,其全部技术通过引用整体并入本文。
通过本发明也涵盖聚乙二醇(PEG)修饰的磷脂和衍生的脂质的使用,例如包括N-辛酰基-神经鞘氨醇-1-[琥珀酰基(甲氧基聚乙二醇)-2000](C8 PEG-2000神经酰胺)的衍生的神经酰胺(PEG-CER),单独使用或者优选联合包含转移媒介物(例如,脂质纳米颗粒)的其他脂质一起使用。涵盖的PEG-修饰的脂质包括但不限于与具有C6-C20长度的烷基链的脂质共价连接的长度至多5kDa的聚乙二醇链。这些组分的加入可防止复杂的聚集以及也可提供增加循环持续时间和增加脂质-核酸组合物递送至靶细胞的方法(Klibanov等人(1990)FEBS Letters,268(1):235-237),或者可选择它们快速体内交换出制剂(参见美国专利No.5,885,613)。
特别有用的可交换脂质是具有较短的酰基链(例如,C14或C18)的PEG-神经酰胺。本发明的PEG修饰的磷脂和衍生的脂质可包含约0%至约20%、约0.5%至约20%、约1%至约15%、约4%至约10%或约2%的摩尔比的存在于脂质体转移媒介物中总脂质。
本发明也涵盖使用非阳离子脂质。如本文所使用,短语“非阳离子脂质”是指任何中性、两性离子或阴离子脂质。如本文所使用,短语“阴离子脂质”是指在诸如生理pH的选择的pH下携带净负电荷的任意数目的脂质类型。非阳离子脂质包括但不限于二硬脂酰基磷脂酰胆碱(DSPC)、二油酰基磷脂酰胆碱(DOPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二油酰基磷脂酰甘油(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、二油酰基磷脂酰乙醇胺(DOPE)、棕榈酰基油酰基磷脂酰胆碱(POPC)、棕榈酰基油酰基-磷脂酰乙醇胺(POPE)、二油酰基-磷脂酰乙醇胺4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(DOPE-mal)、二棕榈酰基磷脂酰基乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、二硬脂酰基-磷脂酰基-乙醇胺(DSPE)、16-O-单甲基PE、16-O-二甲基PE、18-1-反式PE、1-硬脂酰基-2-油酰基-磷脂酰乙醇胺(SOPE)、胆固醇,或其混合物。这些非阳离子脂质可单独使用,或者优选联合诸如阳离子脂质的其他赋形剂一起使用。当联合阳离子脂质一起使用时,非阳离子脂质可包含5%至约90%,或优选约10%至约70%的摩尔比的存在于转移媒介物的总脂质。
优选地,通过联合多种脂质和/或聚合物组分来制备转移媒介物(例如,脂质纳米颗粒)。例如,使用40:30:25:5的摩尔比的C12-200、DOPE、chol、DMG-PEG2K;或18:56:20:6的摩尔比的DODAP、DOPE、胆固醇、DMG-PEG2K;或40:20:35:5的摩尔比的HGT5000、DOPE、chol、DMG-PEG2K;或40:20:35:5的摩尔比的HGT5001、DOPE、chol、DMG-PEG2K可制备转移媒介物。包含脂质纳米颗粒的阳离子脂质、非阳离子脂质和/或PEG-修饰的脂质的选择、以及这些脂质与彼此之间的相对摩尔比基于选择的脂质的特征、预期靶细胞的性质、待递送的mRNA的特征。另外的考虑包括例如烷基链的饱和度、以及选择的脂质的尺寸、电荷、pH、pKa、融合性和毒性。因此,可相应地调节摩尔比。例如,在实施方案中,在脂质纳米颗粒中阳离子脂质的比例可以大于10%、大于20%、大于30%、大于40%、大于50%、大于60%,或者大于70%。在脂质纳米颗粒中非阳离子脂质的比例可以大于5%、大于10%、大于20%、大于30%,或大于40%。在脂质纳米颗粒中胆固醇的比例可以大于10%、大于20%、大于30%,或大于40%。在脂质纳米颗粒中PEG-修饰的脂质的比例可以大于1%、大于2%、大于5%、大于10%,或大于20%。
在某些优选的实施方案中,本发明的脂质纳米颗粒包含以下阳离子脂质至少之一:C12-200、DLin-KC2-DMA、DODAP、HGT4003、ICE、HGT5000,或HGT5001。在实施方案中,转移媒介物包含胆固醇和/或PEG-修饰的脂质。在一些实施方案中,转移媒介物包含DMG-PEG2K。在某些实施方案中,转移媒介物包含以下脂质制剂之一:C12-200、DOPE、chol、DMG-PEG2K;DODAP、DOPE、胆固醇、DMG-PEG2K;HGT5000、DOPE、chol、DMG-PEG2K;HGT5001、DOPE、chol、DMG-PEG2K。
通过目前本领域已知的各种技术能够制备本发明的组合物中使用的脂质体转移媒介物。通过常见技术可制备多层囊泡(MLV),例如,通过沉积选择的脂质在合适容器或器皿的内壁上;通过溶解脂质在合适溶剂中,以及然后蒸发溶剂以在器皿的内侧保留薄膜或者通过喷雾干燥。可将水相加入旋转运动着的器皿,其导致形成MLV。然后通过均质化、超声处理或挤压多层囊泡能够形成单层囊泡(ULV)。此外,通过洗涤剂去除技术能够形成单层囊泡。
在本发明的某些实施方案中,本发明的组合物包含转移媒介物,其中mRNA与转移媒介物的两表面缔合,并包封在相同转移媒介物内。例如,在制备本发明的组合物时,阳离子脂质体转移媒介物可与mRNA通过静电作用缔合。
在某些实施方案中,使用在体外和体内应用中可检测的诊断放射性核素、荧光物质或其他物质可承载本发明的组合物。例如,在本发明中使用的合适的诊断物质可包括若丹明-二油酰基磷脂酰基乙醇胺(Rh-PE)、绿色荧光蛋白mRNA(GFP mRNA)、花虫型荧光素酶mRNA和萤火虫荧光素酶mRNA。
脂质体转移媒介物的合适尺寸的选择必须考虑靶细胞或者组织的尺寸以及待制备的脂质体应用程度。在一些实施方案中,可期望限制mRNA的转染至某些细胞或者组织。例如,为了靶向肝细胞,可定脂质体转移媒介物的尺寸,使得它的尺寸比在肝中内皮层衬里肝窦状隙的开窗缝要小;因此,脂质体转移媒介物能够容易地渗透这些内皮内皮开窗缝以到达靶肝细胞。可选地,可定脂质体转移媒介物的尺寸,使得脂质体的尺寸具有足够大的直径以限制或者明显避免分布至某些细胞或组织内。例如,可定脂质体转移媒介物的尺寸,使得它的尺寸大于内皮层衬里肝窦状隙的开窗缝,从而限制脂质体转移媒介物分布至肝细胞。通常,转移媒介物的尺寸在约25至250nm范围内,优选小于约250nm、175nm、150nm、125nm、l00nm、75nm、50nm、25nm或l0nm。
本领域已知的各种可选择的方法可用于定尺寸多种脂质体转移媒介物。这些定尺寸方法之一描述在美国专利No.4,737,323中,其通过引用方式并入本文。通过水浴或者探针超声处理来超声脂质体混悬物产生逐渐尺寸降低至直径小于约0.05微米的小ULV。均质化是取决于撕裂大脂质体为较小脂质体的剪切能量的另一种方法。在典型的均质化过程中,将MLV通过标准乳剂均化器再循环直至观察到通常介于约0.1至0.5微米的选择的脂质体尺寸。通过如在Bloomfield,Ann.Rev.Biophys.Bioeng.,10:421-450(1981)描述的准电光散射(QELS)可测定脂质体囊泡的尺寸,其通过引用方式并入本文。
通过形成的脂质体的超声处理可降低平均脂质体直径。使用QELS评估可替代间歇的超声处理循环以引导有效的脂质体合成。
靶细胞
如本文所使用,术语“靶细胞”是指本发明的组合物可导向或靶向的细胞或组织。在一些实施方案中,靶细胞缺乏目标蛋白或酶。例如,在期望递送核酸至肝细胞的情况下,肝细胞表示靶细胞。在一些实施方案中,本发明的组合物在差别对待的情况下(即,不转染非靶细胞)转染靶细胞。也可制备优选靶向各种靶细胞的本发明的组合物,其包括但不限于,肝细胞、上皮细胞、造血细胞、上皮细胞、内皮细胞、肺细胞、骨细胞、干细胞、间质细胞、神经细胞(如,脑膜星状细胞、运动神经元、背根神经节细胞和前角神经元)、感光细胞(如,视杆和视锥)、视网膜色素上皮细胞、分泌细胞、心脏细胞、脂肪细胞、血管平滑肌细胞、心肌细胞、骨骼肌细胞、β细胞、脑脑垂体细胞、滑膜衬里细胞、卵巢细胞、睾丸细胞、成纤维细胞、B细胞、T细胞、网状细胞、白细胞、粒细胞和肿瘤细胞。
可制备优先分配在靶细胞中的本发明的组合物,例如在心脏、肺、肾、肝和脾中。在一些实施方案中,本发明的组合物分配至肝细胞中以促进通过肝细胞(例如,肝细胞)包含其中的mRNA的递送和随后的表达。靶向的肝细胞可用作能够产生和系统分泌功能性蛋白或酶的生物“贮库”或“储存库”。因此,在本发明的一个实施方案中,脂质体转移媒介物可靶向肝细胞和/或一旦递送优选分配至肝细胞。在靶肝细胞的转染之后,翻译在脂质体媒介物中承载的mRNA以及产生、分泌和系统分配功能性蛋白产物。在其他实施方案中,除肝细胞之外的细胞(例如,肺、脾、心脏、眼,或者中枢神经系统的细胞)能够用作蛋白产生的储存位置。
在一个实施方案中,本发明的组合物促进受试者的一种或多种功能性蛋白和/或酶的内源性产生,特别是证实其相对于重组制备的对应物具有较少免疫原性的蛋白和/或酶的产生。在本发明的优选实施方案中,转移媒介物包含编码缺乏的蛋白或酶的mRNA。一旦分配这些组合物至靶组织以及经随后转染这些靶细胞,可将承载至脂质体转移媒介物(例如,脂质纳米颗粒)内的外源性mRNA体内翻译以产生通过外源性施用的mRNA编码的功能性蛋白或酶(例如,其中受试者缺乏的蛋白或酶)。因此,本发明的组合物探索受试者翻译外源性或重组制备的mRNA以产生外源性翻译的蛋白或酶、从而产生(以及其中可应用地分泌)功能性蛋白或酶的能力。表达或翻译的蛋白或酶的特征也在于体内包含天然翻译后修饰,其通常在重组制备的蛋白或酶中可缺乏,从而进一步降低翻译的蛋白或酶的免疫原性。
编码缺乏蛋白或酶的mRNA的施用避免需要递送核酸至靶细胞内的特定细胞器(例如,线粒体)。而且,一旦转染靶细胞和递送核酸至靶细胞的细胞质,则可翻译转移媒介物的mRNA内容物和表达功能性蛋白或酶。
本发明也涵盖通过被动和主动靶向方式来差别靶向靶细胞和组织。被动靶向的现象探索在不依赖使用另外的赋形剂或方法下体内自然分配转移媒介物的模式以增强转移媒介物通过靶细胞识别。例如,通过网状内皮系统的细胞经过吞噬作用的转移媒介物可能聚集在肝或者脾中,因而可提供被动引导递送组合物至这些靶细胞的方法。
可选地,本发明涵盖主动靶向,其包括使用本文中称为“靶向脂质”的另外的赋形剂,其可以与转移媒介物结合(共价或非共价)以支持定位这些转移媒介物在某些靶细胞或者靶组织处。例如,通过在转移媒介物中或上包含一种或多种内源性靶向脂质(例如,载脂蛋白E)可介导靶向以支持分配靶细胞或组织。通过靶组织识别靶向脂质主动促进转移媒介物和/或它在靶细胞和组织中的内容物的组织分配和细胞摄取(例如,在转移媒介物中或上包含载脂蛋白-E靶向脂质支持识别和结合转移媒介物至通过肝细胞表达的内源性低密度脂蛋白受体)。如本文所提供,组合物能够包含配基,其能够增强组合物与靶细胞的亲和力。在配制中或配制之后靶向脂质可结合脂质颗粒的外部双层。这些方法是本领域众所周知的。此外,一些脂质颗粒制剂可采用融合聚合物,例如PEAA、血球凝集素、其他脂肽(参见美国专利申请系列No.08/835,281和60/083,294,其通过引用方式并入本文)和用于体内和/或细胞内递送的其他特征物。在其他一些实施方案中,本发明的组合物证实具有改善的转染效率和/或证实对目标靶细胞或组织具有增强的选择性。因此,涵盖包含能够增加组合物与靶细胞或组织的它们核酸内容物的亲和力的一种或多种配基(例如,肽、适体、寡核苷酸、维生素或其他分子)的组合物。合适的配基可任选与转移媒介物的表面结合或连接。在一些实施方案中,靶向脂质可贯穿转移媒介物的表面或者包封在转移媒介物内。基于它们的物理、化学或生物性质(例如,选择性亲和力和/或识别靶细胞表面标志物或特征物)来选择合适的配基。细胞特异性靶向位置和它们对应的靶向脂质能够广泛变化。选择合适的靶向脂质,使得可开发出靶细胞的独特特征,从而使得组合物可差别对待靶和非靶细胞。例如,本发明的组合物可包括表面标志物(例如,载脂蛋白-B或载脂蛋白-E),其选择性增强对肝细胞的识别,或亲和力(例如,通过这些表面标志物的受体介导的识别和结合)。此外,期望使用半乳糖作为靶向脂质引导本发明的组合物至薄壁肝细胞,或者可选地期望使用含有糖残基的甘露糖作为靶向脂质引导本发明的组合物至肝内皮细胞(例如,可优选结合存在于肝细胞中去唾液酸糖蛋白受体的含有糖残基的甘露糖)(参见Hillery AM,等人"DrugDelivery and Targeting:For Pharmacists and Pharmaceutical Scientists"(2002)Taylor&Francis,Inc.)。与在转移媒介物(例如,脂质纳米颗粒)中存在的部分已经缀合的这些靶向脂质的呈现形式因而促进识别和摄取在靶细胞和组织中本发明的组合物。合适的靶向脂质的例子包括一种或多种肽、蛋白、适体、维生素和寡核苷酸。
应用和施用
如本文所使用,术语“受试者”是指本发明的组合物和方法待施用的任何动物(例如,不如动物),包括但不限于人、非人灵长类、啮齿类等。通常,关于人受试者的术语“受试者”和“患者”在本文中可交换使用。
本发明的组合物和方法提供递送mRNA以治疗多种病症。特别地,本发明的组合物和方法适合于治疗与通过靶细胞排泄或分泌至周围细胞外流体内的蛋白和/或酶(例如,编码激素和神经递质的mRNA)的缺乏相关的疾病或病症。在实施方案中,疾病可涉及分泌的蛋白缺陷或缺乏(例如,法布里病或ALS)。在某些实施方案中,通过分泌的蛋白的缺陷或缺乏不能导致疾病,但可受分泌的蛋白影响。例如,通过提供本发明的组合物可改善疾病的症状(例如,囊性纤维化病)。本发明可使用的病症包括但不限于以下病症,例如亨延顿氏舞蹈病(Huntington's Disease);帕金森氏病(Parkinson's Disease);肌肉萎缩症(例如,Duchenne型和Becker型);血友病(例如,B型血友病(FIX)、A型血友病(FVIII);SMN1相关的脊髓性肌萎缩(SMA);肌萎缩性侧索硬化(ALS);GALT相关的半乳糖血症;囊性纤维化病(CF);SLC3A1相关的病症,包括胱氨酸尿症;COL4A5相关的病症,包括奥尔波特综合征(Alport syndrome);半乳糖脑苷脂酶缺乏;X-连锁肾上腺脑白质营养不良和肾上腺髓神经障碍;弗里德赖希氏共济失调(Friedreich’s ataxia);佩-梅二氏病(Pelizaeus-Merzbacher disease);TSC1和TSC2相关的结节性硬化症;圣菲利波综合征B型(MPS IIIB);CTNS相关的胱氨酸贮积病;FMR1相关的病症,包括脆性X染色体综合征、脆性X染色体相关的震颤/共济失调综合征和脆性X染色体未成熟卵巢功能早衰综合征;帕-魏二氏综合征(Prader-Willi syndrome);遗传性出血性毛细血管扩张症(AT);尼曼-皮克二氏病C1型(Niemann-Pick disease Type C1);神经元腊样脂褐质沉积症相关的疾病,包括幼年神经元蜡样质脂褐质沉积症(JNCL)、幼年巴登氏病(Juvenile Batten disease)、桑-哈病(Santavuori-Haltia disease)、詹-比二氏病(Jansky-Bielschowsky disease)及PTT-l和TPP1缺乏;;EIF2B1、EIF2B2、EIF2B3、EIF2B4和EIF2B5相关的儿童共济失调伴中枢神经系统髓鞘化不良/白质消融;CACNA1A和CACNB4相关的周期性共济失调2型;MECP2相关的病症,包括典型雷特综合征、MECP2相关的重度新生儿脑病和PPM-X综合征;CDKL5相关的非典型雷特综合征;肯尼迪病(Kennedy's disease)(SBMA);Notch-3相关的伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL);SCN1A和SCN1B相关的癫痫症;聚合酶G相关的病症,包括阿尔珀斯-胡腾洛歇尔综合征(Alpers-Huttenlocher syndrome)、POLG相关的感觉共济失调性神经病、构音困难和眼肌麻痹及常染色体显性和隐性遗传的进行性外眼肌麻痹伴线粒体DNA缺失;X-连锁肾上腺发育不全;X-连锁血中丙球蛋白贫乏症;威尔森病(Wilson's disease);和法布里病。在一个实施方案中,本发明的核酸、以及特别是mRNA可编码分泌至细胞外空间内的功能性蛋白或酶。例如,分泌的蛋白包括凝固因子、补体途径的组分、细胞因子、趋化因子、化学引诱物、蛋白激素(例如,EGF、PDF)、血清的蛋白组分、抗体、可分泌toll样受体和其他。在一些实施方案中,本发明的组合物可包括编码红细胞生成素、α1-抗胰蛋白酶、羧基肽酶N或人生长激素的mRNA。
在实施方案中,本发明编码由亚单位组成的分泌的蛋白,该亚单位通过大于一种基因编码。例如,分泌的蛋白可以为异源二聚体,其中各链或亚单位通过单独的基因编码。据相信,在转移媒介物中可能有大于一个mRNA分子以及mRNA编码分泌的蛋白的单独的亚单位。可选地,可将单独的mRNA工程化以编码大于一个亚单位(例如,在单链Fv抗体的情况下)。在某些实施方案中,可在单独的转移媒介物中施用编码单一亚单位的单独的mRNA分子。在一个实施方案中,mRNA可编码全长抗体(可变区和恒定区的重链和轻链)或者抗体的片段(例如,Fab、Fv或单链Fv(scFv))以赋予受试者免疫。尽管本发明的一个实施方案涉及用于赋予受试者免疫的方法和组合物(例如,通过编码功能性抗体的mRNA的翻译),但本文公开和在此涵盖的本发明可广泛应用。在可选择的实施方案中,本发明的组合物编码可用于在受试者中短暂或缓慢作用于功能性应答的抗体。例如,本发明的mRNA可编码功能性单克隆或多克隆抗体,一旦由靶细胞翻译和分泌,其可用于靶向和/或失活生物靶(例如,刺激细胞因子,例如肿瘤坏死因子)。类似地,本发明的mRNA核酸可编码例如用于治疗膜性增生性肾小球性肾炎II型或急性溶血性尿毒综合征的功能性抗肾炎因子抗体,或者可选地可编码用于治疗诸如癌症的VEGF介导的疾病的抗血管内皮生长因子(VEGF)抗体。在其他实施方案中,分泌的蛋白是由大于一个亚单位(例如,IL-12或IL-23)组成的细胞因子或其他分泌的蛋白。
能够向受试者施用本发明的组合物。在一些实施方案中,联合一种或多种另外的核酸、载体、靶向脂质或稳定试剂,或者在与合适的赋形剂混合的药物组合物中来配制组合物。例如,在一个实施方案中,可配制本发明的组合物以递送编码两种或多种不同蛋白或酶的mRNA。配制和施用药物的技术可在"Remington's Pharmaceutical Sciences,"MackPublishing Co.,Easton,Pa.,最新版中找到。
使用本发明的组合物和方法能够将发挥药物或治疗作用的大量分子能够递送至靶细胞。分子可以是有机物或无机物。有机分子可以是肽、蛋白、糖、脂质、固醇、核酸(包括肽核酸),或其任意组合。递送至靶细胞内的制剂能够包含大于一种类型的分子,例如,两种不同的核苷酸序列,或蛋白、酶或类固醇。
根据目前的医疗实践,并考虑受试者的临床条件、施用地点和方法、施用方案、受试者的年龄、性别、体重和与本领域普通临床人员相关的其他因素可施用和给药本发明的组合物。通过在试验临床研究、药理学、临床和医学领域普通技术人员已知的这些相关考虑可确定用于本文的“有效量”。在一些实施方案中,施用的量有效地达到至少某些稳定、改善或消除症状和如通过本领域技术人员恰当测定疾病进展、退化或改善所选择的其他指标。例如,合适的量和给药方案是至少导致瞬时蛋白产生的原因之一。
合适的施用途径包括例如口服、直肠、阴道、经粘膜、经肺(包括气管内或吸入),或者肠部施用;胃肠外递送,包括肌肉内、皮下、髓内注射、以及椎管内、直接心室内、静脉内、腹膜内、鼻内,或眼内注射。
可选地,可局部施用本发明的组合物,而不是全身方式,例如,通过直接注射药物组合物至靶向的组织内,优选在持续释放的制剂中。取决于待靶向的组织,能够以各种方式影响局部递送。例如,能够吸入(用于经鼻、经气管或经支气管递送)含有本发明的组合物的气雾剂;能够将本发明的组合物注射至受损伤、疾病迹象或疼痛位置,例如,组合物能够在口服、气管或食管应用的锭剂中提供;能够在施用至胃或小肠的液体、片剂或胶囊剂中提供;能够在用于直肠或阴道应用的栓剂形式中提供;或者通过使用乳剂、滴剂或者甚至注射能够递送至眼。甚至能够手术施用包含与治疗分子或配基复合的本发明的组合物的制剂,例如与聚合物或其他结构或者物质缔合,这能够使得组合物由植入位置扩散至周围细胞。可选地,在没有使用聚合物或支持物下能够将它们手术施用。
在一个实施方案中,配制本发明的组合物,使得它们适合于延长释放包含其中的mRNA。在预期给药间隔下可方便地向受试者施用这些延长释放的组合物。例如,在一个实施方案中,每日两次、每日一次或隔日一次向受试者施用本发明的组合物。在优选的实施方案中,每周两次、每周一次、每十天一次、每两周一次、每三周一次,或者更优选每四周一次、每月一次、每六周一次、每八周一次、隔月一次、每三月一次、每四月一次、每六月一次、每八月一次、每九月一次或每年一次向受试者施用本发明的组合物。也涵盖组合物和脂质体媒介物,将其配制用于储存施用(例如,肌肉内、皮下、玻璃体内)以在延长时间段内递送或释放mRNA。优选地,将采用的延长释放的方式与对mRNA进行的修饰联合使用以增强稳定性。
本文也涵盖包含本文公开的一种或多种脂质体纳米颗粒的冻干的药物组合物以及使用如在例如2011年6月8日提交的美国临时申请No.61/494,882中公开的这些冻干的组合物的相关的方法,其技术通过引用方式整体并入本文。例如,在施用之前可重新配制或者能够体内重新配制根据本发明的冻干的药物组合物。例如,冻干的药物组合物可配制为恰当的剂型(例如,皮内剂型,例如片、棒或膜)并施用它们使得在体内时间内通过个体的体液来再水化剂型。
尽管依照某些实施方案已经描述本发明的某些化合物、组合物和方法的特异性,但以下实施例仅用于示出本发明的化合物,并且不旨在对其进行限制。用于描述本发明的背景和用于提供关于它的实践的另外细节的各出版物、参考资料、登录号和本文类似的引用均通过引用方式整体并入。
除非另有明确相反说明,在本说明书和在权利要求书中如本文所使用的冠词“一个”和“一种”应当理解为包括复数指示物。除非相反说明或者文本中明显表示相反,认为在一个或多个基团成员之间包括“或者”的权利要求或描述中,一个、大于一个,或者所有基团成员存在、采用,或相关于给定产品或方法均满足。本发明包括其中正好一个基团成员存在、采用,或相关于给定产品或方法的实施方案。而且,应理解,除非另有说明或者除非对本领域普通技术人员显然会引起矛盾或者不一致,本发明涵盖所有变化形式、组合和变换,其中来自一个或多个所列权利要求的一种或多种限定条件、元件、条件、描述条件等引入依赖相同基础权利要求(或者如相关,任意其他权利要求)的另一权利要求内。在元件存在于列表的情况下(例如,在马库什基团或类似的格式中),应理解,也公开元件的各亚组,并且任何元件能够由组中去除。应当理解,通常,在本发明、本发明的方面表示包含特定元件、特征等的情况下,本发明的某些实施方案或者本发明的方面组成,或者基本组成于这些元件、特征等。为了简化,在本文中没有用太多辞藻具体描述每一例子的那些实施方案。也应当理解,无论具体排除条件是否在说明书中引用,本发明的任何实施方案或方面均能够由权利要求清楚排除。用于描述本发明的背景和用于提供关于它的实践的另外细节的本文引用的出版物和其他参考资料均通过引用方式并入。
本文还包括以下实施方案:
实施方案1.一种组合物,其包含(a)至少一种mRNA分子,所述mRNA分子的至少一部分编码功能性分泌多肽;以及(b)包含脂质纳米颗粒的转移媒介物。
实施方案2.实施方案1所述的组合物,其中所述mRNA编码在患有溶酶体沉积病的个体中异常缺乏的酶。
实施方案3.实施方案1所述的组合物,其中所述mRNA编码功能性红细胞生成素或者功能性α-半乳糖苷酶多肽。
实施方案4.实施方案1所述的组合物,其中所述RNA分子包含赋予所述RNA分子稳定性的至少一种修饰。
实施方案5.实施方案1所述的组合物,其中所述RNA分子包含所述RNA分子的5'非翻译区的修饰。
实施方案6.实施方案5所述的组合物,其中所述修饰包括Cap1结构的内含物。
实施方案7.实施方案1所述的组合物,其中所述RNA分子包含所述RNA分子的3'非翻译区的修饰。
实施方案8.实施方案7所述的组合物,其中所述修饰包括聚A尾巴的内含物。
实施方案9.实施方案1所述的组合物,其进一步包含促进所述RNA分子转移至靶细胞的细胞内区室的试剂。
实施方案10.实施方案1所述的组合物,其中所述脂质纳米颗粒包含一种或多种阳离子脂质。
实施方案11.实施方案1所述的组合物,其中所述脂质纳米颗粒包含一种或多种非阳离子脂质。
实施方案12.实施方案1所述的组合物,其中所述脂质纳米颗粒包含一种或多种PEG-修饰的脂质。
实施方案13.实施方案1所述的组合物,其中所述脂质纳米颗粒包含C12-200。
实施方案14.实施方案1所述的组合物,其中所述脂质纳米颗粒包含DLinKC2DMA、CHOL、DOPE和DMG-PEG-2000。
实施方案15.实施方案1所述的组合物,其中所述脂质纳米颗粒包含C12-200、DOPE、CHOL和DMGPEG2K。
实施方案16.实施方案1所述的组合物,其中所述脂质纳米颗粒包含可切割的脂质。
实施方案17.实施方案1所述的组合物,其中所述组合物是冻干的。
实施方案18.实施方案1所述的组合物,其中所述组合物是复溶的冻干组合物。
实施方案19.实施方案10所述的组合物,其中所述靶细胞选自肝细胞、上皮细胞、造血细胞、上皮细胞、内皮细胞、肺细胞、骨细胞、干细胞、间质细胞、神经细胞、心脏细胞、脂肪细胞、血管平滑肌细胞、心肌细胞、骨骼肌细胞、β细胞、脑垂体细胞、滑膜衬里细胞、卵巢细胞、睾丸细胞、成纤维细胞、B细胞、T细胞、网状细胞、白细胞、粒细胞和肿瘤细胞。
实施方案20.一种治疗患有功能性多肽缺乏的受试者的方法,其包括施用包含以下的组合物:(a)至少一种mRNA,所述mRNA的至少一部分编码所述功能性分泌多肽;以及(b)包含脂质纳米颗粒的转移媒介物,其中在施用所述组合物之后,所述mRNA表达在靶细胞中以产生所述功能性分泌多肽。
实施方案21.实施方案21所述的方法,其中所述mRNA编码功能性红细胞生成素、α-半乳糖苷酶、LDL受体、因子III、因子IX、α-L-艾杜糖苷酸酶、艾杜糖醛酸硫酸酯酶、肝素-N-硫酸酯酶、α-N-乙酰葡糖胺糖苷酶、半乳糖6-硫酸酯酶、β-半乳糖苷酶、溶酶体酸酯酶或者芳香基硫酸酯酶-A多肽;以及(b)转移媒介物,其中在施用所述组合物之后,所述mRNA表达在靶细胞中以产生功能性分泌多肽。
实施方案22.实施方案21所述的方法,其中所述功能性分泌多肽是在患有溶酶体沉积病的个体中异常缺乏的酶。
实施方案23.实施方案21所述的方法,其中所述mRNA分子包含赋予所述mRNA分子稳定性的至少一种修饰。
实施方案24.实施方案21所述的方法,其中所述mRNA分子包含所述mRNA分子的5'非翻译区的修饰。
实施方案25.实施方案25所述的方法,其中所述修饰包含Cap1结构的内含物。
实施方案26.实施方案21所述的方法,其中所述mRNA分子包含所述mRNA分子的3'非翻译区的修饰。
实施方案27.实施方案27所述的方法,其中所述修饰包括聚A尾巴的内含物。
实施方案28.实施方案21所述的方法,其进一步包含促进所述mRNA分子转移至靶细胞的细胞内区室的试剂。
实施方案29.实施方案21所述的方法,其中所述脂质纳米颗粒包含一种或多种阳离子脂质。
实施方案30.实施方案21所述的方法,其中所述脂质纳米颗粒包含一种或多种非阳离子脂质。
实施方案31.实施方案21所述的方法,其中所述脂质纳米颗粒包含一种或多种PEG-修饰的脂质。
实施方案32.实施方案21所述的方法,其中所述脂质纳米颗粒包含C12-200。
实施方案33.实施方案21所述的方法,其中所述脂质纳米颗粒包含DLinKC2DMA、CHOL、DOPE和DMG-PEG-2000。
实施方案34.实施方案21所述的方法,其中所述脂质纳米颗粒包含C12-200、DOPE、CHOL和DMGPEG2K。
实施方案35.实施方案21所述的方法,其中所述脂质纳米颗粒包含可切割的脂质。
实施方案36.实施方案21所述的方法,其中所述组合物是冻干的。
实施方案37.实施方案21所述的方法,其中所述组合物是复溶的冻干组合物。
实施方案38.实施方案21所述的方法,其中所述靶细胞选自肝细胞、上皮细胞、造血细胞、上皮细胞、内皮细胞、肺细胞、骨细胞、干细胞、间质细胞、神经细胞、心脏细胞、脂肪细胞、血管平滑肌细胞、心肌细胞、骨骼肌细胞、β细胞、脑垂体细胞、滑膜衬里细胞、卵巢细胞、睾丸细胞、成纤维细胞、B细胞、T细胞、网状细胞、白细胞、粒细胞和肿瘤细胞。
实施方案39.一种治疗患有功能性多肽缺乏的受试者的方法,其包括施用包含以下的组合物:(a)至少一种mRNA,所述mRNA的至少一部分编码所述功能性分泌多肽;以及(b)包含脂质纳米颗粒的转移媒介物,其中在施用所述组合物之后,所述mRNA在靶细胞中被翻译以在施用之后在所述靶细胞中产生至少最小治疗水平的功能性多肽超过1小时。
实施方案40.一种在靶细胞中产生功能性分泌多肽的方法,其包括施用包含以下的组合物:(a)至少一种mRNA,所述mRNA的至少一部分编码所述功能性分泌多肽;以及(b)包含脂质纳米颗粒的转移媒介物,其中在施用所述组合物之后,所述mRNA在靶细胞中被翻译以在施用之后产生至少最小治疗水平的功能性多肽超过1小时。
实施例
实施例1:通过多核苷酸组合物的静脉内递送的蛋白产生储存
信使RNA
通过由编码基因的质粒DNA模板体外转录来合成人红细胞生成素(EPO)(SEQ IDNO:3;图3)、人α-半乳糖苷酶(GLA)(SEQ ID NO:4;图4)、人α-1抗胰蛋白酶(A1AT)(SEQ IDNO:5;图5)和人因子IX(FIX)(SEQ ID NO:6;图6),随后加入5'帽结构(Cap1)(Fechter&Brownlee,J.Gen.Virology 86:1239-1249(2005))和如通过凝胶电泳测定的长度为约200个核苷酸的3'聚(A)尾。5'和3'非翻译区存在于以下例子中的各mRNA产品中并且通过SEQID NO:1和2(图1和图2)分别定义。
脂质纳米颗粒制剂
制剂1:将C12-200、DOPE、Chol和DMG-PEG2K(40:30:25:5)等份的50mg/mL乙醇溶液混合,以及使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH 7.4)渗滤,浓缩并保存在2-8℃下。
制剂2:将DODAP、DOPE、胆固醇和DMG-PEG2K(18:56:20:6)等份的50mg/mL乙醇溶液混合,以及使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备EPO mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH 7.4)渗滤,浓缩并保存在2-8℃下。最终浓度=1.35mg/mL EPO mRNA(经包封)。Zave=75.9nm(Dv(50)=57.3nm;Dv(90)=92.1nm)。
制剂3:将HGT4003、DOPE、胆固醇和DMG-PEG2K(50:25:20:5)等份的50mg/mL乙醇溶液混合,并使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH 7.4)渗滤,浓缩并保存在2-8℃下。
制剂4:将ICE、DOPE和DMG-PEG2K(70:25:5)等份的50mg/mL乙醇溶液混合,以及使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH 7.4)渗滤,浓缩并保存在2-8℃下。
制剂5:将HGT5000、DOPE、胆固醇和DMG-PEG2K(40:20:35:5)等份的50mg/mL乙醇溶液混合,以及使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备EPO mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH7.4)渗滤,浓缩并保存在2-8℃下。最终浓度=1.82mg/mL EPO mRNA(经包封)。Zave=105.6nm(Dv(50))=53.7nm;Dv(90)=157nm)。
制剂6:将HGT5001、DOPE、胆固醇和DMG-PEG2K(40:20:35:5)等份的50mg/mL乙醇溶液混合,以及使用乙醇稀释至3mL最终体积。单独地,由1mg/mL储备液制备EPO mRNA的水性缓冲溶液(10mM柠檬酸盐/150mM NaCl,pH 4.5)。将液体溶液快速注入水性mRNA溶液内,并振荡以得到在20%乙醇中的最终混悬液。将所得纳米颗粒混悬液过滤、使用1x PBS(pH7.4)渗滤,浓缩并保存在2-8℃下。
通过静脉内递送的mRNA-承载的纳米颗粒注射方案产生的蛋白分析
除非另有说明,在各试验开始时,使用约6-8周龄的雄性CD-1小鼠进行研究。通过30-200微克的包封的mRNA的等总剂量的单一弹丸尾静脉注射来引入样品。处死小鼠,并在指定时间点处使用盐水灌注。
分析的器官组织分离
收获各小鼠的肝和脾,分成三部分,并保存在10%中性缓冲的福尔马林或者快速冷冻(snap-frozen),并保存在-80℃下用于分析。
分析的血清分离
在给药施用(±5%)之后通过CO2窒息48小时安乐处死所有动物,随后为胸廓切开术和终点心脏血收集。通过心脏穿刺收集在安乐死动物上全部学业(最大可获得体积)至血清分离管内,使得在室温下凝固至少30分钟,在22℃±5℃下在9300g下离心10分钟,并分离血清。对于中间血液收集,通过面静脉穿刺或剪断尾静脉来收集约40-50μL的全血。将由非处理动物收集的样品用作研究动物比较的基线。
酶联免疫吸附测定(ELISA)分析
EPO ELISA:在人EPO ELISA试剂盒(Quantikine IVD,R&D Systems,目录号Dep-00)所记载的过程之后进行EPO蛋白的定量。采用的阳性对照由超纯和组织培养级别重组人红细胞生成素蛋白(R&D Systems,编号分别为#286-EP和287-TC)组成。通过在MolecularDevice Flex Station仪器上吸收(450nm)来监控检测。
GLA ELISA:采用羊抗-α-半乳糖苷酶G-188IgG作为捕捉抗体、使用兔抗-α-半乳糖苷酶TK-88IgG作为继发性(检测)抗体来进行标准ELISA步骤(Shire Human GeneticTherapies)。辣根过氧化物酶(HRP)-缀合的山羊抗兔IgG用于激活3,3',5,5'-四甲联苯胺(TMB)基质溶液。在20分钟之后使用2N H2SO4来猝灭反应。通过在Molecular Device FlexStation仪器上通过吸收(450nm)来监控检测。将未经处理的小鼠血清和人α-半乳糖苷酶蛋白分别用作阴性和阳性对照。
FIX ELISA:在人FIX ELISA试剂盒(AssayMax,Assay Pro,目录号EF1009-1)所记载的工序之后进行FIX蛋白的定量。
A1AT ELISA:在人A1AT ELISA试剂盒(Innovative Research,目录号IRAPKT015)所记载的工序之后进行A1AT蛋白的定量。
蛋白质印迹分析
(EPO):使用抗-hEPO抗体(R&D系统编号MAB2871)和超纯人EPO蛋白(R&D系统编号286-EP)作为对照来进行蛋白质印迹分析。
结果
在该例子中描述的工作证实使用mRNA-包封的脂质纳米颗粒作为产生蛋白的储存来源。在体内多处位置能够达到这种储库效应(即,肝、肾、脾和肌肉)。得到和定量源于通过脂质体纳米颗粒递送的信使RNA的所需基于外源性蛋白的测定,并且证实使用人红细胞生成素(hEPO)、人α-半乳糖苷酶(hGLA)、人α-1抗胰蛋白酶(hA1AT)和人因子IX(hFIX)mRNA由储存的蛋白分泌。
1A.体内人EPO蛋白产生结果
使用各种脂质纳米颗粒制剂证实hEPO蛋白的产生。在四种不同阳离子脂质体系中,在静脉内施用之后四小时C12-200-基脂质纳米颗粒产生如通过ELISA测定的最高量的hEPO蛋白(图7)。该制剂(制剂1)导致分泌至血流的18.3ug/mL hEPO蛋白。在人血清中正常hEPO蛋白水平为3.3-16.6mIU/mL(NCCLS文件C28-P;第12卷,No.2)。基于120,000IU/mg的EPO蛋白的特异性活性,其在正常人个体中产生27.5-138pg/mL hEPO蛋白的量。因此,单次30ug剂量的包封hEPO mRNA的C12-200-基阳离子脂质制剂得到对应蛋白增加超过100,000-倍生理水平。
对于测试的脂质体系,DODAP-基脂质纳米颗粒制剂是效率最差的。然而,由通过包封EPO mRNA的DODAP-基脂质纳米颗粒递送来源的人EPO蛋白观察的量为4.1ng/mL,其仍然超过EPO蛋白的正常生理水平大于30倍(表1)。
表1.如通过ELISA分析测定的各种阳离子脂质基纳米颗粒体系的分泌的hEPO蛋白的原始数值(如在图8中所示)。剂量基于包封的hEPO mRNA。蛋白的数值表示为每毫升血清的人EPO蛋白纳克数。血细胞比容改变基于取血前(第-1天)和第10天的比较。
此外,测试所得蛋白以测定它是否为活性和具有正常功能。在采用hEPO mRNA的mRNA补充疗法(MRT)的情况下,在十天时间段内监控五种不同脂质纳米颗粒制剂(图8,表1)的血细胞比容改变以评估蛋白活性。在该时间段中,表明五种制剂中两种的血细胞比容增加(≥15%),其是由这些体系产生的活性hEPO蛋白的特征。
在另一试验中,在15天时间段内监控血细胞比容改变(图9,表2)。如在第1天、第3天和第5天单次注射30μg剂量,或三次注射更少10μg剂量来施用脂质纳米颗粒制剂(制剂1)。类似地,如在第1天、第3天和第5天3次剂量的50μg来施用制剂2。C12-200产生血细胞比容的显著增加。总之,观察到至多25%增加的改变,其是由这些体系产生的活性人EPO蛋白的特征。
Hct=血细胞比容;SEM=平均标准误差。
a收集血液样品至非肝素化血细胞比容管内。
表2在15天观察期内各组的血细胞比容水平(图9)。给药小鼠为一次注射,或三次注射、隔天一次注射。N=4只小鼠/组。
1B.体内人GLA蛋白产生结果
当采用mRNA-承载的脂质纳米颗粒时,探索第二基于外源性蛋白体系以证实“储库效应”。使用C12-200-基脂质纳米颗粒体系的单次30微克剂量包封的人α-半乳糖苷酶(hGLA)mRNA静脉内注射动物,并在六小时之后处死(制剂1)。通过ELISA进行分泌的hGLA蛋白的定量。使用未经处理的小鼠血清和人α-半乳糖苷酶蛋白作为对照。在48小时时间段内监控人α-半乳糖苷酶蛋白的检测。
在试验的时程中观察hGLA蛋白的可测定水平,其在六小时出具有2.0ug/mL hGLA蛋白的最大水平(图10)。表3列出在血清中发现的hGLA的具体量。据报道,在健康人雄性中正常活性为约3.05纳摩尔/h/mL。α-半乳糖苷酶、重组人α-半乳糖苷酶蛋白的活性为3.56x106纳摩尔/hr/mg。这些值的分析得到在正常健康雄性个体中约856pg/mL的hGLA蛋白的量。当给药hGLA mRNA-承载的脂质纳米颗粒之后观察到2.0ug/mL hGLA蛋白的量超过正常生理水平的2300倍。而且,在48小时之后,人们仍然能够检测明显水平的hGLA蛋白(86.2ng/mL)。该水平表示超过生理量的约100倍量hGLA蛋白在48小时内仍然存在。
表3.如通过ELISA分析测定在时间内分泌的hGLA蛋白的原始数值(如在图10中示出)。数值表示为每毫升的血清的hGLA蛋白的纳克数。N=4只小鼠/组。
此外,当以0.2mg/kg施用时,α-半乳糖苷酶的半衰期为约108分钟。当施用GLAmRNA-承载的脂质纳米颗粒时,通过“储库效应”GLA蛋白的产生显示与裸重组蛋白的直接注射先比,在血液停留时间中显著增加。如上所述,在48小时之后存在显著量的蛋白。
由GLA mRNA-承载的脂质纳米颗粒测定的α-半乳糖苷酶蛋白的活性性质为4-甲基伞形酮基-α-D-乳酸吡喃糖苷甲酯(4-MU-α-gal)代谢的函数。如在图11中显示,由这些纳米颗粒体系产生的蛋白活性大,并反应可获得蛋白的水平(图12,表3)。基于mRNA治疗比对酶补充疗法(ERT)在小鼠和人中hGLA产生的AUC比较显示分别增加182-倍和30-倍(表4)。
表4.在IV给药0.2mg/kg的α-半乳糖苷酶(生理剂量)之后的法布里患者中Cmax和AUCinf的比较,这些小经鼠IV给药α-半乳糖苷酶和GLA mRNA。a数据来自出版的报纸(Gregory M.Pastores等人Safety and Pharmacokinetics of hGLA in patients withFabry disease and end-stage renal disease.Nephrol Dial Transplant(2007)22:1920-1925。b非末期肾病。c在给药6小时后(在该研究中测定的最早时间点)α-半乳糖苷酶活性。
已经证实mRNA包封的脂质纳米颗粒靶向用作产生所需蛋白的储存库的器官的能力。观察的分泌的蛋白水平比正常生理水平高几个数量级。该“储库效应”是可重复的。图12再次显示在单次30ug剂量的hGLA mRNA承载的C12-200-基脂质纳米颗粒(制剂1)给药野生型(CD-1)小鼠之后观察到大量蛋白产生。在该试验中,评估72小时时间段内hGLA水平。在施用6小时之后检测到4.0ug人hGLA蛋白/mL血清的最大平均值。基于正常生理水平的~1ng/mL hGLA蛋白的值,hGLA MRT提供几乎4000-倍更高蛋白水平。与之前一样,在施用之后48hr能够检测到hGLA蛋白(图12)。
由该相同试验分离的组织的分析提供对在hGLA MRT-处理的小鼠中hGLA蛋白的分布的见解(图13)。检测在介于施用之后12和24小时之后观察的最大量处理的所有小鼠的肝、脾和肾中hGLA蛋白的超生理水平。在单次注射hGLA-承载的脂质纳米颗粒之后三天能够观察到来源于MRT的蛋白的可检测水平。
此外,一旦施用hGLA mRNA承载C12-200纳米颗粒,显示hGLA的产生表现出在血清(图14A)、以及在肝(图14B)中剂量应答。
脂质纳米颗粒介导的mRNA补充疗法的一个固有特征是产生的各蛋白的药物代谢动力学性质。例如,采用α-半乳糖苷酶的基于ERT对小鼠的处理导致约100分钟的血浆半衰期。相反,源于MRT的α-半乳糖苷酶具有约72小时的血液停留时间,其峰时间为6小时。这使得可更大地暴露器官,从而可以连续参与所需蛋白的摄取。PK性质的比较显示在图15中,并表明通过基于MRT的处理能够得到清除率的显著差别和最终曲线下面积(AUC)的主要改变。
在单独的试验中,将hGLA MRT应用至小鼠疾病模型,hGLA KO小鼠(法布里小鼠)中。将0.33mg/kg剂量的hGLA mRNA-承载的C12-200-基脂质纳米颗粒(制剂1)向雌性KO小鼠作为单一、静脉内注射施用。在6h下产生峰值的MRT来源的hGLA蛋白的量(-560ng/mL血清),其比正常生理水平高约600-倍。而且,在施用之后72h仍然可检测到hGLA蛋白(图16)。
如图17所示,在关键器官中来源于MRT的GLA蛋白的定量表明大量聚集。绘图在关键器官中发现的观察的来源于MRT的hGLA蛋白与报道的正常生理水平的比较(将正常水平绘图为虚线)。尽管在24小时出蛋白的水平比在施用之后72小时更高,在经处理的法布里小鼠的肝、肾、脾和心脏中检测的hGLA蛋白水平等同于野生型水平。例如,在单次MRT处理之后3天,在经处理的小鼠的肾中发现3.1ng hGLA蛋白/mg组织。
在随后的试验中,进行雄性法布里KO小鼠的ERT-基α-半乳糖苷酶处理比对hGLAMRT-基处理的比较。每次治疗给予1.0mg/kg的单次、静脉内给药,并在施用之后一周处死小鼠。在注射之后6h和1周监控hGLA蛋白的血清水平。在施用之后一周分析肝、肾、脾和心脏的hGLA蛋白聚集。除了生物分布分析之外,通过在肾和心脏中神经酰胺三己糖苷(Gb3)的测定值和lyso-Gb3降低来进行功效的测定。图18显示在雄性法布里小鼠中α-半乳糖苷酶或GLAmRNA承载的脂质纳米颗粒(制剂1)处理之后hGLA蛋白的血清水平。在施用6h和1周之后分析血清样品。在6小时之后检测到MRT-处理的小鼠的强信号,其具有~4.0ug/mL的hGLA蛋白血清水平。相反,在该时间内未检测到在血流中遗留的α-半乳糖苷酶。
在开始注射之后一周处死在该试验中的法布里小鼠,并收集器官并分析(肝、肾、脾、心脏)。图19显示在hGLA MRT或α-半乳糖苷酶ERT处理之后在各器官中分别发现的人GLA蛋白的比较。在施用一周之后表现对应于hGLA的水平。在所有分析的器官中检测hGLA蛋白。例如,经MRT处理的小鼠导致在肾中2.42ng hGLA蛋白/mg蛋白的hGLA蛋白聚集,但α-半乳糖苷酶处理的小鼠仅具有残留水平(0.37ng/mg蛋白)。当通过hGLA MRT处理时,这对应于~6.5-倍更高水平的hGLA蛋白。在分析心脏时,如与仅1.0ng/mg蛋白α-半乳糖苷酶相比,发现MRT-处理的同期组群中11.5ng hGLA蛋白/mg蛋白。对于hGLA MRT-处理的小鼠,这对应于在心脏中超过基于ERT疗法的~11-倍更高聚集。
除了进行的生物分布分析之外,通过在关键器官中神经酰胺三己糖苷(Gb3)和lyso-Gb3水平的测定值来测定功效的评估值。如与等剂量的基于α-半乳糖苷酶ERT治疗相比,在单次、静脉内1.0mg/kg GLA MRT处理之后Gb3降低得到在肾以及心脏中Gb3水平的相当大的差别。例如,GLA MRT比对α-半乳糖苷酶的Gb3水平分别得到60.2%比对26.8%的降低(图20)。而且,对于MRT和α-半乳糖苷酶,在心脏中Gb3水平分别降低92.1%比对66.9%(图21)。
测定功效的第二种相关生物标志物是lyso-Gb3。GLA MRT在肾和心脏中比α-半乳糖苷酶降低lyso-Gb3更加有效(分别为图20和图21)。特别地,如与α-半乳糖苷酶-处理的小鼠分别产生47.8%和61.3%增加相比,MRT-处理的法布里小鼠显示在肾和心脏中lyso-Gb3降低86.1%和87.9%。
在C12-200基脂质纳米颗粒中hGLA的结果扩展至其他脂质纳米颗粒制剂。例如,作为单次给药IV施用的承载至HGT4003(制剂3)或HGT5000-基(制剂5)脂质纳米颗粒内的hGLAmRNA导致在施用24小时之后hGLA的产生(图22)。hGLA的产生表现出剂量相关性。类似地,在施用作为单一给药IV的HGT5001-基(制剂6)脂质纳米颗粒内承载的hGLA mRNA之后6小时和24小时观察hGLA产生。在血清(图23A)中、以及在器官(图23B)中观察到hGLA产生。
总之,作为蛋白产生的储存物质应用的mRNA补充疗法产生大量在超生理水平下的活性、功能性治疗蛋白。已经表明,该方法产生所需蛋白的持续循环半衰期,并且如在法布里小鼠中α-半乳糖苷酶所表明,该MRT来源的蛋白高度有效地治疗。
1C.体内人FIX蛋白产生结果
在野生型小鼠(CD-1)中施用因子IX(FIX)mRNA-承载的脂质纳米颗粒来进行研究,并测定分泌至血流中FIX蛋白。一旦静脉内注射单剂量的30ug C12-200-基(在40:30:25:5的比率下的C12-200:DOPE:Chol:PEG)FIX mRNA-承载的脂质纳米颗粒(基于包封的mRNA给药)(制剂1),观察到大量蛋白产生(图24)。
在72小时内的药物代谢动力学分析显示:在测试的所有时间点下能够检测来源于MRT的FIX蛋白(图24)。在注射之后24h观察到峰血清浓度,其具有~3ug(2995±738ng/mL)FIX蛋白/mL血清的值。这表示储库效应的另一成功例子。
1D.体内人A1AT蛋白产生结果
在野生型小鼠(CD-1)中施用α-1-抗胰蛋白酶(A1AT)mRNA-承载的脂质纳米颗粒来进行研究,并测定分泌至血流中A1AT蛋白。一旦静脉内注射单剂量的30ug C12-200-基A1ATmRNA-承载的脂质纳米颗粒(基于包封的mRNA给药)(制剂1),观察到大量蛋白产生(图25)。
如在图25中所示,在施用之后24小时时间段内能够观察到由A1AT MRT来源的人A1AT蛋白的可检测水平。在注射之后12小时检测到~48ug A1AT蛋白/mL血清的最大血清水平。
实施例2:通过多核苷酸组合物的肺部递送的蛋白产生储存库
注射方案
在各试验的开始时使用约7-10周龄雌性CD-1或BALB/C小鼠进行所有研究。通过单一气管内气雾施用来引入检品。将小鼠处死,并在指定时间点下使用盐水灌注。收获各小鼠的肺,分成两部分,并保存在10%中性缓冲的福尔马林或者快速冷冻,并保存在-80℃用于分析。如在实施例1中描述分离血清。EPO ELISA:如在实施例1中描述。
结果
通过肺部递送(例如,鼻内、气管内、喷雾)能够达到储库效应。得到和定量通过纳米颗粒体系递送的信使RNA来源的基于所需外源性蛋白的测定。
通过单一气管内施用在CD-1小鼠中测试通过hEPO mRNA-承载的脂质纳米颗粒的人EPO蛋白的产生。使用各种阳离子脂质(制剂1、5、6)来测试各种制剂。所有制剂导致人EPO mRNA的高度包封。一旦施用,在施用之后六小时处死动物,并收集肺和血清。
一旦通过气雾递送处理,在施用位置(肺)处检测人EPO蛋白。在施用之后六小时的血清分析显示循环中可检测量的hEPO蛋白。这些数据(显示在图26中)证实肺用作hEPO蛋白产生(和分泌)的“储存库”的能力。
Claims (46)
1.组合物在制备用于治疗受试者中法布里病的药物中的用途,其中所述组合物包含编码功能性分泌多肽的mRNA,其中所述mRNA编码人α-半乳糖苷酶(hGLA)蛋白,使得hGLA蛋白在表达后细胞外分泌并在受试者中系统分布,并且使得与治疗前的基线血清hGLA水平相比,血清hGLA蛋白水平增加了至少72小时,其中所述药物经由静脉内或肺部施用给药。
2.根据权利要求1所述的用途,其中所述mRNA包含SEQ ID NO:4。
3.根据权利要求1所述的用途,其中所述mRNA被包封在脂质体内。
4.根据权利要求3所述的用途,其中所述脂质体包含一种或多种阳离子脂质、一种或多种非阳离子脂质、一种或多种胆固醇基脂质和一种或多种PEG-修饰的脂质。
5.根据权利要求1所述的用途,其中所述mRNA包含非天然存在的核苷酸。
6.根据权利要求5所述的用途,其中所述非天然存在的核苷酸是假尿苷。
7.根据权利要求1所述的用途,其中所述药物通过静脉注射施用。
8.根据权利要求1所述的用途,其中与治疗前的Gb3水平相比,所述mRNA的施用导致受试者中神经酰胺三己糖苷(Gb3)水平的降低。
9.组合物在制备用于蛋白体内表达的药物中的用途,其中所述组合物包含编码囊性纤维化跨膜传导调节因子(CFTR)蛋白的mRNA,其中所述药物通过吸入从雾化器施用给受试者,使得所述施用导致CFTR蛋白在受试者的肺细胞中的体内表达,并且其中所述组合物还包含聚乙烯亚胺(PEI)。
10.根据权利要求9所述的用途,其中所述mRNA包含非天然存在的核苷酸。
11.根据权利要求9所述的用途,其中所述mRNA包含假尿苷。
12.组合物在制备用于蛋白体内表达的药物中的用途,其中所述组合物包含编码囊性纤维化跨膜传导调节因子(CFTR)蛋白的mRNA,其中所述药物通过吸入从雾化器施用给受试者,使得所述施用导致CFTR蛋白在受试者的肺细胞中的体内表达,并且其中所述编码CFTR蛋白的mRNA被包封在包含一种或多种阳离子脂质、一种或多种非阳离子脂质、一种或多种胆固醇基脂质和一种或多种PEG-修饰的脂质的脂质体中。
13.根据权利要求12所述的用途,其中所述mRNA包含非天然存在的核苷酸。
14.根据权利要求12所述的用途,其中所述mRNA包含假尿苷。
15.组合物在制备用于蛋白在肺中体内产生的药物中的用途,其中所述药物通过吸入从雾化器施用至受试者的肺部,其中所述组合物包含编码所述蛋白的mRNA,其中所述mRNA被包封在包含一种或多种PEG-修饰的脂质的脂质纳米颗粒内,并且其中所述药物的施用导致施用后至少72小时受试者肺中的可检测水平的蛋白。
16.根据权利要求15所述的用途,其中所述mRNA包含5’非翻译区。
17.根据权利要求15所述的用途,其中所述mRNA包含3’非翻译区。
18.根据权利要求15所述的用途,其中所述mRNA包含帽结构。
19.根据权利要求15所述的用途,其中所述mRNA包含聚A尾巴。
20.根据权利要求15所述的用途,其中所述脂质纳米颗粒包含一种或多种阳离子脂质。
21.根据权利要求20所述的用途,其中所述脂质纳米颗粒包含一种或多种非阳离子脂质。
22.根据权利要求15所述的用途,其中所述mRNA是未经修饰的。
23.根据权利要求15所述的用途,其中所述组合物是复溶的冻干组合物。
24.根据权利要求15所述的用途,其中所述组合物包含修饰的核苷酸。
25.根据权利要求24所述的用途,其中所述修饰的核苷酸是假尿苷。
26.根据权利要求15所述的用途,其中所述mRNA编码的蛋白是多肽。
27.根据权利要求15所述的用途,其中所述mRNA编码的蛋白是肽。
28.根据权利要求15所述的用途,其中所述脂质纳米颗粒具有小于100nm的尺寸。
29.根据权利要求15所述的用途,其中以摩尔比计,所述一种或多种PEG修饰的脂质占总脂质的0.1%至20%。
30.根据权利要求19所述的用途,其中所述聚A尾巴包含至少90个核苷酸。
31.根据权利要求19所述的用途,其中所述聚A尾巴包含至少500个核苷酸。
32.组合物在制备用于治疗患有蛋白或肽缺乏的受试者的药物中的用途,其中所述组合物包含编码所述蛋白或肽的mRNA,其中所述mRNA被包封在包含一种或多种PEG-修饰的脂质的脂质纳米颗粒内,并且其中施用所述药物导致mRNA编码的所述蛋白或肽的表达,且施用后至少72小时在血清中可检测到所述蛋白或肽的表达。
33.根据权利要求32所述的用途,其中所述脂质纳米颗粒具有小于100nm的尺寸。
34.根据权利要求32所述的用途,其中所述mRNA包含至少一种修饰,所述修饰相对于未经修饰的对应物增强了mRNA的稳定性。
35.根据权利要求34所述的用途,其中所述修饰包含修饰的核苷酸。
36.根据权利要求35所述的用途,其中所述修饰的核苷酸是假尿苷。
37.根据权利要求34所述的用途,其中所述mRNA包含5’非翻译区。
38.根据权利要求34所述的用途,其中所述mRNA包含3’非翻译区。
39.根据权利要求34所述的用途,其中所述mRNA包含帽结构。
40.根据权利要求34所述的用途,其中所述mRNA包含聚A尾巴。
41.根据权利要求32所述的用途,其中所述mRNA是未经修饰的。
42.根据权利要求32所述的用途,其中所述组合物通过静脉注射施用。
43.根据权利要求32所述的用途,其中所述组合物通过肺部递送施用。
44.根据权利要求32所述的用途,其中所述组合物通过肌肉内递送施用。
45.根据权利要求32所述的用途,其中所述mRNA编码的蛋白或肽是细胞因子。
46.根据权利要求45所述的用途,其中所述细胞因子是IL-12。
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Families Citing this family (333)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101734955B1 (ko) | 2008-11-07 | 2017-05-12 | 메사추세츠 인스티튜트 오브 테크놀로지 | 아미노알콜 리피도이드 및 그의 용도 |
SI2506857T1 (en) | 2009-12-01 | 2018-08-31 | Translate Bio, Inc. | Delivery of mRNA for the enrichment of proteins and enzymes in human genetic diseases |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
EP2609135A4 (en) | 2010-08-26 | 2015-05-20 | Massachusetts Inst Technology | POLY (BETA-AMINO ALCOHOLS), THEIR PREPARATION AND USES THEREOF |
EP2857499A1 (en) | 2010-10-01 | 2015-04-08 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US8853377B2 (en) | 2010-11-30 | 2014-10-07 | Shire Human Genetic Therapies, Inc. | mRNA for use in treatment of human genetic diseases |
US9238716B2 (en) | 2011-03-28 | 2016-01-19 | Massachusetts Institute Of Technology | Conjugated lipomers and uses thereof |
EP2691101A2 (en) | 2011-03-31 | 2014-02-05 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
EP2709590A4 (en) * | 2011-05-11 | 2015-05-13 | Nanovalent Pharmaceuticals Inc | REINFORCED GROWTH INHIBITION OF OSTEOSARCOMS THROUGH CYTOTOXIC POLYMERIZED LIPOSOMAL NANOPARTICLES TO AIM AT THE ALCAM CELL SURFACE RECEPTOR |
PL2717893T3 (pl) | 2011-06-08 | 2019-12-31 | Translate Bio, Inc. | Kompozycje nanocząstek lipidowych i sposoby do dostarczania mRNA |
CN103748078B (zh) | 2011-06-08 | 2016-11-09 | 夏尔人类遗传性治疗公司 | 可裂解脂质 |
EP3854413A1 (en) | 2011-07-06 | 2021-07-28 | GlaxoSmithKline Biologicals SA | Immunogenic combination compositions and uses thereof |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
SG10201602654SA (en) | 2011-10-03 | 2016-05-30 | Moderna Therapeutics Inc | Modified nucleosides,nucleotides,and nucleic acids,and uses thereof |
CA3119789A1 (en) | 2011-10-27 | 2013-05-02 | Massachusetts Institute Of Technology | Amino acid derivatives functionalized on the n-terminal capable of forming drug encapsulating microspheres |
CA3018046A1 (en) | 2011-12-16 | 2013-06-20 | Moderna Therapeutics, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
ES2858523T3 (es) | 2012-03-29 | 2021-09-30 | Translate Bio Inc | Nanopartículas neutras derivadas de lípidos |
AU2013243949A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
AU2013243950A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US10501513B2 (en) | 2012-04-02 | 2019-12-10 | Modernatx, Inc. | Modified polynucleotides for the production of oncology-related proteins and peptides |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
MX2014015041A (es) | 2012-06-08 | 2015-06-17 | Shire Human Genetic Therapies | Administración pulmonar de arnm a células objetivo no pulmonares. |
EP2859102A4 (en) | 2012-06-08 | 2016-05-11 | Shire Human Genetic Therapies | NUCLEASE RESISTANT POLYNUCLEOTIDES AND USES THEREOF |
EP2882706A1 (en) | 2012-08-13 | 2015-06-17 | Massachusetts Institute of Technology | Amine-containing lipidoids and uses thereof |
US9512456B2 (en) | 2012-08-14 | 2016-12-06 | Modernatx, Inc. | Enzymes and polymerases for the synthesis of RNA |
PT2922554T (pt) | 2012-11-26 | 2022-06-28 | Modernatx Inc | Arn modificado nas porções terminais |
EP4331620A2 (en) * | 2012-12-07 | 2024-03-06 | Translate Bio, Inc. | Lipidic nanoparticles for mrna delivery |
US20160024181A1 (en) | 2013-03-13 | 2016-01-28 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
KR20150127582A (ko) | 2013-03-14 | 2015-11-17 | 샤이어 휴먼 지네틱 테라피즈 인크. | 4''-티오 개질된 뉴클레오티드를 갖는 리보핵산 및 관련 방법 |
IL290953B2 (en) | 2013-03-14 | 2024-01-01 | Ethris Gmbh | CFTR mRNA Assemblies and Related Methods and Uses |
DK2970955T3 (en) | 2013-03-14 | 2019-02-11 | Translate Bio Inc | METHODS FOR CLEANING MESSENGER RNA |
AU2014239184B2 (en) | 2013-03-14 | 2018-11-08 | Translate Bio, Inc. | Methods and compositions for delivering mRNA coded antibodies |
US10258698B2 (en) | 2013-03-14 | 2019-04-16 | Modernatx, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10130649B2 (en) * | 2013-03-15 | 2018-11-20 | Translate Bio, Inc. | Synergistic enhancement of the delivery of nucleic acids via blended formulations |
WO2014179562A1 (en) | 2013-05-01 | 2014-11-06 | Massachusetts Institute Of Technology | 1,3,5-triazinane-2,4,6-trione derivatives and uses thereof |
EP3033325B1 (en) * | 2013-07-23 | 2019-12-04 | Arbutus Biopharma Corporation | Compositions and methods for delivering messenger rna |
US9163284B2 (en) | 2013-08-09 | 2015-10-20 | President And Fellows Of Harvard College | Methods for identifying a target site of a Cas9 nuclease |
AU2014315287A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
US9340799B2 (en) | 2013-09-06 | 2016-05-17 | President And Fellows Of Harvard College | MRNA-sensing switchable gRNAs |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
ES2954366T3 (es) | 2013-10-22 | 2023-11-21 | Translate Bio Inc | Terapia de ácido ribonucleico mensajero para la deficiencia de argininosuccinato sintetasa |
AU2014340083B2 (en) * | 2013-10-22 | 2019-08-15 | Translate Bio, Inc. | mRNA therapy for phenylketonuria |
KR102096796B1 (ko) | 2013-10-22 | 2020-05-27 | 샤이어 휴먼 지네틱 테라피즈 인크. | 메신저 rna의 전달을 위한 지질 제형 |
BR112016008832A2 (pt) | 2013-10-22 | 2017-10-03 | Shire Human Genetic Therapies | Distribuição de mrna no snc e suas utilizações |
DK3071696T3 (da) | 2013-11-22 | 2019-10-07 | Mina Therapeutics Ltd | C/ebp alfa kort aktiverings-rna-sammensætninger og fremgangsmåder til anvendelse |
LT3116900T (lt) | 2014-03-09 | 2020-12-10 | The Trustees Of The University Of Pennsylvania | Kompozicijos, naudotinos ornitino transkarbamilazės (otc) nepakankamumo gydymui |
SI3122878T1 (sl) * | 2014-03-24 | 2019-05-31 | Translate Bio, Inc. | MRNA terapija za zdravljenje očesnih bolezni |
HRP20220070T1 (hr) | 2014-04-23 | 2022-04-01 | Modernatx, Inc. | Cjepiva nukleinske kiseline |
CN117402871A (zh) | 2014-04-25 | 2024-01-16 | 川斯勒佰尔公司 | 信使rna的纯化方法 |
WO2015173756A2 (en) | 2014-05-16 | 2015-11-19 | Pfizer Inc. | Bispecific antibodies |
EP3148552B1 (en) | 2014-05-30 | 2019-07-31 | Translate Bio, Inc. | Biodegradable lipids for delivery of nucleic acids |
PT3155129T (pt) | 2014-06-10 | 2019-05-16 | Curevac Ag | Método para potenciar a produção de arn |
WO2015200465A1 (en) | 2014-06-24 | 2015-12-30 | Shire Human Genetic Therapies, Inc. | Stereochemically enriched compositions for delivery of nucleic acids |
EP3164379A1 (en) | 2014-07-02 | 2017-05-10 | Massachusetts Institute of Technology | Polyamine-fatty acid derived lipidoids and uses thereof |
JP6782171B2 (ja) | 2014-07-02 | 2020-11-11 | シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド | メッセンジャーrnaのカプセル化 |
US20170204152A1 (en) | 2014-07-16 | 2017-07-20 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
WO2016014846A1 (en) | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of intrabodies |
EP3177718B1 (en) | 2014-07-30 | 2022-03-16 | President and Fellows of Harvard College | Cas9 proteins including ligand-dependent inteins |
GB201420139D0 (en) | 2014-11-12 | 2014-12-24 | Ucl Business Plc | Factor IX gene therapy |
ES2861597T3 (es) | 2014-12-05 | 2021-10-06 | Translate Bio Inc | Terapia de ARN mensajero para el tratamiento de enfermedad articular |
SI3237621T1 (sl) | 2014-12-22 | 2023-11-30 | Codexis, Inc. | Različice humane alfa-galaktozidaze |
CN107530436B (zh) | 2015-01-21 | 2022-03-29 | 菲泽尔克斯公司 | 用于将治疗剂和诊断剂递送到细胞中的方法、组合物和系统 |
JP6929791B2 (ja) | 2015-02-09 | 2021-09-01 | デューク ユニバーシティ | エピゲノム編集のための組成物および方法 |
US20170151281A1 (en) | 2015-02-19 | 2017-06-01 | Batu Biologics, Inc. | Chimeric antigen receptor dendritic cell (car-dc) for treatment of cancer |
JP6895892B2 (ja) | 2015-03-19 | 2021-06-30 | トランスレイト バイオ, インコーポレイテッド | ポンペ病のmRNA治療 |
JP6851319B2 (ja) | 2015-04-27 | 2021-03-31 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | ヒト疾患のCRISPR/Cas9媒介性の修正のためのデュアルAAVベクター系 |
GB201508025D0 (en) * | 2015-05-11 | 2015-06-24 | Ucl Business Plc | Fabry disease gene therapy |
PT3310764T (pt) | 2015-06-19 | 2023-07-11 | Massachusetts Inst Technology | 2,5-piperazinadionas substituídas por alquenilo e o seu uso em composições para entregar um agente a um sujeito ou célula |
EP3324979B1 (en) | 2015-07-21 | 2022-10-12 | ModernaTX, Inc. | Infectious disease vaccines |
US11364292B2 (en) | 2015-07-21 | 2022-06-21 | Modernatx, Inc. | CHIKV RNA vaccines |
EP3325018A4 (en) | 2015-07-22 | 2019-04-24 | Duke University | HIGH EFFICIENCY SCREENING OF REGULATORY ELEMENT FUNCTION USING EPIGENOUS EDITING TECHNOLOGIES |
WO2017031232A1 (en) | 2015-08-17 | 2017-02-23 | Modernatx, Inc. | Methods for preparing particles and related compositions |
CA2996001A1 (en) | 2015-08-25 | 2017-03-02 | Duke University | Compositions and methods of improving specificity in genomic engineering using rna-guided endonucleases |
WO2017049245A2 (en) | 2015-09-17 | 2017-03-23 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
US10849920B2 (en) | 2015-10-05 | 2020-12-01 | Modernatx, Inc. | Methods for therapeutic administration of messenger ribonucleic acid drugs |
EP3362571A4 (en) | 2015-10-13 | 2019-07-10 | Duke University | GENOMIC ENGINEERING WITH TYPE I CRISPRISMS IN EUKARYOTIC CELLS |
US10144942B2 (en) | 2015-10-14 | 2018-12-04 | Translate Bio, Inc. | Modification of RNA-related enzymes for enhanced production |
JP6921833B2 (ja) | 2015-10-22 | 2021-08-18 | モデルナティーエックス, インコーポレイテッド | ヒトサイトメガロウイルスワクチン |
MX2018004916A (es) * | 2015-10-22 | 2019-07-04 | Modernatx Inc | Vacuna contra el virus de la influenza de amplio espectro. |
WO2017070624A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Tropical disease vaccines |
CA3002827A1 (en) | 2015-10-23 | 2017-04-27 | President And Fellows Of Harvard College | Nucleobase editors and uses thereof |
LT3386484T (lt) | 2015-12-10 | 2022-06-10 | Modernatx, Inc. | Gydomųjų medžiagų sudėtis ir pristatymo metodai |
RS63051B1 (sr) | 2015-12-22 | 2022-04-29 | Modernatx Inc | Jedinjenja i kompozicije za intracelularnu isporuku agenasa |
SI3394093T1 (sl) | 2015-12-23 | 2022-05-31 | Modernatx, Inc. | Metode uporabe liganda OX40, ki kodira polinukleotid |
US20190241658A1 (en) | 2016-01-10 | 2019-08-08 | Modernatx, Inc. | Therapeutic mRNAs encoding anti CTLA-4 antibodies |
EP3405579A1 (en) | 2016-01-22 | 2018-11-28 | Modernatx, Inc. | Messenger ribonucleic acids for the production of intracellular binding polypeptides and methods of use thereof |
CA3018904C (en) | 2016-03-31 | 2024-04-02 | Ethris Gmbh | Novel minimal utr sequences |
US10266843B2 (en) | 2016-04-08 | 2019-04-23 | Translate Bio, Inc. | Multimeric coding nucleic acid and uses thereof |
US20190167811A1 (en) | 2016-04-13 | 2019-06-06 | Modernatx, Inc. | Lipid compositions and their uses for intratumoral polynucleotide delivery |
US20180126003A1 (en) * | 2016-05-04 | 2018-05-10 | Curevac Ag | New targets for rna therapeutics |
WO2017201347A1 (en) * | 2016-05-18 | 2017-11-23 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
KR102533456B1 (ko) | 2016-05-18 | 2023-05-17 | 모더나티엑스, 인크. | 릴랙신을 인코딩하는 폴리뉴클레오타이드 |
JP7114485B2 (ja) * | 2016-05-18 | 2022-08-08 | モデルナティエックス インコーポレイテッド | ファブリー病の治療のためのα-ガラクトシダーゼAをコードするポリヌクレオチド |
CA3024470A1 (en) | 2016-05-18 | 2017-11-23 | Modernatx, Inc. | Polynucleotides encoding interleukin-12 (il12) and uses thereof |
EP3842530A1 (en) | 2016-06-13 | 2021-06-30 | Translate Bio, Inc. | Messenger rna therapy for the treatment of ornithine transcarbamylase deficiency |
WO2018006052A1 (en) | 2016-06-30 | 2018-01-04 | Protiva Biotherapeutics, Inc. | Compositions and methods for delivering messenger rna |
IL308426A (en) | 2016-08-03 | 2024-01-01 | Harvard College | Adenosine nuclear base editors and their uses |
CN109804066A (zh) | 2016-08-09 | 2019-05-24 | 哈佛大学的校长及成员们 | 可编程cas9-重组酶融合蛋白及其用途 |
WO2018033454A1 (en) | 2016-08-19 | 2018-02-22 | Fundación Para La Investigación Biomédica Del Hospital Universitario Ramón Y Cajal | Mir-127 agents for use in the treatment of renal fibrosis |
WO2018039438A1 (en) | 2016-08-24 | 2018-03-01 | President And Fellows Of Harvard College | Incorporation of unnatural amino acids into proteins using base editing |
WO2018071868A1 (en) | 2016-10-14 | 2018-04-19 | President And Fellows Of Harvard College | Aav delivery of nucleobase editors |
MA46584A (fr) | 2016-10-21 | 2019-08-28 | Modernatx Inc | Vaccin contre le cytomégalovirus humain |
US11583504B2 (en) | 2016-11-08 | 2023-02-21 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
MA46761A (fr) | 2016-11-10 | 2019-09-18 | Translate Bio Inc | Administration sous-cutanée d'arn messager |
AU2017357758B2 (en) | 2016-11-10 | 2023-11-16 | Translate Bio, Inc. | Improved process of preparing mRNA-loaded lipid nanoparticles |
IL310050A (en) * | 2016-11-10 | 2024-03-01 | Translate Bio Inc | An improved ICE-based lipid nanoparticle formulation for delivery of mRNA |
EP3544591B1 (en) * | 2016-11-23 | 2022-04-20 | Mayo Foundation for Medical Education and Research | Particle-mediated delivery of biologics |
US10745677B2 (en) | 2016-12-23 | 2020-08-18 | President And Fellows Of Harvard College | Editing of CCR5 receptor gene to protect against HIV infection |
EP3565605A1 (en) | 2017-01-03 | 2019-11-13 | ethris GmbH | Ornithine transcarbamylase coding polyribonucleotides and formulations thereof |
WO2018129544A1 (en) | 2017-01-09 | 2018-07-12 | Whitehead Institute For Biomedical Research | Methods of altering gene expression by perturbing transcription factor multimers that structure regulatory loops |
EP3582790A4 (en) | 2017-02-16 | 2020-11-25 | ModernaTX, Inc. | VERY POWERFUL IMMUNOGENIC COMPOSITIONS |
MA47603A (fr) | 2017-02-27 | 2020-01-01 | Translate Bio Inc | Nouvel arnm cftr à codons optimisés |
ES2925083T3 (es) | 2017-02-27 | 2022-10-13 | Translate Bio Inc | Métodos de purificación de ARN mensajero |
CA3054321A1 (en) | 2017-02-27 | 2018-08-30 | Translate Bio, Inc. | Methods for purification of messenger rna |
IL268892B1 (en) * | 2017-02-27 | 2024-03-01 | Translate Bio Inc | Large-scale production of therapeutic preparations enriched in mRNA encoding therapeutic peptides |
DK3589730T3 (da) | 2017-02-28 | 2024-03-04 | Univ Pennsylvania | Klade f adeno-associeret virus (aav) vektor og anvendelse deraf |
JOP20190200A1 (ar) | 2017-02-28 | 2019-08-27 | Univ Pennsylvania | تركيبات نافعة في معالجة ضمور العضل النخاعي |
CA3054136A1 (en) | 2017-03-01 | 2018-09-07 | The Trustees Of The University Of Pennsylvania | Gene therapy for ocular disorders |
WO2018165257A1 (en) | 2017-03-07 | 2018-09-13 | Translate Bio, Inc. | Polyanionic delivery of nucleic acids |
US11898179B2 (en) | 2017-03-09 | 2024-02-13 | President And Fellows Of Harvard College | Suppression of pain by gene editing |
EP3592777A1 (en) | 2017-03-10 | 2020-01-15 | President and Fellows of Harvard College | Cytosine to guanine base editor |
IL298380A (en) | 2017-03-15 | 2023-01-01 | Modernatx Inc | Compounds and preparations for intracellular administration of medical agents |
DK3596042T3 (da) | 2017-03-15 | 2022-04-11 | Modernatx Inc | Krystalformer af aminolipider |
MA52262A (fr) | 2017-03-15 | 2020-02-19 | Modernatx Inc | Vaccin à large spectre contre le virus de la grippe |
MA47787A (fr) | 2017-03-15 | 2020-01-22 | Modernatx Inc | Vaccin contre le virus respiratoire syncytial |
CA3057192A1 (en) | 2017-03-23 | 2018-09-27 | President And Fellows Of Harvard College | Nucleobase editors comprising nucleic acid programmable dna binding proteins |
US11905525B2 (en) | 2017-04-05 | 2024-02-20 | Modernatx, Inc. | Reduction of elimination of immune responses to non-intravenous, e.g., subcutaneously administered therapeutic proteins |
EP3610035A4 (en) | 2017-04-14 | 2021-06-09 | Dana-Farber Cancer Institute, Inc. | COMPOSITIONS AND PROCEDURES FOR TEMPORARY GENE THERAPY WITH IMPROVED STABILITY |
US11879133B2 (en) | 2017-04-24 | 2024-01-23 | The Trustees Of The University Of Pennsylvania | Gene therapy for ocular disorders |
SG11201910015SA (en) | 2017-05-11 | 2019-11-28 | Univ Pennsylvania | Gene therapy for neuronal ceroid lipofuscinoses |
US11560566B2 (en) | 2017-05-12 | 2023-01-24 | President And Fellows Of Harvard College | Aptazyme-embedded guide RNAs for use with CRISPR-Cas9 in genome editing and transcriptional activation |
WO2018213476A1 (en) | 2017-05-16 | 2018-11-22 | Translate Bio, Inc. | Treatment of cystic fibrosis by delivery of codon-optimized mrna encoding cftr |
EP3625246A1 (en) | 2017-05-18 | 2020-03-25 | ModernaTX, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
EP4253544A3 (en) | 2017-05-18 | 2023-12-20 | ModernaTX, Inc. | Modified messenger rna comprising functional rna elements |
US11377643B2 (en) * | 2017-05-31 | 2022-07-05 | Ultragenyx Pharmaceutical Inc. | Therapeutics for glycogen storage disease type III |
CA3098592A1 (en) | 2017-05-31 | 2018-12-06 | The Trustees Of The University Of Pennsylvania | Gene therapy for treating peroxisomal disorders |
MA49395A (fr) | 2017-06-14 | 2020-04-22 | Modernatx Inc | Polynucléotides codant pour le facteur viii de coagulation |
US20200131498A1 (en) | 2017-06-14 | 2020-04-30 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase |
WO2018232357A1 (en) | 2017-06-15 | 2018-12-20 | Modernatx, Inc. | Rna formulations |
US10034951B1 (en) | 2017-06-21 | 2018-07-31 | New England Biolabs, Inc. | Use of thermostable RNA polymerases to produce RNAs having reduced immunogenicity |
CN111801345A (zh) | 2017-07-28 | 2020-10-20 | 哈佛大学的校长及成员们 | 使用噬菌体辅助连续进化(pace)的进化碱基编辑器的方法和组合物 |
EP3676376A2 (en) | 2017-08-30 | 2020-07-08 | President and Fellows of Harvard College | High efficiency base editors comprising gam |
WO2019046809A1 (en) | 2017-08-31 | 2019-03-07 | Modernatx, Inc. | METHODS OF MANUFACTURING LIPID NANOPARTICLES |
EP3679139B1 (en) | 2017-09-08 | 2022-11-02 | MiNA Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
EP3679140B1 (en) | 2017-09-08 | 2022-11-16 | MiNA Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
WO2019055807A1 (en) | 2017-09-14 | 2019-03-21 | Modernatx, Inc. | RNA VACCINES AGAINST ZIKA VIRUS |
WO2019067999A1 (en) * | 2017-09-29 | 2019-04-04 | Intellia Therapeutics, Inc. | IN VITRO METHOD OF ADMINISTERING MRNA USING LIPID NANOPARTICLES |
KR20200121782A (ko) | 2017-10-16 | 2020-10-26 | 더 브로드 인스티튜트, 인코퍼레이티드 | 아데노신 염기 편집제의 용도 |
EP3714045A1 (en) | 2017-11-22 | 2020-09-30 | Modernatx, Inc. | Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia |
EP3714048A1 (en) | 2017-11-22 | 2020-09-30 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
EP3714047A2 (en) | 2017-11-22 | 2020-09-30 | ModernaTX, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
CA3083416A1 (en) | 2017-11-30 | 2019-06-06 | The Trustees Of The University Of Pennsylvania | Gene therapy for mucopolysaccharidosis iii a |
BR112020010977A2 (pt) | 2017-11-30 | 2020-11-17 | The Trustees Of The University Of Pennsylvania | terapia de gene para mucopolissacaridose iiib |
US11167043B2 (en) | 2017-12-20 | 2021-11-09 | Translate Bio, Inc. | Composition and methods for treatment of ornithine transcarbamylase deficiency |
EP3735270A1 (en) | 2018-01-05 | 2020-11-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
WO2019141814A1 (en) * | 2018-01-18 | 2019-07-25 | Etherna Immunotherapies Nv | Lipid nanoparticles |
MA54676A (fr) | 2018-01-29 | 2021-11-17 | Modernatx Inc | Vaccins à base d'arn contre le vrs |
WO2019152802A1 (en) | 2018-02-02 | 2019-08-08 | Translate Bio, Inc. | Cationic polymers |
US20210163928A1 (en) | 2018-04-11 | 2021-06-03 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
US11566246B2 (en) | 2018-04-12 | 2023-01-31 | Mina Therapeutics Limited | SIRT1-saRNA compositions and methods of use |
WO2019204666A1 (en) * | 2018-04-18 | 2019-10-24 | Oisin Biotechnologies, Inc. | Fusogenic lipid nanoparticles and methods for the manufacture and use thereof for the target cell-specific production of a therapeutic protein and for the treatment of a disease, condition, or disorder associated with a target cell |
US20210220449A1 (en) * | 2018-05-15 | 2021-07-22 | Translate Bio, Inc. | Subcutaneous Delivery of Messenger RNA |
MA52625A (fr) | 2018-05-16 | 2021-03-24 | Translate Bio Inc | Lipides cationiques de ribose |
MA52709A (fr) | 2018-05-23 | 2021-03-31 | Modernatx Inc | Administration d'adn |
CN112384205A (zh) * | 2018-05-30 | 2021-02-19 | 川斯勒佰尔公司 | 信使rna疫苗及其用途 |
WO2020023390A1 (en) | 2018-07-25 | 2020-01-30 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
IL267923B2 (en) * | 2018-08-02 | 2023-06-01 | Grifols Worldwide Operations Ltd | The composition containing the most concentrated alpha-1 type protein inhibitor and a method for obtaining it |
US10842885B2 (en) | 2018-08-20 | 2020-11-24 | Ucl Business Ltd | Factor IX encoding nucleotides |
CN112930396A (zh) | 2018-08-24 | 2021-06-08 | 川斯勒佰尔公司 | 用于纯化信使rna的方法 |
JP2021533794A (ja) * | 2018-08-24 | 2021-12-09 | フラッグシップ パイオニアリング イノベーションズ シックス,エルエルシー | 修飾植物メッセンジャーパック及びその使用 |
AU2019333042A1 (en) | 2018-08-29 | 2021-03-04 | Translate Bio, Inc. | Improved process of preparing mRNA-loaded lipid nanoparticles |
MA53545A (fr) | 2018-09-02 | 2021-07-14 | Modernatx Inc | Polynucléotides codant pour l'acyl-coa déshydrogénase à très longue chaîne pour le traitement de l'insuffisance en acyl-coa déshydrogénase à très longue chaîne |
WO2020051220A1 (en) | 2018-09-04 | 2020-03-12 | The Board of the Regents of the University of Texas System | Compositions and methods for organ specific delivery of nucleic acids |
WO2020051223A1 (en) | 2018-09-04 | 2020-03-12 | The Board Of Regents Of The University Of Texas System | Compositions and methods for organ specific delivery of nucleic acids |
US20220243182A1 (en) | 2018-09-13 | 2022-08-04 | Modernatx, Inc. | Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease |
MX2021003015A (es) | 2018-09-13 | 2021-07-15 | Modernatx Inc | Polinucleotidos que codifican glucosa-6-fosfatasa para el tratamiento de la glucogenosis. |
CA3112398A1 (en) | 2018-09-14 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
US20220152225A1 (en) | 2018-09-27 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding arginase 1 for the treatment of arginase deficiency |
BR112021004929A2 (pt) | 2018-09-28 | 2021-06-01 | Nutcracker Therapeutics, Inc. | peptídeos catiônicos terciários amino-lipidados para entrega de ácido nucleico |
US11072808B2 (en) | 2018-10-04 | 2021-07-27 | New England Biolabs, Inc. | Methods and compositions for increasing capping efficiency of transcribed RNA |
WO2020072914A1 (en) | 2018-10-04 | 2020-04-09 | New England Biolabs, Inc. | Methods and compositions for increasing capping efficiency of transcribed rna |
EP3864163B1 (en) | 2018-10-09 | 2024-03-20 | The University of British Columbia | Compositions and systems comprising transfection-competent vesicles free of organic-solvents and detergents and methods related thereto |
WO2020097409A2 (en) | 2018-11-08 | 2020-05-14 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
CA3115119A1 (en) | 2018-11-08 | 2020-05-14 | Translate Bio, Inc. | Methods and compositions for messenger rna purification |
WO2020102172A2 (en) | 2018-11-12 | 2020-05-22 | Translate Bio, Inc. | Methods for inducing immune tolerance |
US20200157157A1 (en) | 2018-11-21 | 2020-05-21 | Translate Bio, Inc. | TREATMENT OF CYSTIC FIBROSIS BY DELIVERY OF NEBULIZED mRNA ENCODING CFTR |
US11685906B2 (en) | 2018-12-06 | 2023-06-27 | Arcturus Therapeutics, Inc. | Compositions and methods for treating ornithine transcarbamylase deficiency |
MX2021007552A (es) | 2018-12-20 | 2021-08-11 | Codexis Inc | Variantes de alfa-galactosidasa humana. |
US20220040281A1 (en) | 2018-12-21 | 2022-02-10 | Curevac Ag | Rna for malaria vaccines |
CA3125511A1 (en) | 2019-02-08 | 2020-08-13 | Curevac Ag | Coding rna administered into the suprachoroidal space in the treatment of ophthalmic diseases |
MX2021011325A (es) | 2019-03-19 | 2022-01-06 | Broad Inst Inc | Metodos y composiciones para editar secuencias de nucleotidos. |
US20220211740A1 (en) | 2019-04-12 | 2022-07-07 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
CN114375190A (zh) | 2019-05-08 | 2022-04-19 | 阿斯利康(瑞典)有限公司 | 用于皮肤和伤口的组合物及其使用方法 |
KR20220024022A (ko) | 2019-05-14 | 2022-03-03 | 트랜슬레이트 바이오 인코포레이티드 | Mrna-로딩된 지질 나노입자를 제조하는 개선된 방법 |
IL310266A (en) | 2019-05-22 | 2024-03-01 | Massachusetts Inst Technology | Circular Rana preparations and methods |
US20220313813A1 (en) | 2019-06-18 | 2022-10-06 | Curevac Ag | Rotavirus mrna vaccine |
AU2020297594A1 (en) * | 2019-06-21 | 2022-02-03 | Kernal Biologics, Inc. | Engineered oncoselective protein expression |
MA56517A (fr) | 2019-06-24 | 2022-04-27 | Modernatx Inc | Arn messager comprenant des éléments d'arn fonctionnels et leurs utilisations |
JPWO2020262150A1 (zh) * | 2019-06-24 | 2020-12-30 | ||
WO2020263883A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Endonuclease-resistant messenger rna and uses thereof |
EP3999097A1 (en) | 2019-07-18 | 2022-05-25 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods for inducing full ablation of hematopoiesis |
KR20220035434A (ko) * | 2019-07-19 | 2022-03-22 | 유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드 | 다중층 rna 나노입자 |
AU2020322014A1 (en) | 2019-07-30 | 2022-02-24 | Translate Bio, Inc. | Treatment of cystic fibrosis by delivery of nebulized mRNA encoding CFTR |
BR112022001947A2 (pt) | 2019-08-14 | 2022-09-20 | Curevac Ag | Combinações e composições de rna com propriedades imunoestimuladoras reduzidas |
CA3154618A1 (en) | 2019-09-19 | 2021-03-25 | Modernatx, Inc. | Branched tail lipid compounds and compositions for intracellular delivery of therapeutic agents |
CN114728176A (zh) | 2019-10-09 | 2022-07-08 | 川斯勒佰尔公司 | 信使rna的组合物、方法和使用 |
JP2023504568A (ja) | 2019-12-04 | 2023-02-03 | オルナ セラピューティクス インコーポレイテッド | 環状rna組成物及び方法 |
CN115335083A (zh) * | 2020-01-10 | 2022-11-11 | 斯特姆詹尼克斯公司 | 用于表达所关注基因和/或调控信号传导通路的纳米颗粒 |
KR20220133224A (ko) | 2020-01-28 | 2022-10-04 | 모더나티엑스, 인크. | 코로나바이러스 rna 백신 |
IL293571A (en) | 2020-02-04 | 2022-08-01 | Curevac Ag | Corona virus vaccine |
EP4100052A2 (en) | 2020-02-07 | 2022-12-14 | ModernaTX, Inc. | Sars-cov-2 mrna domain vaccines |
US20210275689A1 (en) | 2020-02-25 | 2021-09-09 | Translate Bio, Inc. | Processes of preparing mrna-loaded lipid nanoparticles |
GB202307565D0 (en) | 2020-04-22 | 2023-07-05 | BioNTech SE | Coronavirus vaccine |
WO2021222304A1 (en) | 2020-04-27 | 2021-11-04 | Modernatx, Inc. | Sars-cov-2 rna vaccines |
JP2023525304A (ja) | 2020-05-08 | 2023-06-15 | ザ ブロード インスティテュート,インコーポレーテッド | 標的二本鎖ヌクレオチド配列の両鎖同時編集のための方法および組成物 |
WO2021231579A1 (en) | 2020-05-12 | 2021-11-18 | The Trustees Of The University Of Pennsylvania | Compositions for drg-specific reduction of transgene expression |
WO2021159130A2 (en) | 2020-05-15 | 2021-08-12 | Modernatx, Inc. | Coronavirus rna vaccines and methods of use |
CN116322788A (zh) | 2020-05-19 | 2023-06-23 | 奥纳治疗公司 | 环状rna组合物和方法 |
KR20230053008A (ko) | 2020-05-29 | 2023-04-20 | 큐어백 에스이 | 핵산 기반 조합 백신 |
WO2021247507A1 (en) | 2020-06-01 | 2021-12-09 | Modernatx, Inc. | Phenylalanine hydroxylase variants and uses thereof |
EP4165183A1 (en) | 2020-06-12 | 2023-04-19 | University of Rochester | Encoding and expression of ace-trnas |
US20230220069A1 (en) | 2020-06-17 | 2023-07-13 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treatment of gene therapy patients |
JP2023534037A (ja) | 2020-07-13 | 2023-08-07 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | シャルコー・マリー・トゥース病の治療に有用な組成物 |
WO2022015513A2 (en) | 2020-07-13 | 2022-01-20 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods to assess rna stability |
WO2022023559A1 (en) | 2020-07-31 | 2022-02-03 | Curevac Ag | Nucleic acid encoded antibody mixtures |
US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2022043551A2 (en) | 2020-08-31 | 2022-03-03 | Curevac Ag | Multivalent nucleic acid based coronavirus vaccines |
EP4204015A2 (en) | 2020-08-31 | 2023-07-05 | The Board of Trustees of the Leland Stanford Junior University | Systems and methods for producing rna constructs with increased translation and stability |
US20230355743A1 (en) | 2020-09-25 | 2023-11-09 | Modernatx, Inc. | Multi-proline-substituted coronavirus spike protein vaccines |
US20230364206A1 (en) | 2020-10-07 | 2023-11-16 | Regenxbio Inc. | Gene therapy for ocular manifestations of cln2 disease |
CA3193833A1 (en) | 2020-10-09 | 2022-04-14 | Juliette HORDEAUX | Compositions and methods for treatment of fabry disease |
GB2617474A (en) | 2020-11-04 | 2023-10-11 | Myeloid Therapeutics Inc | Engineered chimeric fusion protein compositions and methods of use thereof |
WO2022099003A1 (en) | 2020-11-06 | 2022-05-12 | Sanofi | Lipid nanoparticles for delivering mrna vaccines |
WO2022104131A1 (en) | 2020-11-13 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
WO2022119890A1 (en) | 2020-12-01 | 2022-06-09 | The Trustees Of The University Of Pennsylvania | Compositions and uses thereof for treatment of angelman syndrome |
AU2021390480A1 (en) | 2020-12-01 | 2023-06-22 | The Trustees Of The University Of Pennsylvania | Novel compositions with tissue-specific targeting motifs and compositions containing same |
CN116685356A (zh) * | 2020-12-02 | 2023-09-01 | 默沙东有限责任公司 | 含有单酯阳离子脂质的脂质纳米颗粒组合物 |
GB2603454A (en) | 2020-12-09 | 2022-08-10 | Ucl Business Ltd | Novel therapeutics for the treatment of neurodegenerative disorders |
CA3171051A1 (en) | 2020-12-22 | 2022-06-30 | Curevac Ag | Pharmaceutical composition comprising lipid-based carriers encapsulating rna for multidose administration |
WO2022137133A1 (en) | 2020-12-22 | 2022-06-30 | Curevac Ag | Rna vaccine against sars-cov-2 variants |
US20230000970A1 (en) | 2021-01-11 | 2023-01-05 | Modernatx, Inc. | Seasonal rna influenza virus vaccines |
JP2024504614A (ja) * | 2021-01-14 | 2024-02-01 | トランスレイト バイオ, インコーポレイテッド | mRNAがコードする抗体を送達する方法および組成物 |
AU2022207495A1 (en) | 2021-01-15 | 2023-08-03 | Modernatx, Inc. | Variant strain-based coronavirus vaccines |
AU2022208057A1 (en) | 2021-01-15 | 2023-08-03 | Modernatx, Inc. | Variant strain-based coronavirus vaccines |
EP4087938A2 (en) | 2021-01-27 | 2022-11-16 | CureVac AG | Method of reducing the immunostimulatory properties of in vitro transcribed rna |
WO2022165313A1 (en) | 2021-02-01 | 2022-08-04 | Regenxbio Inc. | Gene therapy for neuronal ceroid lipofuscinoses |
US11524023B2 (en) | 2021-02-19 | 2022-12-13 | Modernatx, Inc. | Lipid nanoparticle compositions and methods of formulating the same |
JP2024511346A (ja) | 2021-03-15 | 2024-03-13 | モデルナティエックス インコーポレイテッド | Sars-cov-2 mrnaドメインワクチンの治療的使用 |
WO2022204043A1 (en) * | 2021-03-22 | 2022-09-29 | The Board Of Regents Of The University Of Texas System | Compositions and methods for targeted delivery to cells |
WO2022204371A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof |
WO2022204380A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof |
WO2022204369A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia |
WO2022204390A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof |
EP4314260A1 (en) | 2021-03-24 | 2024-02-07 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency |
JP2024511092A (ja) | 2021-03-26 | 2024-03-12 | ミナ セラピューティクス リミテッド | TMEM173saRNA組成物及び使用方法 |
EP4313152A1 (en) | 2021-03-26 | 2024-02-07 | GlaxoSmithKline Biologicals S.A. | Immunogenic compositions |
WO2022207862A2 (en) | 2021-03-31 | 2022-10-06 | Curevac Ag | Syringes containing pharmaceutical compositions comprising rna |
US11744902B2 (en) * | 2021-04-06 | 2023-09-05 | Animatus Biosciences, Inc. | Targeting technology to selectively express mRNAs in cardiomyocytes while avoiding stimulation of cardiac fibroblasts |
WO2022221276A1 (en) | 2021-04-12 | 2022-10-20 | The Trustees Of The University Of Pennsylvania | Compositions useful for treating spinal and bulbar muscular atrophy (sbma) |
JP2024514182A (ja) | 2021-04-13 | 2024-03-28 | モデルナティエックス インコーポレイテッド | 呼吸器ウイルス組み合わせワクチン |
WO2022221440A1 (en) | 2021-04-14 | 2022-10-20 | Modernatx, Inc. | Influenza-coronavirus combination vaccines |
TW202305124A (zh) | 2021-04-23 | 2023-02-01 | 賓州大學委員會 | 具有腦特異性靶向模體的新穎構成物及含有其之組成物 |
CA3171589A1 (en) | 2021-05-03 | 2022-11-03 | Moritz THRAN | Improved nucleic acid sequence for cell type specific expression |
WO2022245888A1 (en) | 2021-05-19 | 2022-11-24 | Modernatx, Inc. | Seasonal flu rna vaccines and methods of use |
WO2022266083A2 (en) | 2021-06-15 | 2022-12-22 | Modernatx, Inc. | Engineered polynucleotides for cell-type or microenvironment-specific expression |
WO2022264109A1 (en) | 2021-06-18 | 2022-12-22 | Sanofi | Multivalent influenza vaccines |
WO2022271776A1 (en) | 2021-06-22 | 2022-12-29 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2023002509A1 (en) | 2021-07-23 | 2023-01-26 | Institute For Stem Cell Science And Regenerative Medicine | Lipid formulation for delivery of therapeutic agents |
WO2023025404A1 (en) | 2021-08-24 | 2023-03-02 | BioNTech SE | In vitro transcription technologies |
AU2022337090A1 (en) | 2021-09-03 | 2024-02-15 | Glaxosmithkline Biologicals Sa | Substitution of nucleotide bases in self-amplifying messenger ribonucleic acids |
CA3230031A1 (en) | 2021-09-03 | 2023-03-09 | Patrick Baumhof | Novel lipid nanoparticles for delivery of nucleic acids |
CA3230056A1 (en) | 2021-09-03 | 2023-03-09 | Patrick Baumhof | Novel lipid nanoparticles for delivery of nucleic acids comprising phosphatidylserine |
WO2023056044A1 (en) | 2021-10-01 | 2023-04-06 | Modernatx, Inc. | Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease |
WO2023064599A1 (en) * | 2021-10-14 | 2023-04-20 | Kernal Biologics, Inc. | Compositions and methods for delivery of agents |
WO2023069498A1 (en) | 2021-10-22 | 2023-04-27 | Senda Biosciences, Inc. | Mrna vaccine composition |
WO2023073228A1 (en) | 2021-10-29 | 2023-05-04 | CureVac SE | Improved circular rna for expressing therapeutic proteins |
WO2023077148A1 (en) | 2021-11-01 | 2023-05-04 | Tome Biosciences, Inc. | Single construct platform for simultaneous delivery of gene editing machinery and nucleic acid cargo |
WO2023079507A1 (en) | 2021-11-05 | 2023-05-11 | Sanofi | Respiratory syncytial virus rna vaccine |
WO2023081526A1 (en) | 2021-11-08 | 2023-05-11 | Orna Therapeutics, Inc. | Lipid nanoparticle compositions for delivering circular polynucleotides |
WO2023087019A2 (en) | 2021-11-15 | 2023-05-19 | The Trustees Of The University Of Pennsylvania | Compositions for drg-specific reduction of transgene expression |
WO2023092069A1 (en) | 2021-11-18 | 2023-05-25 | Modernatx, Inc. | Sars-cov-2 mrna domain vaccines and methods of use |
WO2023089183A1 (en) | 2021-11-19 | 2023-05-25 | Branca Bunus Limited | A composition comprising a therapeutically active agent packaged within a drug delivery vehicle |
WO2023096858A1 (en) | 2021-11-23 | 2023-06-01 | Senda Biosciences, Inc. | A bacteria-derived lipid composition and use thereof |
AR127808A1 (es) | 2021-11-30 | 2024-02-28 | Sanofi Pasteur Inc | Vacunas contra el metapneumovirus humano |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023102517A1 (en) | 2021-12-02 | 2023-06-08 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treatment of fabry disease |
WO2023107999A2 (en) | 2021-12-08 | 2023-06-15 | Modernatx, Inc. | Herpes simplex virus mrna vaccines |
GB202117758D0 (en) | 2021-12-09 | 2022-01-26 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2023111262A1 (en) | 2021-12-17 | 2023-06-22 | Sanofi | Lyme disease rna vaccine |
WO2023122080A1 (en) | 2021-12-20 | 2023-06-29 | Senda Biosciences, Inc. | Compositions comprising mrna and lipid reconstructed plant messenger packs |
WO2023122764A1 (en) | 2021-12-22 | 2023-06-29 | Tome Biosciences, Inc. | Co-delivery of a gene editor construct and a donor template |
WO2023122762A1 (en) | 2021-12-22 | 2023-06-29 | Camp4 Therapeutics Corporation | Modulation of gene transcription using antisense oligonucleotides targeting regulatory rnas |
WO2023133574A1 (en) | 2022-01-10 | 2023-07-13 | The Trustees Of The University Of Pennsylvania | Compositions and methods useful for treatment of c9orf72-mediated disorders |
WO2023135298A1 (en) | 2022-01-17 | 2023-07-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of inducing cell death of a population of solid tumor cells |
WO2023141586A1 (en) | 2022-01-21 | 2023-07-27 | Orna Therapeutics, Inc. | Systemic administration of circular rna polynucleotides encoding muscle proteins or protein complexes |
WO2023147090A1 (en) | 2022-01-27 | 2023-08-03 | BioNTech SE | Pharmaceutical compositions for delivery of herpes simplex virus antigens and related methods |
WO2023144330A1 (en) | 2022-01-28 | 2023-08-03 | CureVac SE | Nucleic acid encoded transcription factor inhibitors |
WO2023150753A1 (en) | 2022-02-07 | 2023-08-10 | University Of Rochester | Optimized sequences for enhanced trna expression or/and nonsense mutation suppression |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023177904A1 (en) | 2022-03-18 | 2023-09-21 | Modernatx, Inc. | Sterile filtration of lipid nanoparticles and filtration analysis thereof for biological applications |
US11951177B2 (en) | 2022-03-23 | 2024-04-09 | Nanovation Therapeutics Inc. | High sterol-containing lipid nanoparticles |
WO2023183909A2 (en) | 2022-03-25 | 2023-09-28 | Modernatx, Inc. | Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia |
WO2023196914A1 (en) | 2022-04-08 | 2023-10-12 | Modernatx, Inc. | Influenza nucleic acid compositions and uses thereof |
US20230346977A1 (en) | 2022-04-13 | 2023-11-02 | Universitat Autònoma De Barcelona | Treatment of neuromuscular diseases via gene therapy that expresses klotho protein |
WO2023205744A1 (en) | 2022-04-20 | 2023-10-26 | Tome Biosciences, Inc. | Programmable gene insertion compositions |
WO2023215831A1 (en) | 2022-05-04 | 2023-11-09 | Tome Biosciences, Inc. | Guide rna compositions for programmable gene insertion |
WO2023214082A2 (en) | 2022-05-06 | 2023-11-09 | Sanofi | Signal sequences for nucleic acid vaccines |
WO2023225670A2 (en) | 2022-05-20 | 2023-11-23 | Tome Biosciences, Inc. | Ex vivo programmable gene insertion |
WO2023230481A1 (en) | 2022-05-24 | 2023-11-30 | Modernatx, Inc. | Orthopoxvirus vaccines |
WO2023227608A1 (en) | 2022-05-25 | 2023-11-30 | Glaxosmithkline Biologicals Sa | Nucleic acid based vaccine encoding an escherichia coli fimh antigenic polypeptide |
WO2023231959A2 (en) | 2022-05-30 | 2023-12-07 | Shanghai Circode Biomed Co., Ltd | Synthetic circular rna compositions and methods of use thereof |
WO2023240277A2 (en) | 2022-06-10 | 2023-12-14 | Camp4 Therapeutics Corporation | Methods of modulating progranulin expression using antisense oligonucleotides targeting regulatory rnas |
WO2023242817A2 (en) | 2022-06-18 | 2023-12-21 | Glaxosmithkline Biologicals Sa | Recombinant rna molecules comprising untranslated regions or segments encoding spike protein from the omicron strain of severe acute respiratory coronavirus-2 |
WO2024002985A1 (en) | 2022-06-26 | 2024-01-04 | BioNTech SE | Coronavirus vaccine |
WO2024015890A1 (en) | 2022-07-13 | 2024-01-18 | Modernatx, Inc. | Norovirus mrna vaccines |
WO2024017253A1 (zh) * | 2022-07-19 | 2024-01-25 | 深圳深信生物科技有限公司 | 新型冠状病毒S蛋白的mRNA及其应用 |
WO2024020587A2 (en) | 2022-07-22 | 2024-01-25 | Tome Biosciences, Inc. | Pleiopluripotent stem cell programmable gene insertion |
WO2024026254A1 (en) | 2022-07-26 | 2024-02-01 | Modernatx, Inc. | Engineered polynucleotides for temporal control of expression |
WO2024044108A1 (en) | 2022-08-22 | 2024-02-29 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Vaccines against coronaviruses |
WO2024044147A1 (en) | 2022-08-23 | 2024-02-29 | Modernatx, Inc. | Methods for purification of ionizable lipids |
WO2024050483A1 (en) | 2022-08-31 | 2024-03-07 | Modernatx, Inc. | Variant strain-based coronavirus vaccines and uses thereof |
AU2023274159A1 (en) * | 2022-09-07 | 2024-03-21 | Eyegene Inc. | COMPOSITION FOR IN-VIVO DELIVERING mRNA CONTAINING MODIFIED NUCLEOTIDE |
WO2024064931A1 (en) | 2022-09-23 | 2024-03-28 | BioNTech SE | Compositions for delivery of liver stage antigens and related methods |
WO2024063788A1 (en) | 2022-09-23 | 2024-03-28 | BioNTech SE | Compositions for delivery of malaria antigens and related methods |
WO2024064934A1 (en) | 2022-09-23 | 2024-03-28 | BioNTech SE | Compositions for delivery of plasmodium csp antigens and related methods |
WO2024063789A1 (en) | 2022-09-23 | 2024-03-28 | BioNTech SE | Compositions for delivery of malaria antigens and related methods |
WO2024068545A1 (en) | 2022-09-26 | 2024-04-04 | Glaxosmithkline Biologicals Sa | Influenza virus vaccines |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007024708A2 (en) * | 2005-08-23 | 2007-03-01 | The Trustees Of The University Of Pennsylvania | Rna containing modified nucleosides and methods of use thereof |
WO2010148013A2 (en) * | 2009-06-15 | 2010-12-23 | Alnylam Pharmaceuticals, Inc. | Lipid formulated dsrna targeting the pcsk9 gene |
Family Cites Families (520)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2647121A (en) | 1951-02-02 | 1953-07-28 | Ruth P Jacoby | Diamine-bis-acetamides |
US2819718A (en) | 1953-07-16 | 1958-01-14 | Isidore H Goldman | Drainage tube |
US2717909A (en) | 1953-09-24 | 1955-09-13 | Monsanto Chemicals | Hydroxyethyl-keryl-alkylene-ammonium compounds |
US2844629A (en) | 1956-04-25 | 1958-07-22 | American Home Prod | Fatty acid amides and derivatives thereof |
US3096560A (en) | 1958-11-21 | 1963-07-09 | William J Liebig | Process for synthetic vascular implants |
FR1378382A (fr) | 1962-12-01 | 1964-11-13 | Sandoz Sa | Amides de l'acide amino-propionique, utilisables en particulier pour le traitement des fibres textiles |
GB1072118A (en) | 1962-12-01 | 1967-06-14 | Sandoz Ag | Amides of aminopropionic acid |
JPS5141663B1 (zh) | 1966-03-12 | 1976-11-11 | ||
JPS4822365B1 (zh) | 1968-10-25 | 1973-07-05 | ||
NL143127B (nl) | 1969-02-04 | 1974-09-16 | Rhone Poulenc Sa | Versterkingsorgaan voor een defecte hartklep. |
JPS4822365Y1 (zh) | 1969-11-28 | 1973-06-29 | ||
US3614954A (en) | 1970-02-09 | 1971-10-26 | Medtronic Inc | Electronic standby defibrillator |
US3614955A (en) | 1970-02-09 | 1971-10-26 | Medtronic Inc | Standby defibrillator and method of operation |
JPS5024216Y1 (zh) | 1970-12-29 | 1975-07-21 | ||
JPS5024216B1 (zh) | 1970-12-29 | 1975-08-14 | ||
JPS5012146Y2 (zh) | 1971-07-27 | 1975-04-15 | ||
JPS5123537Y2 (zh) | 1972-01-17 | 1976-06-17 | ||
US3945052A (en) | 1972-05-01 | 1976-03-23 | Meadox Medicals, Inc. | Synthetic vascular graft and method for manufacturing the same |
US3805301A (en) | 1972-07-28 | 1974-04-23 | Meadox Medicals Inc | Tubular grafts having indicia thereon |
JPS5210847Y2 (zh) | 1972-10-11 | 1977-03-09 | ||
JPS49127908A (zh) | 1973-04-20 | 1974-12-07 | ||
JPS5624664B2 (zh) | 1973-06-28 | 1981-06-08 | ||
US4013507A (en) | 1973-09-18 | 1977-03-22 | California Institute Of Technology | Ionene polymers for selectively inhibiting the vitro growth of malignant cells |
JPS5123537A (ja) | 1974-04-26 | 1976-02-25 | Adeka Argus Chemical Co Ltd | Kasozaisoseibutsu |
GB1527592A (en) | 1974-08-05 | 1978-10-04 | Ici Ltd | Wound dressing |
US3995623A (en) | 1974-12-23 | 1976-12-07 | American Hospital Supply Corporation | Multipurpose flow-directed catheter |
JPS5813576B2 (ja) | 1974-12-27 | 1983-03-14 | アデカ ア−ガスカガク カブシキガイシヤ | 安定化された合成高分子組成物 |
JPS5524302Y2 (zh) | 1975-03-31 | 1980-06-10 | ||
DE2520814A1 (de) | 1975-05-09 | 1976-11-18 | Bayer Ag | Lichtstabilisierung von polyurethanen |
US4281669A (en) | 1975-05-09 | 1981-08-04 | Macgregor David C | Pacemaker electrode with porous system |
JPS5210847A (en) | 1975-07-16 | 1977-01-27 | Nippon Steel Corp | Pinch roll |
US4096860A (en) | 1975-10-08 | 1978-06-27 | Mclaughlin William F | Dual flow encatheter |
CA1069652A (en) | 1976-01-09 | 1980-01-15 | Alain F. Carpentier | Supported bioprosthetic heart valve with compliant orifice ring |
US4134402A (en) | 1976-02-11 | 1979-01-16 | Mahurkar Sakharam D | Double lumen hemodialysis catheter |
US4072146A (en) | 1976-09-08 | 1978-02-07 | Howes Randolph M | Venous catheter device |
US4335723A (en) | 1976-11-26 | 1982-06-22 | The Kendall Company | Catheter having inflatable retention means |
US4099528A (en) | 1977-02-17 | 1978-07-11 | Sorenson Research Co., Inc. | Double lumen cannula |
US4140126A (en) | 1977-02-18 | 1979-02-20 | Choudhury M Hasan | Method for performing aneurysm repair |
US4265745A (en) | 1977-05-25 | 1981-05-05 | Teijin Limited | Permselective membrane |
US4182833A (en) | 1977-12-07 | 1980-01-08 | Celanese Polymer Specialties Company | Cationic epoxide-amine reaction products |
US4180068A (en) | 1978-04-13 | 1979-12-25 | Motion Control, Incorporated | Bi-directional flow catheter with retractable trocar/valve structure |
DE2960875D1 (en) | 1978-04-19 | 1981-12-10 | Ici Plc | A method of preparing a tubular product by electrostatic spinning |
US4284459A (en) | 1978-07-03 | 1981-08-18 | The Kendall Company | Method for making a molded catheter |
US4227533A (en) | 1978-11-03 | 1980-10-14 | Bristol-Myers Company | Flushable urinary catheter |
US4375817A (en) | 1979-07-19 | 1983-03-08 | Medtronic, Inc. | Implantable cardioverter |
DE3010841A1 (de) | 1980-03-21 | 1981-10-08 | Ulrich Dr.med. 6936 Haag Uthmann | Katheder |
US4308085A (en) | 1980-07-28 | 1981-12-29 | Jenoptik Jena Gmbh | Process for the preparation of high molecular thermoplastic epoxide-amine-polyadducts |
US4339369A (en) | 1981-04-23 | 1982-07-13 | Celanese Corporation | Cationic epoxide-amine reaction products |
US4406656A (en) | 1981-06-01 | 1983-09-27 | Brack Gillium Hattler | Venous catheter having collapsible multi-lumens |
US4475972A (en) | 1981-10-01 | 1984-10-09 | Ontario Research Foundation | Implantable material |
US4401472A (en) | 1982-02-26 | 1983-08-30 | Martin Marietta Corporation | Hydraulic cement mixes and processes for improving hydraulic cement mixes |
US4568329A (en) | 1982-03-08 | 1986-02-04 | Mahurkar Sakharam D | Double lumen catheter |
US4546499A (en) | 1982-12-13 | 1985-10-15 | Possis Medical, Inc. | Method of supplying blood to blood receiving vessels |
US4530113A (en) | 1983-05-20 | 1985-07-23 | Intervascular, Inc. | Vascular grafts with cross-weave patterns |
US4647416A (en) | 1983-08-03 | 1987-03-03 | Shiley Incorporated | Method of preparing a vascular graft prosthesis |
US4550447A (en) | 1983-08-03 | 1985-11-05 | Shiley Incorporated | Vascular graft prosthesis |
US5104399A (en) | 1986-12-10 | 1992-04-14 | Endovascular Technologies, Inc. | Artificial graft and implantation method |
US4571241A (en) | 1983-12-16 | 1986-02-18 | Christopher T Graham | Urinary catheter with collapsible urethral tube |
US4710169A (en) | 1983-12-16 | 1987-12-01 | Christopher T Graham | Urinary catheter with collapsible urethral tube |
US4737518A (en) | 1984-04-03 | 1988-04-12 | Takeda Chemical Industries, Ltd. | Lipid derivatives, their production and use |
US4562596A (en) | 1984-04-25 | 1986-01-07 | Elliot Kornberg | Aortic graft, device and method for performing an intraluminal abdominal aortic aneurysm repair |
US4782836A (en) | 1984-05-24 | 1988-11-08 | Intermedics, Inc. | Rate adaptive cardiac pacemaker responsive to patient activity and temperature |
US4897355A (en) | 1985-01-07 | 1990-01-30 | Syntex (U.S.A.) Inc. | N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US4662382A (en) | 1985-01-16 | 1987-05-05 | Intermedics, Inc. | Pacemaker lead with enhanced sensitivity |
US4762915A (en) | 1985-01-18 | 1988-08-09 | Liposome Technology, Inc. | Protein-liposome conjugates |
US4860751A (en) | 1985-02-04 | 1989-08-29 | Cordis Corporation | Activity sensor for pacemaker control |
US5223263A (en) | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
CA1320724C (en) | 1985-07-19 | 1993-07-27 | Koichi Kanehira | Terpene amino alcohols and medicinal uses thereof |
US4701162A (en) | 1985-09-24 | 1987-10-20 | The Kendall Company | Foley catheter assembly |
US4737323A (en) | 1986-02-13 | 1988-04-12 | Liposome Technology, Inc. | Liposome extrusion method |
DE3616824A1 (de) | 1986-05-17 | 1987-11-19 | Schering Ag | Verwendung von haertbaren kunstharzmischungen fuer oberflaechenbeschichtungen und druckfarben und verfahren zu ihrer herstellung |
DE3780374D1 (de) | 1986-07-31 | 1992-08-20 | Irnich Werner | Frequenzadaptierender herzschrittmacher. |
US4960409A (en) | 1986-09-11 | 1990-10-02 | Catalano Marc L | Method of using bilumen peripheral venous catheter with adapter |
JPH0829776B2 (ja) | 1986-10-29 | 1996-03-27 | 東燃化学株式会社 | 合成樹脂製容器及びその製造用金型 |
US4720517A (en) | 1986-11-24 | 1988-01-19 | Ciba-Geigy Corporation | Compositions stabilized with N-hydroxyiminodiacetic and dipropionic acids and esters thereof |
US4920016A (en) | 1986-12-24 | 1990-04-24 | Linear Technology, Inc. | Liposomes with enhanced circulation time |
JPS63125144U (zh) | 1987-02-09 | 1988-08-16 | ||
JPS63154788U (zh) | 1987-03-31 | 1988-10-11 | ||
EP0414663A4 (en) | 1987-04-16 | 1991-07-17 | The Liposome Company, Inc. | Liposome continuous size reduction method and apparatus |
JPS63312934A (ja) | 1987-06-16 | 1988-12-21 | Hitachi Cable Ltd | 半導体用リ−ドフレ−ム材 |
DE3728917A1 (de) | 1987-08-29 | 1989-03-09 | Roth Hermann J | Neue lipide mit unsymmetrisch substituierter disulfidbruecke |
US4946683A (en) | 1987-11-18 | 1990-08-07 | Vestar, Inc. | Multiple step entrapment/loading procedure for preparing lipophilic drug-containing liposomes |
US5138067A (en) | 1987-12-17 | 1992-08-11 | Shionogi & Co. Ltd. | Lipid derivatives |
US5047540A (en) | 1987-12-17 | 1991-09-10 | Shionogi & Co., Ltd. | Lipid derivatives |
US4892540A (en) | 1988-04-21 | 1990-01-09 | Sorin Biomedica S.P.A. | Two-leaflet prosthetic heart valve |
US5176661A (en) | 1988-09-06 | 1993-01-05 | Advanced Cardiovascular Systems, Inc. | Composite vascular catheter |
US5024671A (en) | 1988-09-19 | 1991-06-18 | Baxter International Inc. | Microporous vascular graft |
US5200395A (en) | 1988-10-18 | 1993-04-06 | Ajinomoto Company, Inc. | Pharmaceutical composition of BUF-5 for treating anemia |
CA2001401A1 (en) | 1988-10-25 | 1990-04-25 | Claude Piantadosi | Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions |
US5185154A (en) | 1989-02-02 | 1993-02-09 | Liposome Technology, Inc. | Method for instant preparation of a drug containing large unilamellar vesicles |
US6214804B1 (en) | 1989-03-21 | 2001-04-10 | Vical Incorporated | Induction of a protective immune response in a mammal by injecting a DNA sequence |
EP1026253B2 (en) | 1989-03-21 | 2012-12-19 | Vical Incorporated | Expression of exogenous polynucleotide sequences in a vertebrate |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
FR2645866B1 (fr) | 1989-04-17 | 1991-07-05 | Centre Nat Rech Scient | Nouvelles lipopolyamines, leur preparation et leur emploi |
US5194654A (en) | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
US5279833A (en) | 1990-04-04 | 1994-01-18 | Yale University | Liposomal transfection of nucleic acids into animal cells |
US5101824A (en) | 1990-04-16 | 1992-04-07 | Siemens-Pacesetter, Inc. | Rate-responsive pacemaker with circuitry for processing multiple sensor inputs |
US5264618A (en) | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
EP0549590A1 (en) | 1990-07-26 | 1993-07-07 | LANE, Rodney James | Self expanding vascular endoprosthesis for aneurysms |
US5693338A (en) | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
JPH0765267B2 (ja) | 1990-08-22 | 1995-07-12 | 花王株式会社 | 柔軟仕上剤 |
US5206027A (en) | 1990-09-13 | 1993-04-27 | Fuji Photo Film Co., Ltd. | Amphipathic compound and liposome comprising the same |
EP0480667B1 (en) | 1990-10-09 | 1996-03-20 | Cook Incorporated | Percutaneous stent assembly |
ATE120971T1 (de) | 1990-12-19 | 1995-04-15 | Osypka Peter | Herzschrittmacherleitung mit einem inneren kanal und mit einem elektrodenkopf. |
US5116360A (en) | 1990-12-27 | 1992-05-26 | Corvita Corporation | Mesh composite graft |
JP2547524Y2 (ja) | 1991-01-22 | 1997-09-10 | 東洋ラジエーター株式会社 | オイルクーラ |
US5405363A (en) | 1991-03-15 | 1995-04-11 | Angelon Corporation | Implantable cardioverter defibrillator having a smaller displacement volume |
US5330768A (en) | 1991-07-05 | 1994-07-19 | Massachusetts Institute Of Technology | Controlled drug delivery using polymer/pluronic blends |
US5545449A (en) | 1991-10-02 | 1996-08-13 | Weyerhaeuser Company | Polyether-reinforced fiber-based materials |
US5151105A (en) | 1991-10-07 | 1992-09-29 | Kwan Gett Clifford | Collapsible vessel sleeve implant |
JPH0753535B2 (ja) | 1992-02-14 | 1995-06-07 | 株式会社カワタ | 粉粒体の材料供給装置における弁装置 |
US5284491A (en) | 1992-02-27 | 1994-02-08 | Medtronic, Inc. | Cardiac pacemaker with hysteresis behavior |
US5352461A (en) | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
SE9200951D0 (sv) | 1992-03-27 | 1992-03-27 | Kabi Pharmacia Ab | Pharmaceutical composition containing a defined lipid system |
EP0635019B1 (en) | 1992-04-06 | 1999-05-26 | Biosite Diagnostics Inc. | Opiate derivatives and protein and polypeptide opiate derivative conjugates and labels |
US6670178B1 (en) | 1992-07-10 | 2003-12-30 | Transkaryotic Therapies, Inc. | In Vivo production and delivery of insulinotropin for gene therapy |
KR950702628A (ko) | 1992-08-01 | 1995-07-29 | 치세이 라 | 항알레르기 조성물(Antiallergic agent) |
US5334761A (en) | 1992-08-28 | 1994-08-02 | Life Technologies, Inc. | Cationic lipids |
US5461223A (en) | 1992-10-09 | 1995-10-24 | Eastman Kodak Company | Bar code detecting circuitry |
US5300022A (en) | 1992-11-12 | 1994-04-05 | Martin Klapper | Urinary catheter and bladder irrigation system |
US5496362A (en) | 1992-11-24 | 1996-03-05 | Cardiac Pacemakers, Inc. | Implantable conformal coil patch electrode with multiple conductive elements for cardioversion and defibrillation |
US5552155A (en) | 1992-12-04 | 1996-09-03 | The Liposome Company, Inc. | Fusogenic lipsomes and methods for making and using same |
US5716395A (en) | 1992-12-11 | 1998-02-10 | W.L. Gore & Associates, Inc. | Prosthetic vascular graft |
EP0685457B1 (en) | 1993-02-19 | 1999-12-15 | Nippon Shinyaku Company, Limited | Glycerol derivative, device and pharmaceutical composition |
US5395619A (en) | 1993-03-03 | 1995-03-07 | Liposome Technology, Inc. | Lipid-polymer conjugates and liposomes |
US5697953A (en) | 1993-03-13 | 1997-12-16 | Angeion Corporation | Implantable cardioverter defibrillator having a smaller displacement volume |
JPH0753535Y2 (ja) | 1993-03-16 | 1995-12-13 | 株式会社ハンズ | リュックサック |
US5624976A (en) | 1994-03-25 | 1997-04-29 | Dentsply Gmbh | Dental filling composition and method |
EP0702516A4 (en) | 1993-06-01 | 1998-04-22 | Life Technologies Inc | GENETIC IMMUNIZATION WITH CATIONIC LIPIDS |
US5314430A (en) | 1993-06-24 | 1994-05-24 | Medtronic, Inc. | Atrial defibrillator employing transvenous and subcutaneous electrodes and method of use |
DE4325848A1 (de) | 1993-07-31 | 1995-02-02 | Basf Ag | Verfahren zur Herstellung von N-(2-Hydroxyethyl)-piperazin |
EP1062999A3 (en) | 1993-10-06 | 2001-03-14 | The Kansai Electric Power Co., Inc. | Method for removing carbon dioxide from combustion exhaust gas |
US5609624A (en) | 1993-10-08 | 1997-03-11 | Impra, Inc. | Reinforced vascular graft and method of making same |
SE9303481L (sv) | 1993-10-22 | 1995-04-23 | Berol Nobel Ab | Hygienkomposition |
WO1995013033A1 (en) | 1993-11-08 | 1995-05-18 | Lazarus Harrison M | Intraluminal vascular graft and method |
KR960705798A (ko) | 1993-11-24 | 1996-11-08 | 벤자민 에프 맥그로우 | 피페라진의 양쪽친화성 유도체(amphiphilic derivatives of piperazine) |
US5595756A (en) | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
US5464924A (en) | 1994-01-07 | 1995-11-07 | The Dow Chemical Company | Flexible poly(amino ethers) for barrier packaging |
US5844107A (en) | 1994-03-23 | 1998-12-01 | Case Western Reserve University | Compacted nucleic acids and their delivery to cells |
US6077835A (en) | 1994-03-23 | 2000-06-20 | Case Western Reserve University | Delivery of compacted nucleic acid to cells |
KR100315132B1 (ko) | 1994-04-12 | 2002-06-26 | 질레스피 카롤 | 융합할수있는리포좀과이를만드는방법그리고이의용도 |
US5776747A (en) | 1994-07-20 | 1998-07-07 | Cytotherapeutics, Inc. | Method for controlling the distribution of cells within a bioartificial organ using polycthylene oxide-poly (dimethylsiloxane) copolymer |
US5885613A (en) | 1994-09-30 | 1999-03-23 | The University Of British Columbia | Bilayer stabilizing components and their use in forming programmable fusogenic liposomes |
US5820873A (en) | 1994-09-30 | 1998-10-13 | The University Of British Columbia | Polyethylene glycol modified ceramide lipids and liposome uses thereof |
US5641665A (en) | 1994-11-28 | 1997-06-24 | Vical Incorporated | Plasmids suitable for IL-2 expression |
US6071890A (en) | 1994-12-09 | 2000-06-06 | Genzyme Corporation | Organ-specific targeting of cationic amphiphile/DNA complexes for gene therapy |
US5965434A (en) | 1994-12-29 | 1999-10-12 | Wolff; Jon A. | Amphipathic PH sensitive compounds and delivery systems for delivering biologically active compounds |
US6485726B1 (en) | 1995-01-17 | 2002-11-26 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
US5830430A (en) | 1995-02-21 | 1998-11-03 | Imarx Pharmaceutical Corp. | Cationic lipids and the use thereof |
EP0822835A1 (en) | 1995-04-17 | 1998-02-11 | Imarx Pharmaceutical Corp. | Hybrid magnetic resonance contrast agents |
US5772694A (en) | 1995-05-16 | 1998-06-30 | Medical Carbon Research Institute L.L.C. | Prosthetic heart valve with improved blood flow |
US5783383A (en) | 1995-05-23 | 1998-07-21 | The Board Of Trustees Of The Leland Stanford Junior University | Method of detecting cytomegalovirus (CMV) |
US5705385A (en) | 1995-06-07 | 1998-01-06 | Inex Pharmaceuticals Corporation | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US5609629A (en) | 1995-06-07 | 1997-03-11 | Med Institute, Inc. | Coated implantable medical device |
US5981501A (en) | 1995-06-07 | 1999-11-09 | Inex Pharmaceuticals Corp. | Methods for encapsulating plasmids in lipid bilayers |
US5976567A (en) | 1995-06-07 | 1999-11-02 | Inex Pharmaceuticals Corp. | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US7422902B1 (en) | 1995-06-07 | 2008-09-09 | The University Of British Columbia | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US5607385A (en) | 1995-08-17 | 1997-03-04 | Medtronic, Inc. | Device and algorithm for a combined cardiomyostimulator and a cardiac pacer-carioverter-defibrillator |
US5744335A (en) | 1995-09-19 | 1998-04-28 | Mirus Corporation | Process of transfecting a cell with a polynucleotide mixed with an amphipathic compound and a DNA-binding protein |
FR2740978B1 (fr) | 1995-11-10 | 1998-01-02 | Ela Medical Sa | Dispositif medical actif du type defibrillateur/cardioverteur implantable |
US5874105A (en) | 1996-01-31 | 1999-02-23 | Collaborative Laboratories, Inc. | Lipid vesicles formed with alkylammonium fatty acid salts |
US6183774B1 (en) | 1996-01-31 | 2001-02-06 | Collaborative Laboratories, Inc. | Stabilizing vitamin A derivatives by encapsulation in lipid vesicles formed with alkylammonium fatty acid salts |
US5783566A (en) * | 1996-05-10 | 1998-07-21 | California Institute Of Technology | Method for increasing or decreasing transfection efficiency |
AU2284697A (en) | 1996-04-11 | 1997-10-29 | University Of British Columbia, The | Fusogenic liposomes |
US5935936A (en) | 1996-06-03 | 1999-08-10 | Genzyme Corporation | Compositions comprising cationic amphiphiles and co-lipids for intracellular delivery of therapeutic molecules |
US5913848A (en) | 1996-06-06 | 1999-06-22 | Luther Medical Products, Inc. | Hard tip over-the-needle catheter and method of manufacturing the same |
US5677124A (en) | 1996-07-03 | 1997-10-14 | Ambion, Inc. | Ribonuclease resistant viral RNA standards |
US5736573A (en) | 1996-07-31 | 1998-04-07 | Galat; Alexander | Lipid and water soluble derivatives of drugs |
US7288266B2 (en) | 1996-08-19 | 2007-10-30 | United States Of America As Represented By The Secretary, Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
CA2264140A1 (en) | 1996-08-26 | 1998-03-05 | Transgene S.A. | Cationic lipid-nucleic acid complexes |
US6458574B1 (en) | 1996-09-12 | 2002-10-01 | Transkaryotic Therapies, Inc. | Treatment of a α-galactosidase a deficiency |
ES2187812T3 (es) | 1996-09-13 | 2003-06-16 | Lipoxen Technologies Ltd | Composicion de liposomas. |
TW520297B (en) | 1996-10-11 | 2003-02-11 | Sequus Pharm Inc | Fusogenic liposome composition and method |
EP1003556B1 (en) | 1996-11-04 | 2006-03-01 | Qiagen GmbH | Cationic reagents for transfection |
US6887665B2 (en) | 1996-11-14 | 2005-05-03 | Affymetrix, Inc. | Methods of array synthesis |
US5985930A (en) | 1996-11-21 | 1999-11-16 | Pasinetti; Giulio M. | Treatment of neurodegenerative conditions with nimesulide |
US6204297B1 (en) | 1996-11-26 | 2001-03-20 | Rhodia Inc. | Nonionic gemini surfactants |
JPH10197978A (ja) | 1997-01-09 | 1998-07-31 | Mitsubishi Paper Mills Ltd | ハロゲン化銀写真感光材料 |
EP0853123A1 (de) | 1997-01-10 | 1998-07-15 | Roche Diagnostics GmbH | Reinigung von DNA durch Cross-Flow-Filtration |
FR2760193B1 (fr) | 1997-02-28 | 1999-05-28 | Transgene Sa | Lipides et complexes de lipides cationiques et de substances actives, notamment pour la transfection de cellules |
US5837283A (en) | 1997-03-12 | 1998-11-17 | The Regents Of The University Of California | Cationic lipid compositions targeting angiogenic endothelial cells |
ES2355588T3 (es) * | 1997-03-14 | 2011-03-29 | The Children's Hospital Of Philadelphia | Composiciones para uso en terapia génica para el tratamiento de hemofilia. |
US5945326A (en) | 1997-03-20 | 1999-08-31 | New England Biolabs, Inc. | Method for cloning and producing the Spel restriction endonuclease |
US6060082A (en) | 1997-04-18 | 2000-05-09 | Massachusetts Institute Of Technology | Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery |
AU733310C (en) | 1997-05-14 | 2001-11-29 | University Of British Columbia, The | High efficiency encapsulation of charged therapeutic agents in lipid vesicles |
US6835395B1 (en) | 1997-05-14 | 2004-12-28 | The University Of British Columbia | Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles |
US20030104044A1 (en) | 1997-05-14 | 2003-06-05 | Semple Sean C. | Compositions for stimulating cytokine secretion and inducing an immune response |
JPH115786A (ja) | 1997-06-13 | 1999-01-12 | Pola Chem Ind Inc | 新規アミノヒドロキシプロピルピペラジン誘導体 |
US6067471A (en) | 1998-08-07 | 2000-05-23 | Cardiac Pacemakers, Inc. | Atrial and ventricular implantable cardioverter-defibrillator and lead system |
US6165484A (en) | 1997-08-26 | 2000-12-26 | Wake Forest University | EDTA and other chelators with or without antifungal antimicrobial agents for the prevention and treatment of fungal infections |
US6060308A (en) | 1997-09-04 | 2000-05-09 | Connaught Laboratories Limited | RNA respiratory syncytial virus vaccines |
JPH1180142A (ja) | 1997-09-05 | 1999-03-26 | Pola Chem Ind Inc | ジフェニルアルキル化合物の製造法 |
US20030083272A1 (en) | 1997-09-19 | 2003-05-01 | Lahive & Cockfield, Llp | Sense mrna therapy |
US6734171B1 (en) | 1997-10-10 | 2004-05-11 | Inex Pharmaceuticals Corp. | Methods for encapsulating nucleic acids in lipid bilayers |
ATE355826T1 (de) | 1997-10-10 | 2007-03-15 | Inex Pharmaceuticals Corp | Verfahren zur verkapselung von nukleinsäuren in lipiddoppelschichten |
WO2000009153A1 (en) | 1997-10-29 | 2000-02-24 | Genzyme Corporation | Compositions and methods for treating lysosomal storage disease |
US6165763A (en) | 1997-10-30 | 2000-12-26 | Smithkline Beecham Corporation | Ornithine carbamoyltransferase |
US6096075A (en) | 1998-01-22 | 2000-08-01 | Medical Carbon Research Institute, Llc | Prosthetic heart valve |
US6617171B2 (en) | 1998-02-27 | 2003-09-09 | The General Hospital Corporation | Methods for diagnosing and treating autoimmune disease |
US6271209B1 (en) | 1998-04-03 | 2001-08-07 | Valentis, Inc. | Cationic lipid formulation delivering nucleic acid to peritoneal tumors |
US6176877B1 (en) | 1998-04-20 | 2001-01-23 | St. Jude Medical, Inc. | Two piece prosthetic heart valve |
DE19822602A1 (de) | 1998-05-20 | 1999-11-25 | Goldschmidt Ag Th | Verfahren zur Herstellung von Polyaminosäureestern durch Veresterung von sauren Polyaminosäuren oder Umesterung von Polyaminosäureestern |
NO313244B1 (no) | 1998-07-08 | 2002-09-02 | Crew Dev Corp | Fremgangsmåte for isolering og produksjon av magnesitt eller magnesiumklorid |
US6055454A (en) | 1998-07-27 | 2000-04-25 | Cardiac Pacemakers, Inc. | Cardiac pacemaker with automatic response optimization of a physiologic sensor based on a second sensor |
AU5068999A (en) | 1998-07-31 | 2000-02-21 | Korea Institute Of Science And Technology | Lipid emulsion and solid lipid nanoparticle as a gene or drug carrier |
US6299604B1 (en) | 1998-08-20 | 2001-10-09 | Cook Incorporated | Coated implantable medical device |
US6210892B1 (en) | 1998-10-07 | 2001-04-03 | Isis Pharmaceuticals, Inc. | Alteration of cellular behavior by antisense modulation of mRNA processing |
US6656498B1 (en) | 1998-11-25 | 2003-12-02 | Vanderbilt University | Cationic liposomes for gene transfer |
US6248725B1 (en) | 1999-02-23 | 2001-06-19 | Amgen, Inc. | Combinations and methods for promoting in vivo liver cell proliferation and enhancing in vivo liver-directed gene transduction |
JP2003503011A (ja) | 1999-04-02 | 2003-01-28 | エムティー テクノロジー,インコーポレイテッド | 固定プローブを使用する微生物の検出方法 |
US6379698B1 (en) | 1999-04-06 | 2002-04-30 | Isis Pharmaceuticals, Inc. | Fusogenic lipids and vesicles |
US8647864B2 (en) | 1999-04-14 | 2014-02-11 | Novartis Ag | Compositions and methods for generating an immune response utilizing alphavirus-based vector systems |
WO2000062813A2 (en) | 1999-04-20 | 2000-10-26 | The University Of British Columbia | Cationic peg-lipids and methods of use |
US6169923B1 (en) | 1999-04-23 | 2001-01-02 | Pacesetter, Inc. | Implantable cardioverter-defibrillator with automatic arrhythmia detection criteria adjustment |
EP1579874A3 (en) | 1999-04-23 | 2006-01-25 | ALZA Corporation | Conjugate having a cleavable linkage for use in a liposome |
ES2291205T3 (es) | 1999-05-19 | 2008-03-01 | Merck Patent Gmbh | Expresion y exportacion de proteinas interferon alfa como proteinas de fusion fc. |
US6696424B1 (en) | 1999-05-28 | 2004-02-24 | Vical Incorporated | Cytofectin dimers and methods of use thereof |
US6346382B1 (en) | 1999-06-01 | 2002-02-12 | Vanderbilt University | Human carbamyl phosphate synthetase I polymorphism and diagnostic methods related thereto |
US7094423B1 (en) | 1999-07-15 | 2006-08-22 | Inex Pharmaceuticals Corp. | Methods for preparation of lipid-encapsulated therapeutic agents |
EP1202714A1 (en) | 1999-07-16 | 2002-05-08 | Purdue Research Foundation | Vinyl ether lipids with cleavable hydrophilic headgroups |
EP1200578B1 (en) | 1999-07-23 | 2004-04-14 | Genentech, Inc. | Method for rnase- and organic solvent-free plasmid dna purification using tangential flow filtration |
US6358278B1 (en) | 1999-09-24 | 2002-03-19 | St. Jude Medical, Inc. | Heart valve prosthesis with rotatable cuff |
AU7725500A (en) | 1999-09-30 | 2001-04-30 | National Jewish Medical And Research Center | Method for inhibition of pathogenic microorganisms |
US6371983B1 (en) | 1999-10-04 | 2002-04-16 | Ernest Lane | Bioprosthetic heart valve |
WO2001026625A2 (en) | 1999-10-08 | 2001-04-19 | Alza Corp | Neutral-cationic lipid for nucleic acid and drug delivery |
US7060291B1 (en) | 1999-11-24 | 2006-06-13 | Transave, Inc. | Modular targeted liposomal delivery system |
AU3366901A (en) | 1999-12-30 | 2001-07-16 | Novartis Ag | Novel colloid synthetic vectors for gene therapy |
JP2003533437A (ja) | 2000-02-17 | 2003-11-11 | ジェンザイム・コーポレイション | 遺伝子デリバリーのための門戸としての肺の遺伝的修飾 |
US6370434B1 (en) | 2000-02-28 | 2002-04-09 | Cardiac Pacemakers, Inc. | Cardiac lead and method for lead implantation |
US6565960B2 (en) | 2000-06-01 | 2003-05-20 | Shriners Hospital Of Children | Polymer composite compositions |
EP1297169B1 (en) | 2000-06-26 | 2012-08-08 | Ethris Gmbh | Method for transfecting cells using a magnetic field |
IL138474A0 (en) | 2000-09-14 | 2001-10-31 | Epox Ltd | Highly branched water-soluble polyamine oligomers, process for their preparation and applications thereof |
USRE43612E1 (en) | 2000-10-10 | 2012-08-28 | Massachusetts Institute Of Technology | Biodegradable poly(β-amino esters) and uses thereof |
US6998115B2 (en) | 2000-10-10 | 2006-02-14 | Massachusetts Institute Of Technology | Biodegradable poly(β-amino esters) and uses thereof |
US7427394B2 (en) | 2000-10-10 | 2008-09-23 | Massachusetts Institute Of Technology | Biodegradable poly(β-amino esters) and uses thereof |
ATE354350T1 (de) | 2000-10-25 | 2007-03-15 | Univ British Columbia | Lipidformulierungen zur zielgerichteten abgabe |
GB0028361D0 (en) | 2000-11-21 | 2001-01-03 | Glaxo Group Ltd | Method of separating extra chromosomal dna from other cellular components |
US20020094528A1 (en) | 2000-11-29 | 2002-07-18 | Salafsky Joshua S. | Method and apparatus using a surface-selective nonlinear optical technique for detection of probe-target interations |
JP2002167368A (ja) | 2000-12-01 | 2002-06-11 | Nitto Denko Corp | アルキル置換デンドリマーおよびその製造法 |
US20050004058A1 (en) | 2000-12-07 | 2005-01-06 | Patrick Benoit | Sequences upstream of the carp gene, vectors containing them and uses thereof |
DE10109897A1 (de) | 2001-02-21 | 2002-11-07 | Novosom Ag | Fakultativ kationische Liposomen und Verwendung dieser |
US20020192721A1 (en) | 2001-03-28 | 2002-12-19 | Engeneos, Inc. | Modular molecular clasps and uses thereof |
KR100823815B1 (ko) | 2001-04-23 | 2008-04-21 | 신에쓰 가가꾸 고교 가부시끼가이샤 | 에스테르 구조를 갖는 신규 3급 아민 화합물 및 그 제조방법 |
US6585410B1 (en) | 2001-05-03 | 2003-07-01 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Radiant temperature nulling radiometer |
EP1800697B1 (de) | 2001-06-05 | 2010-04-14 | CureVac GmbH | Stabilisierte mRNA mit erhöhtem G/C-Gehalt für die Gentherapie |
EP2385123B1 (en) | 2001-09-28 | 2018-04-25 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Microrna molecules |
WO2003040288A2 (de) | 2001-11-09 | 2003-05-15 | Bayer Healthcare Ag | Isotopencodierte affinitätsmarker 3 |
DE10162480A1 (de) | 2001-12-19 | 2003-08-07 | Ingmar Hoerr | Die Applikation von mRNA für den Einsatz als Therapeutikum gegen Tumorerkrankungen |
DE10207178A1 (de) | 2002-02-19 | 2003-09-04 | Novosom Ag | Komponenten für die Herstellung amphoterer Liposomen |
DE10214983A1 (de) | 2002-04-04 | 2004-04-08 | TransMIT Gesellschaft für Technologietransfer mbH | Vernebelbare Liposomen und ihre Verwendung zur pulmonalen Applikation von Wirkstoffen |
US20030215395A1 (en) | 2002-05-14 | 2003-11-20 | Lei Yu | Controllably degradable polymeric biomolecule or drug carrier and method of synthesizing said carrier |
US7601367B2 (en) | 2002-05-28 | 2009-10-13 | Mirus Bio Llc | Compositions and processes using siRNA, amphipathic compounds and polycations |
WO2004002453A1 (en) | 2002-06-28 | 2004-01-08 | Protiva Biotherapeutics Ltd. | Method and apparatus for producing liposomes |
DE10229872A1 (de) | 2002-07-03 | 2004-01-29 | Curevac Gmbh | Immunstimulation durch chemisch modifizierte RNA |
US20040028804A1 (en) | 2002-08-07 | 2004-02-12 | Anderson Daniel G. | Production of polymeric microarrays |
JP2005536214A (ja) | 2002-08-22 | 2005-12-02 | セルトラン リミテッド | 細胞培養表面 |
CN100457804C (zh) | 2002-11-04 | 2009-02-04 | Ge拜尔硅股份有限公司 | 线性聚氨基-和/或聚铵聚硅氧烷共聚物ⅰ |
WO2004048345A2 (en) | 2002-11-22 | 2004-06-10 | Novo Nordisk A/S | 2,5-diketopiperazines for the treatment of obesity |
WO2004060363A1 (en) | 2002-12-23 | 2004-07-22 | Vical Incorporated | Method for producing sterile polynucleotide based medicaments |
WO2004060059A2 (en) | 2002-12-23 | 2004-07-22 | Vical Incorporated | Method for freeze-drying nucleic acid/block copolymer/cationic surfactant complexes |
DK2311848T3 (da) | 2002-12-23 | 2013-10-14 | Vical Inc | Kodon-optimerede polynukleotidbaserede vacciner mod human cytomegalovirus-infektion |
US7169892B2 (en) | 2003-01-10 | 2007-01-30 | Astellas Pharma Inc. | Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems |
WO2004066138A1 (ja) | 2003-01-20 | 2004-08-05 | Asahi Kasei Emd Corporation | ポインティングデバイス |
KR20050098954A (ko) | 2003-03-05 | 2005-10-12 | 세네스코 테크놀로지스 인코포레이티드 | 이아이에프-5에이1의 발현을 억제하기 위한 안티센스올리고뉴클레오타이드 또는 에스아이알엔에이의 이용 |
US20040224912A1 (en) | 2003-05-07 | 2004-11-11 | Isis Pharmaceuticals Inc. | Modulation of PAI-1 mRNA-binding protein expression |
US7619017B2 (en) | 2003-05-19 | 2009-11-17 | Wacker Chemical Corporation | Polymer emulsions resistant to biodeterioration |
EP1644479A4 (en) | 2003-06-16 | 2008-04-23 | Mark W Grinstaff | MACROMOLECULES AND FUNCTIONAL SYNTHETIC MOLECULES FOR GENES ADMINISTRATION |
US20070003607A1 (en) | 2003-09-02 | 2007-01-04 | Vibhudutta Awasthi | Neutral liposome-encapsulated compounds and methods of making and using thereof |
EP1675943A4 (en) | 2003-09-15 | 2007-12-05 | Massachusetts Inst Technology | NANOLITRE SYNTHESIS OF BIOMATERIALS IN NETWORKS AND SCREENING THEREOF |
US7803397B2 (en) | 2003-09-15 | 2010-09-28 | Protiva Biotherapeutics, Inc. | Polyethyleneglycol-modified lipid compounds and uses thereof |
US20050069590A1 (en) | 2003-09-30 | 2005-03-31 | Buehler Gail K. | Stable suspensions for medicinal dosages |
DK1685251T3 (en) | 2003-10-10 | 2014-03-24 | Powderject Vaccines Inc | Nucleic acid |
WO2005037226A2 (en) | 2003-10-17 | 2005-04-28 | Georgia Tech Research Corporation | Genetically engineered enteroendocrine cells for treating glucose-related metabolic disorders |
AU2004287652A1 (en) | 2003-11-10 | 2005-05-19 | Nippon Kayaku Kabushiki Kaisha | Diimonium salt compound and use thereof |
CN1906308B (zh) * | 2003-12-19 | 2011-09-14 | 诺华疫苗和诊断公司 | 小干扰rna的细胞转染制剂、相关组合物以及制备和使用方法 |
US7022214B2 (en) | 2004-01-21 | 2006-04-04 | Bio-Rad Laboratories, Inc. | Carrier ampholytes of high pH range |
US7556684B2 (en) | 2004-02-26 | 2009-07-07 | Construction Research & Technology Gmbh | Amine containing strength improvement admixture |
US20060228404A1 (en) | 2004-03-04 | 2006-10-12 | Anderson Daniel G | Compositions and methods for treatment of hypertrophic tissues |
CA2566355C (en) | 2004-05-18 | 2014-04-15 | Vical Incorporated | Influenza virus vaccine composition and methods of use |
AU2005245687A1 (en) | 2004-05-19 | 2005-12-01 | Clariant Finance (Bvi) Limited | Monoazo dyes |
AU2005252273B2 (en) | 2004-06-07 | 2011-04-28 | Arbutus Biopharma Corporation | Lipid encapsulated interfering RNA |
CA2569645C (en) | 2004-06-07 | 2014-10-28 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods of use |
US7670595B2 (en) | 2004-06-28 | 2010-03-02 | Merck Patent Gmbh | Fc-interferon-beta fusion proteins |
GB0418172D0 (en) | 2004-08-13 | 2004-09-15 | Ic Vec Ltd | Vector |
DE102004042546A1 (de) | 2004-09-02 | 2006-03-09 | Curevac Gmbh | Kombinationstherapie zur Immunstimulation |
DE102004043342A1 (de) | 2004-09-08 | 2006-03-09 | Bayer Materialscience Ag | Blockierte Polyurethan-Prepolymere als Klebstoffe |
WO2006048329A1 (en) | 2004-11-05 | 2006-05-11 | Novosom Ag | Improvements in or relating to pharmaceutical compositions comprising an oligonucleotide as an active agent |
WO2006060723A2 (en) | 2004-12-03 | 2006-06-08 | Vical Incorporated | Methods for producing block copolymer/amphiphilic particles |
WO2006074546A1 (en) | 2005-01-13 | 2006-07-20 | Protiva Biotherapeutics, Inc. | Lipid encapsulated interfering rna |
GB0502482D0 (en) | 2005-02-07 | 2005-03-16 | Glaxo Group Ltd | Novel compounds |
EP1922300A2 (en) | 2005-02-14 | 2008-05-21 | Sirna Therapeutics Inc. | Cationic lipids and formulated molecular compositions containing them |
US7977452B2 (en) | 2005-03-28 | 2011-07-12 | Dendritic Nanotechnologies, Inc. | Janus dendrimers and dendrons |
AU2006259415B2 (en) | 2005-06-15 | 2012-08-30 | Massachusetts Institute Of Technology | Amine-containing lipids and uses thereof |
US9012219B2 (en) | 2005-08-23 | 2015-04-21 | The Trustees Of The University Of Pennsylvania | RNA preparations comprising purified modified RNA for reprogramming cells |
WO2007031091A2 (en) | 2005-09-15 | 2007-03-22 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of p21 ras expression |
AU2006308765B2 (en) | 2005-11-02 | 2013-09-05 | Arbutus Biopharma Corporation | Modified siRNA molecules and uses thereof |
WO2007070705A2 (en) | 2005-12-15 | 2007-06-21 | The Trustees Of The University Of Pennsylvania | Cationic lipid-mediated vectors |
US7238791B1 (en) | 2005-12-16 | 2007-07-03 | Roche Diagnostics Operations, Inc. | 6-monoacetylmorphine derivatives useful in immunoassay |
WO2007073489A2 (en) | 2005-12-22 | 2007-06-28 | Trustees Of Boston University | Molecules for gene delivery and gene therapy, and methods of use thereof |
CN100569877C (zh) | 2005-12-30 | 2009-12-16 | 财团法人工业技术研究院 | 含多uv交联反应基的分枝状结构化合物及其应用 |
EP2010659B1 (en) | 2006-04-14 | 2014-06-18 | CellScript, Inc. | Kits and methods for generating 5' capped RNA |
US9085778B2 (en) | 2006-05-03 | 2015-07-21 | VL27, Inc. | Exosome transfer of nucleic acids to cells |
US20070275923A1 (en) | 2006-05-25 | 2007-11-29 | Nastech Pharmaceutical Company Inc. | CATIONIC PEPTIDES FOR siRNA INTRACELLULAR DELIVERY |
CA2654302A1 (en) | 2006-06-05 | 2007-12-13 | Massachusetts Institute Of Technology | Crosslinked, degradable polymers and uses thereof |
US20090186805A1 (en) | 2006-07-06 | 2009-07-23 | Aaron Thomas Tabor | Compositions and Methods for Genetic Modification of Cells Having Cosmetic Function to Enhance Cosmetic Appearance |
FR2904144A1 (fr) | 2006-07-19 | 2008-01-25 | St Microelectronics Rousset | Procede de fabrication d'un wafer de semi-conducteur comprenant un filtre optique integre |
ES2293834B1 (es) | 2006-07-20 | 2009-02-16 | Consejo Superior Investig. Cientificas | Compuesto con actividad inhibidora de las interacciones ubc13-uev, composiciones farmaceuticas que lo comprenden y sus aplicaciones terapeuticas. |
WO2008011561A2 (en) | 2006-07-21 | 2008-01-24 | Massachusetts Institute Of Technology | End-modified poly(beta-amino esters) and uses thereof |
ES2430206T3 (es) | 2006-10-03 | 2013-11-19 | Tekmira Pharmaceuticals Corporation | Formulación que contiene lípidos |
WO2008045548A2 (en) | 2006-10-12 | 2008-04-17 | Copernicus Therapeutics Inc. | Codon optimized cftr |
DE102006051516A1 (de) | 2006-10-31 | 2008-05-08 | Curevac Gmbh | (Basen-)modifizierte RNA zur Expressionssteigerung eines Proteins |
EP1920765A1 (en) | 2006-11-07 | 2008-05-14 | Medigene AG | Liposome preparation by single-pass process |
US8268586B2 (en) | 2006-12-21 | 2012-09-18 | Novozymes, Inc. | Modified messenger RNA stabilizing sequences for expressing genes in bacterial cells |
DE102007001370A1 (de) | 2007-01-09 | 2008-07-10 | Curevac Gmbh | RNA-kodierte Antikörper |
US7700734B2 (en) * | 2007-01-09 | 2010-04-20 | Shu-Wha Lin | Recombinant human factor IX and use thereof |
WO2008097926A2 (en) | 2007-02-02 | 2008-08-14 | Yale University | Transient transfection with rna |
WO2008113364A2 (en) | 2007-03-20 | 2008-09-25 | Recepticon Aps | Amino derivatives to prevent nephrotoxicity and cancer |
JP5186126B2 (ja) | 2007-03-29 | 2013-04-17 | 公益財団法人地球環境産業技術研究機構 | 新規トリアジン誘導体ならびにその製法およびそのガス分離膜としての用途 |
JP5480804B2 (ja) | 2007-04-18 | 2014-04-23 | コーナーストーン ファーマシューティカルズ,インコーポレーテッド | リポ酸誘導体を含有する医薬製剤 |
WO2008137470A1 (en) | 2007-05-01 | 2008-11-13 | Pgr-Solutions | Multi-chain lipophilic polyamines |
US20090163705A1 (en) | 2007-05-21 | 2009-06-25 | Alnylam Pharmaceuticals, Inc. | Cationic lipids |
CN101835903A (zh) | 2007-08-23 | 2010-09-15 | 诺瓦提斯公司 | 检测寡核苷酸的方法 |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
AU2008308679B2 (en) | 2007-10-02 | 2015-01-29 | Marina Biotech, Inc. | Lipopeptides for delivery of nucleic acids |
WO2009046739A1 (en) | 2007-10-09 | 2009-04-16 | Curevac Gmbh | Composition for treating prostate cancer (pca) |
EP2221371B1 (en) | 2007-11-22 | 2013-11-13 | Japan Science and Technology Agency | Translation regulation system in cell or artificial cell model by using low-molecular-weight rna |
US20090247608A1 (en) | 2007-12-04 | 2009-10-01 | Alnylam Pharmaceuticals, Inc. | Targeting Lipids |
CA2710983A1 (en) | 2007-12-27 | 2009-10-01 | The Ohio State University Research Foundation | Lipid nanoparticle compositions and methods of making and using the same |
CA2710713C (en) | 2007-12-27 | 2017-09-19 | Protiva Biotherapeutics, Inc. | Silencing of polo-like kinase expression using interfering rna |
CA2711236A1 (en) | 2008-01-02 | 2009-07-16 | Alnylam Pharmaceuticals, Inc. | Screening method for selected amino lipid-containing compositions |
US20110117125A1 (en) | 2008-01-02 | 2011-05-19 | Tekmira Pharmaceuticals Corporation | Compositions and methods for the delivery of nucleic acids |
US8715999B2 (en) | 2008-02-08 | 2014-05-06 | Valneva Austria Gmbh | Flaviviridae mutants comprising a deletion in the capsid protein for use as vaccines |
CA2721183C (en) | 2008-04-11 | 2019-07-16 | Alnylam Pharmaceuticals, Inc. | Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components |
NZ588583A (en) | 2008-04-15 | 2012-08-31 | Protiva Biotherapeutics Inc | Novel lipid formulations for nucleic acid delivery |
US20090263407A1 (en) | 2008-04-16 | 2009-10-22 | Abbott Laboratories | Cationic Lipids and Uses Thereof |
WO2009127230A1 (en) | 2008-04-16 | 2009-10-22 | Curevac Gmbh | MODIFIED (m)RNA FOR SUPPRESSING OR AVOIDING AN IMMUNOSTIMULATORY RESPONSE AND IMMUNOSUPPRESSIVE COMPOSITION |
US8222221B2 (en) | 2008-06-04 | 2012-07-17 | The Board Of Regents Of The University Of Texas System | Modulation of gene expression through endogenous small RNA targeting of gene promoters |
EP2313085A2 (en) | 2008-07-15 | 2011-04-27 | Novartis AG | Immunogenic amphipathic peptide compositions |
WO2010009065A2 (en) | 2008-07-15 | 2010-01-21 | Novartis Ag | Amphipathic peptide compositions |
JP5024216B2 (ja) | 2008-07-23 | 2012-09-12 | トヨタ自動車株式会社 | 内燃機関の点火時期制御装置及び点火時期制御方法 |
US20100035249A1 (en) | 2008-08-05 | 2010-02-11 | Kabushiki Kaisha Dnaform | Rna sequencing and analysis using solid support |
US8404198B2 (en) | 2008-08-27 | 2013-03-26 | Life Technologies Corporation | Apparatus for and method of processing biological samples |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
EP3225621A1 (en) | 2008-10-09 | 2017-10-04 | Arbutus Biopharma Corporation | Improved amino lipids and methods for the delivery of nucleic acids |
KR20110071017A (ko) | 2008-10-16 | 2011-06-27 | 마리나 바이오테크, 인크. | 유전자 침묵 치료제의 리포좀에 의한 효율적인 전달을 위한 프로세스 및 조성물 |
US9080211B2 (en) | 2008-10-24 | 2015-07-14 | Epicentre Technologies Corporation | Transposon end compositions and methods for modifying nucleic acids |
WO2010062322A2 (en) | 2008-10-27 | 2010-06-03 | Massachusetts Institute Of Technology | Modulation of the immune response |
KR101734955B1 (ko) * | 2008-11-07 | 2017-05-12 | 메사추세츠 인스티튜트 오브 테크놀로지 | 아미노알콜 리피도이드 및 그의 용도 |
CA3039251C (en) | 2008-11-10 | 2024-01-09 | Arbutus Biopharma Corporation | Novel lipids and compositions for the delivery of therapeutics |
TW201019969A (en) | 2008-11-17 | 2010-06-01 | Enzon Pharmaceuticals Inc | Branched cationic lipids for nucleic acids delivery system |
EP2405921A4 (en) | 2009-01-26 | 2013-05-22 | Protiva Biotherapeutics Inc | COMPOSITIONS AND METHODS FOR INACTIVATION OF APOLIPOPROTEIN C-III EXPRESSION |
AU2010208035B2 (en) | 2009-01-29 | 2016-06-23 | Arbutus Biopharma Corporation | Improved lipid formulation for the delivery of nucleic acids |
US20100222489A1 (en) | 2009-02-27 | 2010-09-02 | Jiang Dayue D | Copolymer composition, membrane article, and methods thereof |
NZ594995A (en) | 2009-03-12 | 2013-06-28 | Alnylam Pharmaceuticals Inc | LIPID FORMULATED COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF HUMAN KINESIN FAMILY MEMBER 11 (Eg5) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) GENES |
EP2415124B1 (en) | 2009-04-02 | 2017-02-15 | The Siemon Company | Telecommunications patch panel |
DK2419144T3 (da) | 2009-04-17 | 2019-10-21 | Univ Oxford Innovation Ltd | Sammensætning til levering af genetisk materiale |
US9220682B2 (en) | 2009-04-22 | 2015-12-29 | Emory University | Nanocarrier therapy for treating invasive tumors |
CN102421417B (zh) | 2009-05-05 | 2016-03-02 | 阿尔尼拉姆医药品有限公司 | 脂质组合物 |
EP2440183B1 (en) | 2009-06-10 | 2018-07-18 | Arbutus Biopharma Corporation | Improved lipid formulation |
US9051567B2 (en) | 2009-06-15 | 2015-06-09 | Tekmira Pharmaceuticals Corporation | Methods for increasing efficacy of lipid formulated siRNA |
US9018187B2 (en) | 2009-07-01 | 2015-04-28 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods for the delivery of therapeutic agents |
US8236943B2 (en) | 2009-07-01 | 2012-08-07 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing apolipoprotein B |
WO2011000106A1 (en) | 2009-07-01 | 2011-01-06 | Protiva Biotherapeutics, Inc. | Improved cationic lipids and methods for the delivery of therapeutic agents |
US20120100207A1 (en) | 2009-07-02 | 2012-04-26 | Konica Minolta Holdings, Inc. | Process for producing liposomes by two-step emulsification method utilizing outer aqueous phase containing specific dispersing agent, process for producing liposome dispersion or dry powder thereof using the process for producing liposomes, and liposome dispersion or dry powder thereof produced thereby |
EP2451475A2 (en) | 2009-07-06 | 2012-05-16 | Novartis AG | Self replicating rna molecules and uses thereof |
WO2011011447A1 (en) | 2009-07-20 | 2011-01-27 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing ebola virus gene expression |
EA021838B1 (ru) | 2009-07-30 | 2015-09-30 | Лабораториос Салват, С.А. | Производные 2,5-пиперазиндиона в качестве ингибиторов apaf-1 |
BR112012002291A2 (pt) | 2009-07-31 | 2016-11-29 | Ethris Gmbh | "polirribonucleotídeo com uma sequência que codifica uma proteína ou fragmento de proteína, implante, e, processo para a seleção de sequências de nucleotídeos" |
DE102009043342A1 (de) | 2009-09-29 | 2011-03-31 | Bayer Technology Services Gmbh | Stoffe für selbstorganisierte Träger zur kontrollierten Freisetzung eines Wirkstoffs |
WO2011062132A1 (ja) | 2009-11-20 | 2011-05-26 | コニカミノルタホールディングス株式会社 | W/o/wエマルションの製造方法およびこれを用いたリポソームの製造方法、並びにこれらの方法に用いられる孔膜 |
SI2506857T1 (en) | 2009-12-01 | 2018-08-31 | Translate Bio, Inc. | Delivery of mRNA for the enrichment of proteins and enzymes in human genetic diseases |
LT3112467T (lt) | 2009-12-07 | 2018-06-25 | The Trustees Of The University Of Pennsylvania | Išgrynintą modifikuotą rnr apimantys rnr preparatai, skirti ląstelių perprogramavimui |
WO2011069529A1 (en) | 2009-12-09 | 2011-06-16 | Curevac Gmbh | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
NZ600725A (en) | 2009-12-18 | 2015-08-28 | Univ British Colombia | Methods and compositions for delivery of nucleic acids |
EP2338520A1 (de) | 2009-12-21 | 2011-06-29 | Ludwig Maximilians Universität | Konjugat mit Zielfindungsligand und dessen Verwendung |
AU2014259532B2 (en) | 2009-12-23 | 2016-09-08 | Novartis Ag | Lipids, lipid compositions, and methods of using them |
WO2011076807A2 (en) | 2009-12-23 | 2011-06-30 | Novartis Ag | Lipids, lipid compositions, and methods of using them |
CA2799091A1 (en) | 2010-05-12 | 2011-11-17 | Protiva Biotherapeutics, Inc. | Cationic lipids and methods of use thereof |
KR101198715B1 (ko) * | 2010-05-14 | 2012-11-13 | 한국생명공학연구원 | 핵산 및 친수성 음이온 화합물의 고효율 포획을 위한 비대칭 리포솜 및 이의 제조방법 |
JP5893611B2 (ja) | 2010-06-03 | 2016-03-23 | アルニラム・ファーマシューティカルズ・インコーポレーテッド | 活性剤の送達のための生分解性脂質 |
CN101863544B (zh) | 2010-06-29 | 2011-09-28 | 湖南科技大学 | 一种氰尿酸基重金属螯合絮凝剂及其制备方法 |
WO2012000104A1 (en) | 2010-06-30 | 2012-01-05 | Protiva Biotherapeutics, Inc. | Non-liposomal systems for nucleic acid delivery |
HRP20221522T1 (hr) | 2010-07-06 | 2023-02-17 | Glaxosmithkline Biologicals S.A. | Čestice za dostavljanje nalik virionu za samo-replicirajuće rna molekule |
MX343410B (es) | 2010-07-06 | 2016-11-04 | Novartis Ag * | Emulsiones cationicas de agua en aceite. |
ES2557382T3 (es) | 2010-07-06 | 2016-01-25 | Glaxosmithkline Biologicals Sa | Liposomas con lípidos que tienen un valor de pKa ventajoso para el suministro de ARN |
US9770463B2 (en) | 2010-07-06 | 2017-09-26 | Glaxosmithkline Biologicals Sa | Delivery of RNA to different cell types |
ES2586580T3 (es) | 2010-07-06 | 2016-10-17 | Glaxosmithkline Biologicals Sa | Inmunización de mamíferos grandes con dosis bajas de ARN |
HUE047796T2 (hu) | 2010-07-06 | 2020-05-28 | Glaxosmithkline Biologicals Sa | RNS bevitele több immunútvonal bekapcsolására |
WO2012016184A2 (en) | 2010-07-30 | 2012-02-02 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for delivery of active agents |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
WO2012019630A1 (en) | 2010-08-13 | 2012-02-16 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
EP2609135A4 (en) | 2010-08-26 | 2015-05-20 | Massachusetts Inst Technology | POLY (BETA-AMINO ALCOHOLS), THEIR PREPARATION AND USES THEREOF |
FI4043040T3 (fi) | 2010-08-31 | 2023-04-04 | Glaxosmithkline Biologicals Sa | Pieniä liposomeja immunogeeniä koodaavan rna:n toimittamiseksi |
US20130189351A1 (en) | 2010-08-31 | 2013-07-25 | Novartis Ag | Lipids suitable for liposomal delivery of protein coding rna |
HUE058361T2 (hu) | 2010-08-31 | 2022-07-28 | Glaxosmithkline Biologicals Sa | Pegilált liposzómák immunogént kódoló RNA bejuttatására |
EP2857499A1 (en) | 2010-10-01 | 2015-04-08 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US8853377B2 (en) | 2010-11-30 | 2014-10-07 | Shire Human Genetic Therapies, Inc. | mRNA for use in treatment of human genetic diseases |
WO2012116715A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in newborns and infants |
WO2012113413A1 (en) | 2011-02-21 | 2012-08-30 | Curevac Gmbh | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
WO2012116714A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in elderly patients |
US9238716B2 (en) | 2011-03-28 | 2016-01-19 | Massachusetts Institute Of Technology | Conjugated lipomers and uses thereof |
WO2012133737A1 (ja) | 2011-03-31 | 2012-10-04 | 公益財団法人地球環境産業技術研究機構 | 架橋性アミン化合物、該化合物を用いた高分子膜及びその製造方法 |
EP2691101A2 (en) | 2011-03-31 | 2014-02-05 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
CN103687957A (zh) | 2011-05-17 | 2014-03-26 | 现代治疗公司 | 工程化核酸及其用于非人类脊椎动物的方法 |
EP2532649B1 (en) | 2011-06-07 | 2015-04-08 | Incella GmbH | Amino lipids, their synthesis and uses thereof |
CN103748078B (zh) | 2011-06-08 | 2016-11-09 | 夏尔人类遗传性治疗公司 | 可裂解脂质 |
PL2717893T3 (pl) | 2011-06-08 | 2019-12-31 | Translate Bio, Inc. | Kompozycje nanocząstek lipidowych i sposoby do dostarczania mRNA |
WO2013003475A1 (en) | 2011-06-27 | 2013-01-03 | Cellscript, Inc. | Inhibition of innate immune response |
EP3854413A1 (en) | 2011-07-06 | 2021-07-28 | GlaxoSmithKline Biologicals SA | Immunogenic combination compositions and uses thereof |
WO2013006825A1 (en) | 2011-07-06 | 2013-01-10 | Novartis Ag | Liposomes having useful n:p ratio for delivery of rna molecules |
EP3508219A1 (en) | 2011-07-06 | 2019-07-10 | GlaxoSmithKline Biologicals S.A. | Self-replicating rna prime - protein boost vaccines |
JP6120839B2 (ja) | 2011-07-06 | 2017-04-26 | ノバルティス アーゲー | カチオン性水中油型エマルジョン |
TR201802662T4 (tr) | 2011-07-06 | 2018-03-21 | Glaxosmithkline Biologicals Sa | Nükleik asitler içeren su içinde yağ emülsiyonları. |
EP3508220A1 (en) | 2011-08-31 | 2019-07-10 | GlaxoSmithKline Biologicals S.A. | Pegylated liposomes for delivery of immunogen-encoding rna |
EP2755986A4 (en) | 2011-09-12 | 2015-05-20 | Moderna Therapeutics Inc | MODIFIED NUCLEIC ACIDS AND METHODS OF USE |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
EP2755693A4 (en) | 2011-09-12 | 2015-05-20 | Moderna Therapeutics Inc | MODIFIED NUCLEIC ACIDS AND METHODS OF USE |
SG10201602654SA (en) | 2011-10-03 | 2016-05-30 | Moderna Therapeutics Inc | Modified nucleosides,nucleotides,and nucleic acids,and uses thereof |
EP2764007A4 (en) | 2011-10-05 | 2015-05-06 | Protiva Biotherapeutics Inc | COMPOSITIONS AND METHODS FOR DISABLING ALDEHYDE DEHYDROGENASE |
CA3119789A1 (en) | 2011-10-27 | 2013-05-02 | Massachusetts Institute Of Technology | Amino acid derivatives functionalized on the n-terminal capable of forming drug encapsulating microspheres |
EP2791364A4 (en) | 2011-12-14 | 2015-11-11 | Moderna Therapeutics Inc | METHODS OF RESPONSE TO A BIOLOGICAL THREAT |
EP2791159A4 (en) | 2011-12-14 | 2015-10-14 | Moderna Therapeutics Inc | MODIFIED NUCLEIC ACIDS, AND SHORT-TERM CARE USES THEREOF |
CA3018046A1 (en) | 2011-12-16 | 2013-06-20 | Moderna Therapeutics, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
CN104968354A (zh) | 2011-12-21 | 2015-10-07 | 现代治疗公司 | 增加器官或器官外植体的活力或寿命的方法 |
EP2797634A4 (en) | 2011-12-29 | 2015-08-05 | Moderna Therapeutics Inc | MODIFIED mRNA ENCODING POLYPEPTIDES PENETRATING IN CELLS |
AU2012362113B2 (en) | 2011-12-30 | 2017-08-03 | Cellscript, Llc | Making and using in vitro-synthesized ssRNA for introducing into mammalian cells to induce a biological or biochemical effect |
US20150030576A1 (en) | 2012-01-10 | 2015-01-29 | Moderna Therapeutics, Inc. | Methods and compositions for targeting agents into and across the blood-brain barrier |
WO2013120497A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein |
WO2013120499A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen |
EP2817287B1 (en) | 2012-02-24 | 2018-10-03 | Arbutus Biopharma Corporation | Trialkyl cationic lipids and methods of use thereof |
ES2654205T3 (es) | 2012-03-27 | 2018-02-12 | Curevac Ag | Moléculas artificiales de ácido nucleico para la expresión mejorada de proteínas o péptidos |
WO2013149140A1 (en) | 2012-03-29 | 2013-10-03 | Shire Human Genetic Therapies, Inc. | Ionizable cationic lipids |
ES2858523T3 (es) | 2012-03-29 | 2021-09-30 | Translate Bio Inc | Nanopartículas neutras derivadas de lípidos |
US20150050354A1 (en) | 2012-04-02 | 2015-02-19 | Moderna Therapeutics, Inc. | Modified polynucleotides for the treatment of otic diseases and conditions |
US20140275229A1 (en) | 2012-04-02 | 2014-09-18 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding udp glucuronosyltransferase 1 family, polypeptide a1 |
AU2013243950A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides |
AU2013243949A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
WO2013182683A1 (en) | 2012-06-08 | 2013-12-12 | Ethris Gmbh | Pulmonary delivery of messenger rna |
MX2014015041A (es) | 2012-06-08 | 2015-06-17 | Shire Human Genetic Therapies | Administración pulmonar de arnm a células objetivo no pulmonares. |
EP2859102A4 (en) | 2012-06-08 | 2016-05-11 | Shire Human Genetic Therapies | NUCLEASE RESISTANT POLYNUCLEOTIDES AND USES THEREOF |
RU2488732C1 (ru) | 2012-07-26 | 2013-07-27 | Общество с ограниченной ответственностью "Новые композитные технологии" | Способ изготовления напорной комбинированной трубы |
EP2882706A1 (en) | 2012-08-13 | 2015-06-17 | Massachusetts Institute of Technology | Amine-containing lipidoids and uses thereof |
US20150307542A1 (en) | 2012-10-03 | 2015-10-29 | Moderna Therapeutics, Inc. | Modified nucleic acid molecules and uses thereof |
PT2922554T (pt) | 2012-11-26 | 2022-06-28 | Modernatx Inc | Arn modificado nas porções terminais |
US9636301B2 (en) | 2012-12-04 | 2017-05-02 | Arbutus Biopharma Corporation | In vitro release assay for liposome encapsulated vincristine |
EP4331620A2 (en) | 2012-12-07 | 2024-03-06 | Translate Bio, Inc. | Lipidic nanoparticles for mrna delivery |
EP2931914A4 (en) | 2012-12-13 | 2016-08-17 | Moderna Therapeutics Inc | MODIFIED POLYNUCLEOTIDES FOR CHANGING THE CELL PHENOTYPE |
EP3434774A1 (en) | 2013-01-17 | 2019-01-30 | ModernaTX, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
WO2014158795A1 (en) | 2013-03-12 | 2014-10-02 | Moderna Therapeutics, Inc. | Diagnosis and treatment of fibrosis |
US20160024181A1 (en) | 2013-03-13 | 2016-01-28 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
AU2014239184B2 (en) | 2013-03-14 | 2018-11-08 | Translate Bio, Inc. | Methods and compositions for delivering mRNA coded antibodies |
KR20150127582A (ko) | 2013-03-14 | 2015-11-17 | 샤이어 휴먼 지네틱 테라피즈 인크. | 4''-티오 개질된 뉴클레오티드를 갖는 리보핵산 및 관련 방법 |
DK2970955T3 (en) | 2013-03-14 | 2019-02-11 | Translate Bio Inc | METHODS FOR CLEANING MESSENGER RNA |
CN105209633A (zh) | 2013-03-14 | 2015-12-30 | 夏尔人类遗传性治疗公司 | 信使rna加帽效率的定量评估 |
US10258698B2 (en) | 2013-03-14 | 2019-04-16 | Modernatx, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
DK2971102T3 (en) | 2013-03-14 | 2018-08-27 | Translate Bio Inc | QUANTITATIVE DETERMINATION FOR CAPPING EFFECTIVENESS OF MESSENGER RNA |
IL290953B2 (en) | 2013-03-14 | 2024-01-01 | Ethris Gmbh | CFTR mRNA Assemblies and Related Methods and Uses |
ES2692363T3 (es) | 2013-03-14 | 2018-12-03 | Translate Bio, Inc. | Composiciones terapéuticas de ARNm y su uso para tratar enfermedades y trastornos |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10590161B2 (en) | 2013-03-15 | 2020-03-17 | Modernatx, Inc. | Ion exchange purification of mRNA |
US10130649B2 (en) | 2013-03-15 | 2018-11-20 | Translate Bio, Inc. | Synergistic enhancement of the delivery of nucleic acids via blended formulations |
EP2971165A4 (en) | 2013-03-15 | 2016-11-23 | Moderna Therapeutics Inc | DISSOLUTION OF DNA FRAGMENTS IN MRNA MANUFACTURING METHODS |
EP3578652B1 (en) | 2013-03-15 | 2023-07-12 | ModernaTX, Inc. | Ribonucleic acid purification |
US20160017313A1 (en) | 2013-03-15 | 2016-01-21 | Moderna Therapeutics, Inc. | Analysis of mrna heterogeneity and stability |
WO2014152027A1 (en) | 2013-03-15 | 2014-09-25 | Moderna Therapeutics, Inc. | Manufacturing methods for production of rna transcripts |
US20160032273A1 (en) | 2013-03-15 | 2016-02-04 | Moderna Therapeutics, Inc. | Characterization of mrna molecules |
WO2014179562A1 (en) | 2013-05-01 | 2014-11-06 | Massachusetts Institute Of Technology | 1,3,5-triazinane-2,4,6-trione derivatives and uses thereof |
US9895443B2 (en) | 2013-06-26 | 2018-02-20 | Massachusetts Institute Of Technology | Multi-tailed lipids and uses thereof |
HUE056760T2 (hu) | 2013-07-11 | 2022-03-28 | Modernatx Inc | A CRISPR-hez kapcsolódó fehérjéket és a szintetikus SGRNS-ket kódoló szintetikus polinukleotidokat tartalmazó készítmények és felhasználási módjaik |
EP3033325B1 (en) | 2013-07-23 | 2019-12-04 | Arbutus Biopharma Corporation | Compositions and methods for delivering messenger rna |
SG10201801431TA (en) | 2013-08-21 | 2018-04-27 | Curevac Ag | Respiratory syncytial virus (rsv) vaccine |
US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
AU2014315287A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
EP3052479A4 (en) | 2013-10-02 | 2017-10-25 | Moderna Therapeutics, Inc. | Polynucleotide molecules and uses thereof |
EP3052511A4 (en) | 2013-10-02 | 2017-05-31 | Moderna Therapeutics, Inc. | Polynucleotide molecules and uses thereof |
AU2014337156A1 (en) | 2013-10-18 | 2016-05-12 | Modernatx, Inc. | Compositions and methods for tolerizing cellular systems |
ES2954366T3 (es) | 2013-10-22 | 2023-11-21 | Translate Bio Inc | Terapia de ácido ribonucleico mensajero para la deficiencia de argininosuccinato sintetasa |
AU2014340083B2 (en) | 2013-10-22 | 2019-08-15 | Translate Bio, Inc. | mRNA therapy for phenylketonuria |
KR102096796B1 (ko) * | 2013-10-22 | 2020-05-27 | 샤이어 휴먼 지네틱 테라피즈 인크. | 메신저 rna의 전달을 위한 지질 제형 |
BR112016008832A2 (pt) | 2013-10-22 | 2017-10-03 | Shire Human Genetic Therapies | Distribuição de mrna no snc e suas utilizações |
US20170173128A1 (en) | 2013-12-06 | 2017-06-22 | Moderna TX, Inc. | Targeted adaptive vaccines |
EP2918275B1 (en) | 2013-12-13 | 2016-05-18 | Moderna Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
RU2717986C2 (ru) | 2013-12-30 | 2020-03-27 | Куревак Аг | Искусственные молекулы нуклеиновой кислоты |
US20170002060A1 (en) | 2014-01-08 | 2017-01-05 | Moderna Therapeutics, Inc. | Polynucleotides for the in vivo production of antibodies |
ES2754239T3 (es) | 2014-03-12 | 2020-04-16 | Curevac Ag | Combinación de vacunación y agonistas de OX40 |
US10405937B2 (en) | 2014-04-09 | 2019-09-10 | Arbutus Medical Inc. | Drill cover and chuck mechanism |
HRP20220070T1 (hr) | 2014-04-23 | 2022-04-01 | Modernatx, Inc. | Cjepiva nukleinske kiseline |
PT3155129T (pt) | 2014-06-10 | 2019-05-16 | Curevac Ag | Método para potenciar a produção de arn |
US10286086B2 (en) | 2014-06-19 | 2019-05-14 | Modernatx, Inc. | Alternative nucleic acid molecules and uses thereof |
US20170175129A1 (en) | 2014-06-19 | 2017-06-22 | Moderna Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
CA3179824A1 (en) | 2014-06-25 | 2015-12-30 | Acuitas Therapeutics Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2016005004A1 (en) | 2014-07-11 | 2016-01-14 | Biontech Rna Pharmaceuticals Gmbh | Stabilization of poly(a) sequence encoding dna sequences |
WO2016009000A1 (en) | 2014-07-16 | 2016-01-21 | Ethris Gmbh | Rna for use in the treatment of ligament or tendon lesions |
SG11201702662UA (en) | 2014-10-02 | 2017-04-27 | Protiva Biotherapeutics Inc | Compositions and methods for silencing hepatitis b virus gene expression |
WO2016071857A1 (en) | 2014-11-07 | 2016-05-12 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing ebola virus expression |
EP3218508A4 (en) | 2014-11-10 | 2018-04-18 | Modernatx, Inc. | Multiparametric nucleic acid optimization |
EP3041948B1 (en) | 2014-11-10 | 2019-01-09 | Modernatx, Inc. | Alternative nucleic acid molecules containing reduced uracil content and uses thereof |
US20180000953A1 (en) | 2015-01-21 | 2018-01-04 | Moderna Therapeutics, Inc. | Lipid nanoparticle compositions |
EP3247398A4 (en) | 2015-01-23 | 2018-09-26 | Moderna Therapeutics, Inc. | Lipid nanoparticle compositions |
WO2016154127A2 (en) | 2015-03-20 | 2016-09-29 | Protiva Biotherapeutics, Inc. | Compositions and methods for treating hypertriglyceridemia |
WO2016164762A1 (en) | 2015-04-08 | 2016-10-13 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor egf-a and intracellular domain mutants and methods of using the same |
WO2016183366A2 (en) | 2015-05-12 | 2016-11-17 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing expression of hepatitis d virus rna |
US20180245074A1 (en) | 2015-06-04 | 2018-08-30 | Protiva Biotherapeutics, Inc. | Treating hepatitis b virus infection using crispr |
US10626393B2 (en) | 2015-06-04 | 2020-04-21 | Arbutus Biopharma Corporation | Delivering CRISPR therapeutics with lipid nanoparticles |
EP3307305A4 (en) | 2015-06-10 | 2019-05-22 | Modernatx, Inc. | TARGETED ADAPTIVE VACCINES |
CN108350455A (zh) | 2015-07-29 | 2018-07-31 | 阿布特斯生物制药公司 | 用于使b型肝炎病毒基因表达沉默的组合物和方法 |
US11434486B2 (en) | 2015-09-17 | 2022-09-06 | Modernatx, Inc. | Polynucleotides containing a morpholino linker |
DK3350333T3 (da) | 2015-09-17 | 2022-01-31 | Modernatx Inc | Polynukleotider, der indeholder en stabiliserende haleregion |
US20190054112A1 (en) | 2015-09-18 | 2019-02-21 | Moderna Therapeutics, Inc. | Polynucleotide formulations for use in the treatment of renal diseases |
WO2017102010A1 (en) | 2015-12-17 | 2017-06-22 | Biontech Rna Pharmaceuticals Gmbh | Novel cytokine fusion proteins |
EP3394237A1 (en) | 2015-12-21 | 2018-10-31 | CureVac AG | Inlay for a culture plate and corresponding method for preparing a culture plate system with such inlay |
WO2017109134A1 (en) | 2015-12-22 | 2017-06-29 | Curevac Ag | Method for producing rna molecule compositions |
WO2017109161A1 (en) | 2015-12-23 | 2017-06-29 | Curevac Ag | Method of rna in vitro transcription using a buffer containing a dicarboxylic acid or tricarboxylic acid or a salt thereof |
WO2017117528A1 (en) | 2015-12-30 | 2017-07-06 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US9834510B2 (en) | 2015-12-30 | 2017-12-05 | Arcturus Therapeutics, Inc. | Aromatic ionizable cationic lipid |
WO2019207060A1 (en) | 2018-04-25 | 2019-10-31 | Ethris Gmbh | Lipid-based formulations for the delivery of rna |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007024708A2 (en) * | 2005-08-23 | 2007-03-01 | The Trustees Of The University Of Pennsylvania | Rna containing modified nucleosides and methods of use thereof |
WO2010148013A2 (en) * | 2009-06-15 | 2010-12-23 | Alnylam Pharmaceuticals, Inc. | Lipid formulated dsrna targeting the pcsk9 gene |
Non-Patent Citations (3)
Title |
---|
GEERTRUI TAVERNIER等: "mRNA as gene therapeutic: How to control protein expression", JOURNAL OF CONTROLLED RELEASE, vol. 150, 21 October 2010 (2010-10-21), pages 238 * |
KATALIN KARIKÓ等: "Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability", MOLECULAR THERAPY, vol. 16, no. 11, 10 November 2009 (2009-11-10), pages 1833 - 1840, XP055920956, DOI: 10.1038/mt.2008.200 * |
MICHAEL S D KORMANN等: "Expression of therapeutic proteins after delivery of chemically modified mRNA in mice", NATURE BIOTECHNOLOGY, vol. 29, no. 2, 9 January 2011 (2011-01-09), pages 154, XP055040839, DOI: 10.1038/nbt.1733 * |
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