CN108291221B - 向天然杀伤细胞、造血干细胞和巨噬细胞的增强化基因递送 - Google Patents
向天然杀伤细胞、造血干细胞和巨噬细胞的增强化基因递送 Download PDFInfo
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Abstract
本发明包括一种通过给予奥索恩诺((5Z)‑7‑Oxozeaenol)下调胞内防御的方法。该方法能改善基于RNA的基因载体向天然杀伤细胞、干细胞和巨噬细胞的递送。所得细胞能用于过继细胞转移疗法。还提供了通过给予奥索恩诺和抗病毒治疗来治疗病毒诱导的炎症的方法。
Description
优先权和引用纳入
本申请要求2015年9月30日提交的临时申请62/235,427的优先权。本文所引用的所有文献通过引用明确纳入本文。
背景技术
天然杀伤(NK)细胞是先天免疫系统中的淋巴细胞。它们产生细胞因子并具有细胞毒作用，从而杀伤被病毒感染的细胞或肿瘤细胞。因此，采用NK细胞的过继免疫疗法是癌症治疗中具有前景的方式。在过去十年中，数种基于NK 细胞的抗癌产品已进入临床试验阶段，且获得了理想的临床结果。然而，为了制造更有效的NK细胞疗法产品，开发出新的策略(例如NK细胞的基因修饰)至关重要。并且，采用通过引入活化或嵌合抗原受体来重定向于肿瘤靶标的基因修饰NK细胞在进一步的临床应用中展示出诱人前景。导入表达各种细胞因子的基因以提高过继性转移的NK细胞的体内存活和细胞毒性也是各种方式中的一种。仍然存在的问题是NK细胞对逆转录病毒的固有抗性(Lanier 2008；Alici 等,2009；Brandstadler和Yang,2011；Sutlu等,2012)。业已显示通过提高增殖和用小分子抑制剂靶向胞内病毒防御机制能够增强向NK细胞的逆转录病毒和慢病毒基因递送。但通过病毒载体向巨噬细胞和干细胞递送遗传物质还是个问题。本领域中仍然需要更有效地转染细胞，尤其是转染NK细胞、造血干细胞和巨噬细胞。
本发明的一个目的是通过共同给予奥索恩诺((5Z)-7-Oxozeaenol)和病毒载体来改善细胞转染。
本发明的一个目的是通过给予奥索恩诺来下调胞内防御机制。
本发明的一个目的是通过给予细胞奥索恩诺来改善过继细胞转移治疗。
本发明的一个目的是通过给予天然杀伤细胞、巨噬细胞和干细胞奥索恩诺和病毒载体来改善对这些细胞的转染。
本发明的一个目的是采用以表达载体和奥索恩诺转染的细胞来治疗人类疾病。
本发明的一个目的是用基于慢病毒或逆转录病毒的载体来转导细胞。
本发明的一个目的是采用以奥索恩诺和RNA病毒载体转染的细胞来治疗癌症和增殖性疾病。
本发明的一个目的是采用以奥索恩诺和RNA病毒载体转染的细胞来治疗由遗传突变引起的疾病。
本发明的一个目的是采用以奥索恩诺和RNA病毒载体转染的细胞来治疗代谢性疾病。
本发明的一个目的是治疗由病毒感染引起的炎症。
发明内容
本发明包括在体外给予细胞奥索恩诺和RNA病毒载体以改善转染，并由此增强NK细胞、干细胞和巨噬细胞的增殖。虽然不希望受到任何理论的限制，据信所观察到的基因修饰增加是由于下调了由Rig I介导的胞内防御机制。通过该方式处理的细胞能用于治疗癌症、由已知基因突变导致的疾病以及由已知基因突变导致的代谢性疾病。
附图简要说明
图1包括两张柱状图，显示了采用iX的先天免疫信号传导抑制在NK细胞中增强了慢病毒转导效率。在6μM BX795或iX的存在下，对NK-92细胞和分离自健康供体PBMC的原代人NK细胞进行6小时的慢病毒转导。在72小时后获得 GFP表达。+图中显示了细胞百分比。
图2A的图表显示iX对NK细胞具有剂量依赖性效果且低毒。在不同剂量 BX795或iX的存在下，用LeGO-G2病毒转导原代人NK细胞和NK-92细胞6小时。转导后72小时，用流式细胞术分析GFP表达。图中显示了GFP+细胞的百分比。数据获自三个独立的试验，各重复三次。
图2B包含两张柱状图，图中比较了凋亡和死亡膜联蛋白-V+/PI-细胞。
图3包含凝胶照片，显示了在慢病毒转导期间用iX处理减少了RIG-I和 IRF-3。
图4包含两张柱状图，显示了iX处理干扰了抗病毒细胞因子IFNγ和TNF的分泌。
图5显示了与BX795相比，iX处理具有独特的转录组标记。
图6A-D显示据信被BXx795影响的信号传导途径。
图6E-H显示据信被iX影响的信号传导途径。
图7显示给予iX增加基因编辑。
发明详述
细胞疗法迅速成为用于治疗哺乳动物疾病的可行方法。然而不幸的是，许多治疗应用受限于基因能被递送到靶细胞的低效性。在如下所述的方法中合用 iX获得了预料不到的结果。在这些试验事前，已知小分子可靶向RIG I并下调胞内防御机制。采用本发明，能够更容易地将所需基因导入靶细胞。据信iX的类似物、衍生物或模拟物也能起效。
实施例1
材料和方法
细胞系：
293FT细胞购自英杰公司(生命技术公司，美国纽约州格兰德岛)，并保存在杜尔贝科改良的伊格培养基(DMEM，GIBCO，生命技术公司，美国纽约州格兰德岛)中，该培养基补充有10％胎牛血清(FBS，GIBCO)、0.1mM非必需氨基酸(Sigma-Aldrich公司，美国密苏里州圣路易斯)、6mM L-谷氨酰胺 (Sigma-Aldrich公司)、1mM丙酮酸钠(Sigma-Aldrich公司)和20mM HEPES (Sigma-Aldrich公司)。NK92细胞保存在CellGro SCGM(Cellgenix公司)培养基中，该培养基补充有20％FBS和1000U/ml rhIL-2(阿地白介素Proleukin，希龙公司)。
慢病毒载体的生产
为了生产VSV-G假型慢病毒载体，将14×106个293FT细胞接种至聚-D赖氨酸包被的150mm培养皿(美国加利福尼亚州圣何塞的BD生物科学公司)。次日，如下转染细胞：在25μM氯喹(Sigma-Aldrich公司)的存在下，采用磷酸钙转染试剂盒(Sigma-Aldrich)，用30μgLeGO-G2质粒(德国汉堡的汉堡-埃普多夫大学医学中心的Boris Fehse教授惠赠)、15μgpMDLg/pRRE(美国马萨诸塞州坎布里奇的Addgene公司)、10μg pRSV-REV(Addgene公司)和5μg phCMV-VSV-G (Addgene公司)转染细胞。转染后10小时，更换培养基，然后在2-3天内每24小时收集含病毒的上清液，存储于-80℃直至进一步使用。用每次生产的一小份通过用系列稀释量的病毒上清液转导293FT细胞来测定病毒滴度。
原代天然杀伤细胞的分离和培养
从位于胡丁格的卡罗林斯卡大学医院的血库获得健康供体的白细胞层。该试验方案经当地研究伦理委员会批准。
通过梯度离心，采用淋巴细胞分离剂(Lymphoprep，挪威奥斯陆的Nyegaard 公司)分离外周血单核细胞(PBMC)，用磷酸盐缓冲盐水(PBS，GIBCO公司，美国纽约州格兰德岛)洗涤两次。通过Türk和台盼蓝染料排除法评估细胞计数和存活度。采用NK细胞分离试剂盒(德国科隆的美天旎生物技术公司(Miltenyi Biotec,Cologne,Germany))和AutoMACS仪(美天旎生物技术公司)，根据制造商说明书获得NK细胞。分离后，将NK细胞以1×106个细胞/ml的浓度置于CellGro SCGM(Cellgenix公司)中培养，该CellGro SCGM中补充有10％人AB血清(瑞士巴塞尔的龙沙公司)和1000U/ml rhIL-2(阿地白介素Proleukin，希龙公司)。为了在转导前初始测试细胞因子刺激(图1)，使用了浓度为20ng/ml的IL-12(美国新泽西州洛基山的派罗科技公司(Peprotech))、IL-15(派罗科技公司)和IL-21(派罗科技公司)。其余试验中，仅使用1000U/ml rhIL-2和20ng/ml IL-21。
天然杀伤细胞的慢病毒转导
对于各次慢病毒转导，将NK细胞以0.25×106个/孔接种在24孔板(BD生物科学公司)中，并在8μg/ml硫酸鱼精蛋白(Sigma-Aldrich公司)或聚凝胺 (Sigma-Aldrich公司)的存在下，以不超过1ml的最终体积与适量的病毒上清液混合。补充细胞因子，并在室温下以1000×g对板离心1小时。离心后，不去除病毒上清液，将板在37℃、5％CO2中孵育4～6小时。孵育结束时，在室温下以1000×g进行第二次离心，然后从孔中分离上清液，在每孔中加入1ml新鲜NK 细胞生长培养基(补充有10％人AB血清的(CellGro SCGM)。将细胞保持在该培养基中，每日加入细胞因子(IL-2：1000U/ml，IL-21：20ng/ml)。如图1所示使用细胞因子的组合。其余试验仅使用IL-2和IL-21至少3天，然后进行eGFP表达采集。在所示试验中，在转导中存在以下抑制剂：BX795(Invivogen公司) 和奥索恩诺(iX)(Tocris公司)。
NK92细胞系的慢病毒转导
为了转导细胞系，将细胞以2×105个细胞/孔接种至24孔板。在转导过程的同时，开始用6μM BX795和奥索恩诺(iX)处理。将适合量的病毒上清液和硫酸鱼精蛋白(NK92，细胞)加入孔中，将总体积调整到500μl。将板以1000×g离心1小时，然后在37℃、5％CO2中孵育4～6小时，随后去除包含病毒的上清液，加入新鲜生长培养基。使细胞生长至少3天，然后测定eGFP表达。
基因编辑
最近提出的用于基因编辑的成簇规律间隔性短回文重复(CRISPR)系统具有克服这些限制的潜能。CRISPR技术采用固定化的核酸酶(通常为获自酿脓链球菌的CRISPR相关蛋白9，Cas9)和短引导RNA(gRNA)来将该核酸酶靶向特定 DNA序列。我们确认了通过引入iX抑制剂可提高gRNA识别并由此提高编辑效力。采用相应的Amaxa试剂盒和细胞特异性程序，使用Nucleofector II仪器，用 Cas9-2A-GFP和gRNA编码质粒转染人原代巨噬细胞、CD34+HSC和NK92细胞系(将VAPA-1003用于CD34+HSC，将VAPA-1008用于巨噬细胞，将VVPA-1005用于NK92细胞)，根据制造商的说明书进行操作，除了在一半组中，我们在生产商的转染试剂中加入1uM iX。
针对β2微球蛋白测试了从Origene科技公司市售购得的如下引导RNA：GATGTCTCGCTCCGTGGCCT(Seq.ID No.1)；CTCGCGCTACTCTCTCTTTC (Seq.1D No.2)；GACTCACGCTGGATAGCCTC(Seq.ID No. 3)；CCAGAAAGAGAGAGTAGCGC(Seq.ID No.4)CACAGCTAAGGCCACGGAGC(Seq.ID No.5)； GGCCGAGATGTCTCGCTCCG(Seq.ID No.6)；TTGCGGGAGCGCATGCCTTT (Seq.ID No.7)；CCACCTCTTGATGGGGCTAG(Seq.ID No.8)；ATACCTTGGGTTGATCCACT(Seq.ID No.9)；CGTGAGTAAACCTGAATCTT (Seq.ID No.10)；AAGTCAACTTCAATGTCGGA(Seq.ID No.11)； CATAGATCGAGACATGTAAG(Seq.ID No.12)；GCTACTCTCTCTTTCTGGCC(Seq.ID No.13)；ACCCAAACCAAGCCTTTCTA (Seq.ID No.14)；和TATAAGTGGAGGCGTCGCGC(Seq.ID No15)。转染后48 小时，用抗B2M抗体(克隆：2M2，Bi01egend公司)对细胞进行染色以比较β2m 表达的损失。然后如下所述采用流式细胞术分析细胞。
流式细胞术
根据如下方案进行用于流式细胞术的所有抗体染色：对于表面染色，用 PBS洗涤细胞一次，与适合量的抗体在4℃孵育30分钟。然后用PBS洗涤标记的细胞，并用1％PFA固定，然后采集数据。数据采集在FACSCalibur(BD生物科学公司)、CyFlow ML(德国明斯特的Partec公司(Partec GmbH))和LSRII-Fortessa (BD生物科学公司)上采用标准过滤器进行。用FlowJo软件(TreeStar公司)分析数据。用于NK细胞的抗体是CD56(NCAM16.2)、CD56(B159)、CD3(SK7)、 CD3(SP34-2)，购自BD生物科学公司。
结果和讨论
对胞内先天免疫传感(innate immune sensor)途径的抑制增强NK细胞中的慢病毒基因递送效率
我们已发现先天免疫传感介导的病毒载体检测组分在NK细胞中活化抗病毒应答，从而对慢病毒转导效率产生不良影响。我们在慢病毒转导过程中成功地利用先天免疫信号传导的小分子抑制剂使得该抗病毒应答失效或减少。
如我们之前所报道(Sutlu等，2012)，采用BX795显著地提高了NK细胞中的转导效率。BX795是TBK1/IKKε复合物的抑制剂，该复合物作为RIG-I、MDA-5 和TLR3信号传导途径中的通用介导物起作用(Clark等，2009)。因此，可能可以如此认为：慢病毒RNA被一个或多个此类受体所识别并由此引发了抗病毒应答，而该过程可通过使用BX795来抑制。
在此，我们显示了与使用BX795相比，采用TAK1抑制剂iX增强慢病毒基因向NK细胞递送的程度更大。在慢病毒转导过程中采用6μM浓度的iX时，其在向人原代NK细胞和人NK细胞系NK-92的基因递送中均提供了统计学上的显著性改善(图1)。
综上所述，这些结果支持了如下的假设：在转导过程中，胞内抗病毒防御机制被活化并且是NK细胞抵抗慢病毒基因修饰的重要因素。使用小分子抑制剂抑制该应答显著增强了基因递送效率。
我们已显示iX在造血干细胞、巨噬细胞和NK细胞中提高基因编辑效力。用1μM水平的iX进行短时测试在三种细胞类型中均显著提高了β2M编辑。结果总结在图7中(n＝4)。
iX对NK细胞显示剂量依赖性效果且毒性最小
对不同浓度iX的测试显示该抑制剂(如之前用BX795所示)在NK细胞中对提高基因修饰效率具有剂量依赖性效果(图2A)。对于iX，虽然在0.5μM浓度时已观察到显著效果，该效果随浓度增加而进一步提高，直到1.5μM之后效果才趋于稳定。与BX795相比，iX在较低剂量的表现更佳，且增强慢病毒基因递送效率的程度明显更高。
值得注意的是，在BX795处理后用膜联蛋白-V/PI染色测定显示，采用最适浓度的iX对NK细胞并无直接毒性作用。与DMSO对照相比，在1.5μM的最适剂量下，iX对NK细胞没有显著毒性。在1.5μM时，BX795类似地不显示毒性，但在6μM的最适浓度时，在培养基中的凋亡和死亡细胞增加，增加虽小但统计学上具有显著性。相反，iX即便是在6μM的浓度时也未显示出对NK细胞的直接毒性。
综上所述，这些结果表明iX不仅就增强慢病毒基因递送效率而言比BX795 更有效，且对细胞的毒性明显更低。
iX处理在慢病毒基因递送过程中下调RIG-I和IRF3
为了更好地表征先天免疫信号传导抑制剂在慢病毒转导过程中的效果，我们分析了病毒RNA传感分子RIG-I以及在其下游作用的转录因子IRF3的表达。在6小时的转导过程之后未检测到这些基因的表达变化，但在24小时时观察到因采用BX795和iX而导致的RIG-I和IRF3表达显著减少。
此外，我们还观察到与使用BX795相比，使用iX时RIG-I和IRF3的下调程度明显更大。这或许可以解释为何iX增强慢病毒基因递送的作用优于BX795。
慢病毒基因递送过程中的iX处理抑制了IFNγ和TNF应答
为了进一步表征iX引发优异慢病毒基因递送背后的机理，我们在BX795和 iX存在下测试了接触慢病毒颗粒时细胞因子介导的应答。在慢病毒基因递送过程中用iX处理NK92细胞，在6h时就能显著减少抗病毒细胞因子IFNγ的分泌，而BX795则在接触慢病毒颗粒24h之后才能显著引发类似的效果(图4)。此外，在相同的设定下，对于另一抗病毒细胞因子TNF也观察到了类似的趋势(图4)。总之，在慢病毒递送过程中采用iX优于采用BX795，这可能是由于RIG-I途径及其下游信号传导分子IRF-3失效，从而导致危险信号(即抗病毒细胞因子)的分泌减少(图4)。
iX和BX795的基因表达谱差异
在存在或不存在小分子抑制剂的情况下，通过识别慢病毒进入所引发的途径对RNAseq所得基因表达谱进行评估。如前所述转导NK-92细胞。在6小时转导方案结束时，提取来自细胞的RNA，在HiSeq 2500测序仪上进行测序。在质控之后，采用STAR比对软件将读取结果定位到人类基因组，用HT-Seq估算基因丰度。采用DeSeq软件分析差异表达。简而言之，用iX和BX795预处理导致不同的mRNA谱(图5)。此外，与之前的体外试验一致，在慢病毒基因递送过程中用iX处理影响了与抗病毒应答相关的途径，例如TNF、IFN和模式识别途径(图6E-H)，而BX795则未能在mRNA水平上完全抑制相似的抗病毒应答(图6A-D)。
实施例2：体内给予
虽然由于iX本身对胞内RNA识别途径具有抑制效果、且可能导致不可控的病毒感染易感性提高而并不推荐，iX能以0.2～6mM的血清浓度用于体内基因递送。可采用本领域中已知的技术，通过注射、口服、鼻腔或黏膜递送给予iX。 iX潜在的治疗应用包括癌症、肝基因治疗、单基因异常、贮积症和肿瘤再定位基因(tumor retargeting gene)。
可用本发明治疗的癌症包括癌、肉瘤、淋巴瘤、白细胞和母细胞瘤：急性淋巴细胞白血病(all)、急性髓细胞性白血病、肾上腺皮质癌、艾滋病相关癌症、肛门癌、星形细胞癌、基底细胞癌、肝外胆管癌(胆管癌)、膀胱癌、骨肿瘤(骨肉瘤/ 恶性纤维性组织细胞瘤)、脑干神经胶质瘤、脑癌、脑星状细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视觉途径和下丘脑胶质瘤、乳腺癌、支气管腺瘤/类癌、伯基特淋巴瘤、中枢神经系统淋巴瘤、宫颈癌、软骨肉瘤、慢性淋巴细胞性白血病、慢性髓细胞性白血病、慢性骨髓增殖性疾病、结肠癌、皮肤T细胞淋巴瘤、促纤维组织增生性小圆细胞肿瘤、子宫内膜癌、室管膜细胞瘤、食道癌、尤因肉瘤、眼内黑色素瘤、视网膜母细胞瘤、胆囊癌、胃(胃部) 癌、胃肠道类癌肿瘤、胃肠道间质瘤(gist)、颅外或性腺外或卵巢生殖细胞肿瘤、妊娠性滋养层细胞瘤、脑干胶质瘤、儿童脑星形细胞瘤胶质瘤、毛细胞白血病、头部颈部癌、心脏癌、肝细胞(肝)癌、霍奇金淋巴瘤、眼内黑色素瘤、胰岛细胞癌 (内分泌胰腺)、卡波西肉瘤、肾癌(肾细胞癌)、急性成淋巴细胞白血病(也称急性淋巴细胞性白血病)、急性髓细胞性白血病(也称急性骨髓性白血病)、慢性淋巴细胞性白血病、慢性骨髓性白血病(也称慢性髓细胞性白血病)、毛细胞白血病、唇部和口腔癌、脂肪肉瘤、非小细胞肺癌、小细胞肺癌、巨球蛋白血症、瓦尔登斯特伦病
男性乳腺癌、恶性骨纤维性组织细胞瘤/骨肉瘤、成神经管细胞瘤、黑色素瘤、眼内(眼部)黑色素瘤、默克尔细胞瘤、间皮瘤、转移性鳞状颈癌伴隐蔽性原发口腔癌、多发性内分泌肿瘤综合症、多发性骨髓瘤/浆细胞肿瘤、蕈样真菌病、骨髓增生异常综合症、骨髓增生异常/骨髓增殖性疾病、慢性骨髓性白血病、急性髓样白血病、骨髓性白血病、多发性骨髓瘤(骨髓的癌症)、骨髓增殖性疾病、粘液瘤、鼻腔和鼻旁窦癌、鼻咽癌、成神经细胞瘤、非小细胞肺癌、少突神经胶质瘤、口腔癌、口咽癌、骨肉瘤/恶性骨纤维性组织细胞瘤、卵巢癌、卵巢上皮癌(表面上皮-间质肿瘤)、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤、胰腺癌、胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞癌、松果体星状细胞癌、松果体生殖细胞癌、松果体母细胞癌和幕上原始神经外胚层肿瘤、脑垂体腺瘤、浆细胞癌/多发性骨髓瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、软组织肉瘤、子宫肉瘤、Sézary综合症、黑色素瘤和非黑色素瘤皮肤癌、默克尔细胞皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状颈部癌伴隐蔽性原发胃癌、幕上原始神经外胚层肿瘤、T细胞淋巴瘤(蕈样真菌病和sézary综合症)、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行细胞癌、滋养细胞肿瘤、输尿管和肾盂移行细胞癌、尿道癌、子宫癌、子宫肉瘤、阴道癌、视觉通路和下丘脑神经胶质瘤、外阴癌、瓦尔登斯特伦巨球蛋白血症、维尔姆斯瘤(肾癌)。
本发明也可用于治疗遗传疾病，例如：21-羟化酶缺陷、软骨发育不全症、急性间歇性卟啉症、腺苷酸琥珀酸裂解酶缺陷、肾上腺脑白质失养症、阿拉吉耶综合症、亚力山大病、
综合症、釉质发生不全、生物素酶缺陷、CGD 慢性肉芽肿病、先天性胸腺萎缩综合症(Di George's syndrome)、范可尼贫血、 G6PD缺陷、脂蛋白脂肪酶缺陷、肌肉营养不良、由PHF8基因中的突变引起的邓肯型赛德李斯X连锁精神发育迟缓综合征、X染色体连锁重度联合免疫缺陷病(X-SCID)或X-连锁铁粒细胞性贫血(XLSA)。
可用本发明治疗的代谢疾病包括：尼曼-匹克氏病(Niemann-Pick disease)、泰伊-萨克斯二氏病(Tay-Sachs disease)、高雪氏病(Gaucher disease)、法布里病 (Fabrydisease)。
实施例3：过继细胞转移
在最优选的使用中，将iX用于处理细胞，然后将过继细胞转移给患者。采用如上所述的方案，可在离体操作过程中的任何时间使用iX。iX在培养基中的优选浓度为约0.4mM～约10mM。更优选为0.5mM～6mM。可用本领域中熟知的方案，立即输注这些细胞或先冷冻再以后输注。可以单剂量或重复在体内和离体施用iX，所用剂量窗为该抑制剂的血清浓度为0.4～6uM，优选较低的剂量。该过继细胞转移可用于治疗如上实施例2中所述的病症。
实施例4：病毒性炎症的治疗
本发明还可用于治疗患有病毒感染引起的炎症(如肌肉炎、心肌炎、病毒性关节炎、病毒性脑炎和脑膜炎)的患者。针对这些疾病时，iX可与抗病毒治疗共同给予以减少或停止免疫系统对病毒的识别，从而减轻、防止或消除炎症。这仅能与不依赖于或不完全利用免疫应答的抗病毒治疗一起使用。这类抗病毒剂包括：金刚烷抗病毒物质，如金刚烷胺(amandatind)和金刚乙胺；抗病毒增效剂，如利托那韦和可比司他；趋化因子受体拮抗剂，如马拉维诺；整合酶链转移抑制剂，如马拉维诺、度鲁特韦和埃替格韦；混合抗病毒物质，如索菲布韦、恩夫韦肽、膦甲酸和福米韦生；神经氨酸酶抑制剂，如帕拉米韦、奥司他韦和扎纳米韦；非核苷逆转录酶抑制剂(NNRTI)，如法韦伦(favirenz)、奈韦拉平、地拉夫定、依曲韦林和利匹韦林；NS5a抑制剂，如达卡他韦；核苷逆转录酶抑制剂(NRTI)，如齐多夫定、地达诺新、司他夫定、拉米夫定、阿巴卡韦、恩曲他滨和恩替卡韦；蛋白酶抑制剂，如沙奎那韦、利托那韦、茚地那韦、奈非那韦、安普那韦、洛匹那韦、阿扎那韦、福沙那韦、替拉那韦和地瑞那韦；以及，嘌呤核苷物质，如利巴韦林、伐昔洛韦、泛昔洛韦、阿昔洛韦、更昔洛韦、缬更昔洛韦和西多福韦。这些药物单独和联用的剂量说明在本领域中是熟知的。
实施例5：提高RNA病毒治疗的体内效力
本发明体内给予时还可用于提高基于RNA病毒的溶瘤病毒疗法的体内效力，例如水疱性口炎病毒、脊髓灰质炎病毒、呼肠孤病毒、塞内卡病毒、ECHO 病毒如Rigvir病毒，其适应症可为例如膀胱癌、脑肿瘤、妇科肿瘤、肝细胞癌、黑色素瘤、多发性骨髓瘤、前列腺癌、软组织肉瘤和实体瘤。iX可有助于抑制胞内抗病毒防御机制，由此提高肿瘤内溶瘤病毒分布效力。体内给予iX的目标血清水平为0.2～6mM。
***
因此，虽然描述了目前据信为本发明的优选实施方式，但本领域技术人员应理解，也可使用其它和进一步的实施方式而不背离本发明的精神，且意在包括所有落入本文权利要求的真实范围内的进一步改变和变化。
参考文献
Alici,E.,Sutlu,T.,和Sirac Dilber,M.(2009).Retroviral gene transferinto primary human natural killer cells(“逆转录病毒转移入原代人天然杀伤细胞”). Methods Mol Biol 506,127-137.
Brandstadter,J.D.,和Yang,Y.(2011).Natural killer cell responses toviral infection(“天然杀伤细胞对病毒感染的应答”).J Innate Immun 3,274-279.
Clark,K.,Plater,L.,Peggie,M.,和Cohen,P.(2009).Use of thepharmacological inhibitor BX795to study the regulation and physiologicalroles of TBK1and IkappaB kinase epsilon:a distinct upstream kinase mediatesSer-172phosphorylation and activation(“利用药理学抑制剂BX795研究TBK1 和IκB激酶ε(介导Ser-172磷酸化和活化的独特上游激酶)的调节和生理作用”). J Biol Chem284,14136-14146.
Lanier,L.L.(2008).Evolutionary struggles between NK cells and viruses(“NK细胞和病毒间的进化斗争”).Nat Rev Immunol 8,259-268.
Pegram,H.J.,Kershaw,M.H.,和Darcy,P.K.(2009).Genetic modification ofnatural killer cells for adoptive cellular immunotherapy(用于过继细胞免疫疗法的天然杀伤细胞的基因修饰).Immunotherapy 1,623-630.
Sutlu,T.,Nystrom,S.,Gilljam,M.,Stellan,B.,Applequist,S.E.,和Alici,E.(2012).Inhibition of intracellular antiviral defense mechanisms augmentslentiviral transduction of human natural killer cells:implications for genetherapy(抑制胞内抗病毒防御机制促进人天然杀伤细胞的慢病毒转导：对基因治疗的影响).Hum Gene Ther 23,1090-1100.
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Claims (27)
1.一种增强向细胞的基因递送的体外方法，所述方法包括向营养培养基中的细胞共同给予奥索恩诺(5Z)-7-Oxozeaenol和RNA病毒载体，其中，所述细胞选自天然杀伤细胞、干细胞和巨噬细胞，其中，所述RNA病毒载体选自：逆转录病毒载体和慢病毒载体。
2.如权利要求1所述的方法，其中，所述载体是逆转录病毒载体。
3.如权利要求1所述的方法，其中，所述载体是慢病毒载体。
4.如权利要求1所述的方法，其中，所述细胞是造血干细胞。
5.如权利要求1所述的方法，其中，所述细胞是天然杀伤细胞。
6.如权利要求1所述的方法，其中，所述细胞是NK92细胞。
7.如权利要求1所述的方法，其中，奥索恩诺抑制所述细胞的胞内防御机制。
8.如权利要求7所述的方法，其中，通过给予有效量的奥索恩诺抑制RIG-I和/或IRF3的表达。
9.如权利要求7所述的方法，其中，所述抑制针对处于RIG-I和/或IRF3下游的路径。
10.如权利要求1所述的方法，其中，奥索恩诺的给予量足以在所述营养培养基中获得0.5 μM～6 μM的浓度。
11.一种制备适用于患者的过继细胞转移治疗的细胞的离体方法，所述方法包括用一定量奥索恩诺处理所述细胞，所述奥索恩诺的量有效抑制胞内防御机制，并共同给予递送基因的RNA病毒载体，其中，所述细胞选自天然杀伤细胞、干细胞和巨噬细胞，且其中，所述RNA病毒载体选自：逆转录病毒载体和慢病毒载体。
12.如权利要求11所述的方法，其中，所述方法抑制了RIG-I和/或IRF3在所述细胞中的表达。
13.如权利要求12所述的方法，其中，奥索恩诺在培养基中的浓度为0.4 mM～10 mM。
14.如权利要求13所述的方法，其中，奥索恩诺在培养基中的浓度是0.5 mM～6 mM。
15.如权利要求11所述的方法，其中，所述细胞适用于癌症的过继细胞转移治疗。
16.如权利要求15所述的方法，其中，所述癌症为肿瘤。
17.如权利要求15所述的方法，其中，所述癌症选自：肉瘤、淋巴瘤和白血病。
18.如权利要求15所述的方法，其中，所述癌症为母细胞瘤。
19.如权利要求15所述的方法，其中，所述癌症选自肝癌、多发性骨髓瘤或肉瘤。
20.如权利要求15所述的方法，其中，所述癌症是肝癌。
21.如权利要求15所述的方法，其中，所述癌症是多发性骨髓瘤。
22.如权利要求15所述的方法，其中，所述癌症是肉瘤。
23.如权利要求11所述的方法，其中，所述细胞适用于由基因突变导致的疾病的过继细胞转移治疗。
24.如权利要求23所述的方法，其中，所述疾病选自：21-羟化酶缺陷、软骨发育不全症、急性间歇性卟啉症、腺苷酸琥珀酸裂解酶缺陷、肾上腺脑白质失养症、阿拉吉耶综合症、亚力山大病、Alström综合症、釉质发生不全、生物素酶缺陷、CGD慢性肉芽肿病、先天性胸腺萎缩综合症、范可尼贫血、G6PD缺陷、脂蛋白脂肪酶缺陷、肌肉营养不良、由PHF8基因中的突变引起的邓肯型赛德李斯X连锁精神发育迟缓综合征、X染色体连锁重度联合免疫缺陷病或X-连锁铁粒细胞性贫血。
25.如权利要求24所述的方法，其中，所述疾病是X染色体连锁重度联合免疫缺陷病。
26.如权利要求23所述的方法，其中，所述疾病是由已知基因突变导致的代谢疾病。
27.如权利要求26所述的方法，其中，所述代谢疾病选自：尼曼-匹克氏病、泰伊-萨克斯二氏病、高雪氏病、法布里病。
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| CN109722437B (zh) * | 2018-12-29 | 2020-01-07 | 广州百暨基因科技有限公司 | 一种通用型car-t细胞及其制备方法和用途 |
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