摘要
血友病A是一种导致凝血因子VIII(FVIII)缺陷的单基因疾病,适合进行基因治疗。我们的愿望是通过单基因疗法,产生足够的内源性FVIII,以恢复止血和其他生物过程。这可能会产生可靠的保护,防止出血及免受其相关的身体和情绪影响。基因治疗提供了临床相关的疾病表型改善和生活质量包括更自信地参与体育锻炼的机会的变革性改善的可能性。正在进行高级临床开发的血友病A基因治疗产品使用腺相关病毒(AAV)载体和删除B结构域的FVIII转基因优化密码子。然而,不同的基于AAV的基因疗法具有不同的设计特征,如载体衣壳、增强子和启动子区域、FVIII转基因序列和制造工艺的选择。这些反过来又会影响对患者的合格性、安全性和有效性。理想情况下,血友病的基因治疗技术应提供出血保护、持久的FVIII表达、广泛的纳入标准和患者之间有限的应答变异性,以及长期安全性。然而,必须克服若干限制和挑战。在此,我们介绍了BAY 2599023(AAVhu37.hFVIIIco,DTX 201)基因治疗产物,包括抗AAV-hu37抗体在一般人群中的低流行率,以及其他基因治疗AAV产物和方法。我们将带着改善A型血友病患者的生活的终极目标去检验这些产品如何潜在地应对基因治疗的挑战。
关键词: AAV载体,制造,血友病A,基因疗法,治疗格局,凝血因子VIII, BAY 2599023
[http://dx.doi.org/10.1038/d41573-021-00017-7] [PMID: 33495615]
[http://dx.doi.org/10.3389/fgeed.2021.618346] [PMID: 34713249]
[http://dx.doi.org/10.1182/blood-2018-07-820720] [PMID: 30559260]
[http://dx.doi.org/10.1016/j.blre.2021.100890] [PMID: 34736780]
[http://dx.doi.org/10.1111/j.1538-7836.2010.03962.x] [PMID: 20586922]
[http://dx.doi.org/10.4081/hr.2019.7894] [PMID: 31285808]
[http://dx.doi.org/10.7326/M19-1208] [PMID: 31499529]
[http://dx.doi.org/10.1016/j.blre.2019.03.002] [PMID: 30922616]
[http://dx.doi.org/10.1002/ajh.24133] [PMID: 26257191]
[http://dx.doi.org/10.1182/blood-2010-01-264507] [PMID: 21048155]
[http://dx.doi.org/10.3324/haematol.2019.232132] [PMID: 32060150]
[http://dx.doi.org/10.1016/S0140-6736(11)61139-2] [PMID: 22456059]
[http://dx.doi.org/10.1111/j.1538-7836.2011.04214.x] [PMID: 21255253]
[http://dx.doi.org/10.1056/NEJMoa067659] [PMID: 17687129]
[http://dx.doi.org/10.18553/jmcp.2020.20199] [PMID: 32820685]
[http://dx.doi.org/10.1046/j.1365-2141.1999.01463.x] [PMID: 10554828]
[http://dx.doi.org/10.1111/hae.12959] [PMID: 27396935]
[http://dx.doi.org/10.1111/jth.14124] [PMID: 29665204]
[http://dx.doi.org/10.1111/hae.12479] [PMID: 25039669]
[http://dx.doi.org/10.1002/ajh.23957] [PMID: 25616111]
[http://dx.doi.org/10.1080/17474086.2018.1435269] [PMID: 29383965]
[PMID: 30747705]
[PMID: 31846611]
[http://dx.doi.org/10.2147/PPA.S139851] [PMID: 29033555]
[http://dx.doi.org/10.1111/j.1365-2516.2009.02036.x] [PMID: 19493018]
[http://dx.doi.org/10.1111/hae.12905] [PMID: 26930418]
[http://dx.doi.org/10.1182/hematology.2019000007] [PMID: 31808868]
[http://dx.doi.org/10.1016/j.ymthe.2020.12.007] [PMID: 33309881]
[http://dx.doi.org/10.1128/jvi.45.2.555-564.1983] [PMID: 6300419]
[http://dx.doi.org/10.1073/pnas.162250899] [PMID: 12136130]
[http://dx.doi.org/10.1128/JVI.78.12.6381-6388.2004] [PMID: 15163731]
[http://dx.doi.org/10.1128/JVI.00254-08] [PMID: 18400866]
[http://dx.doi.org/10.1016/0042-6822(84)90272-1] [PMID: 6200995]
[http://dx.doi.org/10.1186/1743-422X-10-74] [PMID: 23497173]
[http://dx.doi.org/10.1128/jvi.68.9.5656-5666.1994] [PMID: 8057446]
[http://dx.doi.org/10.1038/s41573-019-0012-9] [PMID: 30710128]
[http://dx.doi.org/10.1016/j.ophtha.2021.03.031] [PMID: 33798654]
[http://dx.doi.org/10.1001/jamaneurol.2021.1272] [PMID: 33999158]
[http://dx.doi.org/10.1111/jth.12412] [PMID: 24118899]
[http://dx.doi.org/10.1038/303530a0] [PMID: 6406906]
[http://dx.doi.org/10.1128/JVI.01056-06] [PMID: 16956943]
[http://dx.doi.org/10.1182/blood-2012-10-460733] [PMID: 23325831]
[http://dx.doi.org/10.1128/JVI.76.20.10497-10502.2002] [PMID: 12239326]
[http://dx.doi.org/10.1128/JVI.80.1.426-439.2006] [PMID: 16352567]
[http://dx.doi.org/10.1016/j.omtm.2020.05.018] [PMID: 32995354]
[http://dx.doi.org/10.1128/JVI.72.2.1438-1445.1998] [PMID: 9445046]
[http://dx.doi.org/10.1038/nature16465] [PMID: 26814968]
[http://dx.doi.org/10.1038/gt.2012.6] [PMID: 22357511]
[http://dx.doi.org/10.1016/j.neures.2014.09.002] [PMID: 25240284]
[http://dx.doi.org/10.1016/j.ymthe.2017.09.021] [PMID: 29055620]
[http://dx.doi.org/10.3324/haematol.2019.221093] [PMID: 31399527]
[http://dx.doi.org/10.1038/312326a0] [PMID: 6438525]
[http://dx.doi.org/10.1021/bi00335a049] [PMID: 2994716]
[http://dx.doi.org/10.1038/312342a0] [PMID: 6438528]
[http://dx.doi.org/10.1182/blood-2005-12-5115] [PMID: 16522813]
[http://dx.doi.org/10.1038/312330a0] [PMID: 6438526]
[http://dx.doi.org/10.1089/hum.1996.7.17-2101] [PMID: 8934224]
[http://dx.doi.org/10.1038/312337a0] [PMID: 6438527]
[http://dx.doi.org/10.1073/pnas.83.16.5939] [PMID: 3016730]
[http://dx.doi.org/10.1182/blood.V81.11.2925.2925] [PMID: 8499631]
[http://dx.doi.org/10.1111/j.1432-1033.1995.tb20776.x] [PMID: 7556150]
[http://dx.doi.org/10.1182/blood-2012-10-462200] [PMID: 23426947]
[http://dx.doi.org/10.1055/s-0037-1612910] [PMID: 11204595]
[http://dx.doi.org/10.1016/j.omtm.2018.01.004] [PMID: 29552578]
[http://dx.doi.org/10.1002/j.1460-2075.1990.tb08184.x] [PMID: 1690125]
[http://dx.doi.org/10.1016/0092-8674(86)90519-2] [PMID: 3779841]
[http://dx.doi.org/10.1089/hum.1996.7.5-637] [PMID: 8845389]
[http://dx.doi.org/10.3390/biomedicines2010080] [PMID: 28548061]
[http://dx.doi.org/10.1089/hgtb.2016.158] [PMID: 28504553]
[http://dx.doi.org/10.1089/hgtb.2013.046] [PMID: 23848282]
[http://dx.doi.org/10.1089/hum.1995.6.10-1329] [PMID: 8590738]
[http://dx.doi.org/10.1089/10430340260355347] [PMID: 12427305]
[http://dx.doi.org/10.1208/s12248-021-00628-3] [PMID: 34529177]
[http://dx.doi.org/10.1128/JVI.74.19.9281-9293.2000] [PMID: 10982375]
[http://dx.doi.org/10.1089/hum.2017.150] [PMID: 28835127]
[http://dx.doi.org/10.1111/hae.13769] [PMID: 31115117]
[http://dx.doi.org/10.1128/JVI.74.20.9451-9463.2000] [PMID: 11000214]
[http://dx.doi.org/10.1128/JVI.75.15.6969-6976.2001] [PMID: 11435577]
[http://dx.doi.org/10.1146/annurev-physiol-021113-170255] [PMID: 25668020]
[http://dx.doi.org/10.1038/nm1549] [PMID: 17369837]
[http://dx.doi.org/10.1016/j.ymthe.2020.06.001] [PMID: 32559433]
[http://dx.doi.org/10.1038/s41467-018-06621-3] [PMID: 30291246]
[http://dx.doi.org/10.1371/journal.pone.0001692] [PMID: 18301769]
[http://dx.doi.org/10.1038/s41591-020-0911-7] [PMID: 32483358]
[http://dx.doi.org/10.1172/jci.insight.139881] [PMID: 32941184]
[http://dx.doi.org/10.1038/s41598-020-57893-z] [PMID: 31965041]
[http://dx.doi.org/10.1038/s41587-020-0741-7] [PMID: 33199875]
[http://dx.doi.org/10.1182/blood-2018-99-118334]
[http://dx.doi.org/10.1111/hae.12592] [PMID: 25582282]
[http://dx.doi.org/10.1172/JCI37607] [PMID: 19587448]
[http://dx.doi.org/10.1038/35047123] [PMID: 11130078]
[http://dx.doi.org/10.1182/blood.2019004625] [PMID: 33067633]
[http://dx.doi.org/10.1038/mtm.2016.64] [PMID: 27738645]
[http://dx.doi.org/10.1038/nm1358] [PMID: 16474400]
[http://dx.doi.org/10.1016/j.ymthe.2020.07.009] [PMID: 32710826]
[http://dx.doi.org/10.1089/hum.2021.29182.bfs] [PMID: 34662231]
[http://dx.doi.org/10.1089/hum.2020.29133.bfs] [PMID: 32945722]
[http://dx.doi.org/10.1038/mtm.2016.63] [PMID: 27738644]
[http://dx.doi.org/10.1038/mt.2016.52] [PMID: 26948440]
[http://dx.doi.org/10.1126/science.1142658] [PMID: 17656716]
[http://dx.doi.org/10.1111/ejh.13339] [PMID: 31606899]
[http://dx.doi.org/10.1055/s-0037-1598058] [PMID: 28264199]
[http://dx.doi.org/10.1056/NEJMoa1708483] [PMID: 29224506]
[http://dx.doi.org/10.1182/blood.2020005683] [PMID: 32915950]
[http://dx.doi.org/10.1089/hum.2018.080] [PMID: 29890905]
[http://dx.doi.org/10.1089/hum.2016.128] [PMID: 28056565]
[http://dx.doi.org/10.1016/j.omtm.2019.08.015] [PMID: 31660419]
[http://dx.doi.org/10.1038/mt.2009.246] [PMID: 19861950]
[http://dx.doi.org/10.1038/mt.2015.179] [PMID: 26412589]
[http://dx.doi.org/10.1016/j.omtm.2019.03.006] [PMID: 31193016]
[http://dx.doi.org/10.1182/blood-2019-123666]
[http://dx.doi.org/10.1111/hae.14391] [PMID: 34378280]
[http://dx.doi.org/10.3390/jcm10112471] [PMID: 34199563]
[http://dx.doi.org/10.1182/blood-2021-148651]
[http://dx.doi.org/10.1056/NEJMoa2104205] [PMID: 34788507]
[http://dx.doi.org/10.1086/595830] [PMID: 19133809]
[http://dx.doi.org/10.1111/hae.14056] [PMID: 32537776]
[http://dx.doi.org/10.1038/nbt.2623] [PMID: 23792628]
[http://dx.doi.org/10.3389/fcell.2021.672564] [PMID: 34485274]
[http://dx.doi.org/10.2147/PPA.S239810] [PMID: 32368018]
[http://dx.doi.org/10.1182/bloodadvances.2018021345] [PMID: 30042145]
[http://dx.doi.org/10.1111/hae.14015] [PMID: 32462720]
[http://dx.doi.org/10.1016/j.blre.2020.100759] [PMID: 33183859]
[http://dx.doi.org/10.1038/s41467-020-20096-1] [PMID: 33293538]
[http://dx.doi.org/10.1111/hae.14027] [PMID: 32490590]