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AAV5-凝血因子Ⅷ转基因治疗重度血友病A
AAV5–Factor VIII Gene Transfer in Severe Hemophilia A


Savita Rangarajan ... 其他 • 2017.12.28
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• 第59届美国血液学会年会报告——良性血液病 • 因子Ⅸ缺乏型血友病的基因治疗 • 采用高特异性活性因子Ⅸ变体的血友病B基因疗法

摘要


背景

血友病A患者依赖外源性凝血因子Ⅷ,以防止关节、软组织和中枢神经系统出血。尽管对血友病B患者成功实施的基因转移治疗已有报道,但对于血友病A患者而言,由于因子Ⅷ的编码区较大,基因治疗的结局尚未得到改善。

 

方法

我们对B结构域删除的人因子Ⅷ进行了密码子优化,使用了编码该因子Ⅷ的腺相关病毒血清型5(AAV5)载体(AAV5- hFⅧ-SQ),再对9例男性重度血友病A患者实施单剂静脉输注。研究共分小、中、大三个剂量队列,参与者序贯纳入三个队列中的一个(小剂量队列1例,中剂量队列1例,大剂量队列7例)。对参与者进行52周的随访。

 

结果

小剂量和中剂量接受者的因子Ⅷ活性水平维持在3 IU/dL或更低。大剂量队列中的全部7例参与者在基因转移后第2周和第9周之间,因子Ⅷ活性水平达到5 IU/dL以上,有6例参与者的因子Ⅷ活性升至正常水平(>50 IU/dL),且这一水平在接受单剂输注后1年仍然保持。大剂量队列中既往接受过预防性治疗的参与者,其年出血率中位值从研究开始前的16次出血事件降至基因转移后的1次,而且到第22周时该队列的全部参与者均已不再因参与者报告出血而使用因子Ⅷ。主要不良事件是血清谷丙转氨酶水平升高至正常范围上限的1.5倍或低于1.5倍。唯一的1例严重不良事件是1例参与者原有的慢性关节病出现进展。未检测到因子Ⅷ的中和抗体。

 

结论

输注AAV5-hFⅧ-SQ后,大剂量队列的7例参与者中有6例在一年期间因子Ⅷ活性水平保持正常化,所有这7例患者的止血均已稳定,且因子Ⅷ的使用均大幅减少。这项小型研究中虽然未观察到安全性事件,但是尚不能就安全性得出结论(研究由拜玛林制药[BioMarin Pharmaceutical]资助;ClinicalTrials.gov注册号为NCT02576795;EudraCT注册号为2014-003880-38)。





作者信息

Savita Rangarajan, M.B., B.S., Liron Walsh, M.D., Will Lester, M.B., Ch.B., Ph.D., David Perry, M.D., Ph.D., Bella Madan, M.D., Michael Laffan, D.M., Hua Yu, Ph.D., Christian Vettermann, Ph.D., Glenn F. Pierce, M.D., Ph.D., Wing Y. Wong, M.D., and K. John Pasi, M.B., Ch.B., Ph.D.
From Hampshire Hospitals NHS Foundation Trust, Basingstoke (S.R.), University Hospitals Birmingham NHS Foundation Trust, Edgbaston (W.L.), Cambridge University Hospital NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge (D.P.), and the Centre for Haemostasis and Thrombosis, St. Thomas’ Hospital (B.M.), Imperial College London and NIHR Clinical Research Facility at Imperial College Healthcare NHS Trust (M.L.), and Barts and the London School of Medicine and Dentistry (K.J.P.), London — all in the United Kingdom; and BioMarin Pharmaceutical, Novato (L.W., H.Y., C.V., W.Y.W.), and private consultant, La Jolla (G.F.P.) — both in California. Address reprint requests to Dr. Pasi at the Royal London Hospital Haemophilia Centre, 2nd Fl. Central Tower, Whitechapel, London E1 1BB, United Kingdom, or at k.j.pasi@qmul.ac.uk.

 

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