英国伦敦皇家医院K. John Pasi课题组取得一项新突破。他们的研究对AAV5-hFVIII-SQ基因治疗血友病A进行了多年随访。相关论文于2020年1月2日发表在《新英格兰医学杂志》上。

腺相关病毒（AAV）介导的基因治疗可作为血友病A患者的一种潜在治疗选择。

研究组报告了15例严重血友病A（因子VIII水平每分升≤1 IU）成人接受不同剂量AAV5-hFVIII-SQ单次输注的持久疗效、长期安全性和临床及生物学结果，并进行了长达3年的随访。

输注3年后，经显色分析评估，有2名受试者的因子VIII表达低于每分升1 IU。7名受试者的因子VIII表达中位值为每分升20 IU，出血事件年化中值为0，外源因子VIII输注次数中位值从每年138.5次减少到0次。所有靶关节出血事件均得到解决。输注2年后，6名受试者的因子VIII表达中位值为每分升13 IU，出血事件年化中值为0，因子VIII输注次数中位值从每年155.5次减少到0.5次。6名受试者中有5名靶关节出血症状消失。

因子VIII的药效学特征反映了血液中的细胞更替和分子事件导致体外DNA稳定持续表达，这一发现与之前两个模型系统中的观察结果一致。转基因人凝血因子VIII（hFVIII）蛋白的活性反映了hFVIII的止血能力。在患者的肝功能试验中均未观察到抑制剂发展、血栓形成、死亡或持续变化。

综上，采用AAV5-hFVIII-SQ载体对血友病A患者进行基因治疗，可获得持续的临床益处，具体表现为出血事件的年化发生率显著降低，部分受试者可完全停止预防性因子VIII的治疗。

附：英文原文

Title: Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A

Author: K. John Pasi, M.B., Ch.B., Ph.D.,, Savita Rangarajan, M.B., B.S.,, Nina Mitchell, M.B., B.Chir.,, Will Lester, M.B., Ch.B., Ph.D.,, Emily Symington, M.B., B.S.,, Bella Madan, M.D.,, Michael Laffan, D.M.,, Chris B. Russell, Ph.D.,, Mingjin Li, M.Sc.,, Glenn F. Pierce, M.D., Ph.D.,, and Wing Y. Wong, M.D.

Issue&Volume: 2020-01-01

Abstract:

BACKGROUND

Adeno-associated virus (AAV)–mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.

METHODS
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.

RESULTS
Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.

CONCLUSIONS
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. 

DOI: 10.1056/NEJMoa1908490

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1908490