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A型血友病患者AAV基因转移后可持续表达因子VIII
作者:小柯机器人 发布时间:2021/11/22 13:21:10

美国费城儿童医院Lindsey A. George团队研究了A型血友病AAV基因转移后因子VIII的多年表达情况。该项研究成果发表在2021年11月17日出版的《新英格兰医学杂志》上。

对A型血友病患者进行基因治疗的目的是通过使用尽可能低的载体剂量安全、长期稳定地表达因子VIII,并前瞻性地改善出血。

在这项临床1-2期试验中,研究组输注了一种实验性腺相关病毒(AAV)载体(SPK-8011),以检测18例A型血友病患者的肝细胞中VIII因子的表达。共纳入4个剂量组;最低剂量组每千克体重接受5×1011载体基因组(vg),最高剂量组每千克体重接受2×1012vg。一些参与者在给药后52周内服用糖皮质激素,以预防或治疗假定的AAV衣壳免疫反应。试验目标包括评价SPK-8011的安全性和初步疗效,以及因子VIII的表达和持久性。

中位安全性观察期为36.6个月。8名参与者共发生33起治疗相关不良事件;17起与载体相关,包括1起严重不良事件,16起与糖皮质激素相关。由于抗AAV衣壳细胞免疫反应对免疫抑制不敏感,两名参与者失去了所有因子VIII的表达。在剩下的16名参与者中,因子VIII的表达保持不变;其中12名参与者的随访时间超过2年,1期因子VIII分析显示因子VIII活性随时间没有明显下降(当受试者未服用糖皮质激素时,26至52周时因子VIII活性为正常值的12.9%,而在载体给药后>52周时为正常值的12.0%)。受试者的年化出血率降低了91.5%,从给药前每年8.5次出血事件降低至给药后每年0.3次。

研究结果表明,在接受SPK-8011治疗的18名参与者中,有16名参与者持续表达VIII因子,可暂停预防治疗,并减少出血事件。未报告重大安全问题。

附:英文原文

Title: Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

Author: Lindsey A. George, M.D.,, Paul E. Monahan, M.D.,, M. Elaine Eyster, M.D.,, Spencer K. Sullivan, M.D.,, Margaret V. Ragni, M.D., M.P.H.,, Stacy E. Croteau, M.D., M.M.S.,, John E.J. Rasko, M.B., B.S., Ph.D.,, Michael Recht, M.D., Ph.D.,, Benjamin J. Samelson-Jones, M.D., Ph.D.,, Amy MacDougall, B.S.N.,, Kristen Jaworski, M.S.N., F.N.P.,, Robert Noble, Ph.D.,, Marla Curran, Dr.P.H.,, Klaudia Kuranda, Ph.D.,, Federico Mingozzi, Ph.D.,, Tiffany Chang, M.D.,, Kathleen Z. Reape, M.D.,, Xavier M. Anguela, Ph.D.,, and Katherine A. High, M.D.

Issue&Volume: 2021-11-17

Abstract:

Background

The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose.

Methods

In this phase 1–2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5×1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2×1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII.

Results

The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti–AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], 2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration).

Conclusions

Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported.

DOI: 10.1056/NEJMoa2104205

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2104205

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home