Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hematology Am Soc Hematol Educ Program. 2012;2012:375-81. doi: 10.1182/asheducation-2012.1.375.
Since the isolation and characterization of the genes for FVIII and FIX some 30 years ago, a longstanding goal of the field has been development of successful gene therapy for the hemophilias. In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno-associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of > 2 years. This review discusses obstacles that were overcome to reach this goal and the next steps in clinical investigation. Safety issues that will need to be addressed before more widespread use of this approach are discussed. Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed.
自 30 年前 FVIII 和 FIX 基因的分离和鉴定以来，该领域的一个长期目标一直是成功开发治疗血友病的基因疗法。在 2011 年发表的一项具有里程碑意义的研究中，Nathwani 等人证明，6 名接受表达因子 IX 的腺相关病毒 (AAV) 载体静脉输注的重度血友病 B 男性患者的疾病已成功转为轻度或中度。这些 6 名受试者现在已经表现出 FIX 的表达水平在正常水平的 1%到 6%之间，持续时间超过 2 年。本文讨论了为实现这一目标而克服的障碍以及临床研究的下一步。讨论了在更广泛地应用这种方法之前需要解决的安全性问题。还讨论了将 AAV 介导的基因疗法扩展到血友病 A 的努力，以及对于可能不适合肝脏基因转移的严重肝脏疾病患者可能有用的替代方法。
