Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Haemophilia. 2014 May;20 Suppl 4:43-9. doi: 10.1111/hae.12411.
After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno-associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV-mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future.
经过许多小型和大型动物血友病模型中基因治疗研究成功的报道后，我们终于在人类患者中看到了成功的初步迹象。这些非常令人鼓舞的结果是使用腺相关病毒（AAV）载体在严重血友病 B 患者中实现的。继这些初步有希望的研究之后，现在有三项正在进行的血友病 B 基因转移的 AAV 介导的临床试验，均旨在从肝脏表达因子 IX 基因。然而，如本文第一节所讨论的，如果要使血友病 B 基因治疗更广泛地应用，仍有许多重大障碍需要克服。本文的第二节涉及与因子 VIII 基因转移相关的挑战。虽然最近在血友病 B 中的结果令人非常鼓舞，但因子 VIII 基因治疗目前尚无类似数据。人们普遍认为，由于多种原因，包括容纳更大的因子 VIII cDNA、实现足够水平的转基因表达以及防止更频繁的抗因子 VIII 免疫并发症，这个治疗靶点将成为一个更大的问题。在文章的最后一节中，讨论了慢病毒载体介导的基因转移的替代方法。虽然 AAV 介导的转基因传递方法在临床血友病基因治疗中处于领先地位，但使用替代传递载体仍具有许多潜在优势，包括体外宿主细胞转导将避免对载体产生免疫反应的可能性。总体而言，血友病基因治疗正处于激动人心的时刻，在不久的将来可能会有更多的临床成功。
