Willem-Alexander Children's Hospital, Department of Pediatrics, Pediatric Stem Cell Transplantation Program and Laboratory for Pediatric Immunology.
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.
Curr Opin Allergy Clin Immunol. 2023 Dec 1;23(6):467-477. doi: 10.1097/ACI.0000000000000952. Epub 2023 Oct 13.
Provide an overview of the landmark accomplishments and state of the art of gene therapy for inborn errors of immunity (IEI).
Three decades after the first clinical application of gene therapy for IEI, there is one market authorized product available, while for several others efficacy has been demonstrated or is currently being tested in ongoing clinical trials. Gene editing approaches using programmable nucleases are being explored preclinically and could be beneficial for genes requiring tightly regulated expression, gain-of-function mutations and dominant-negative mutations.
Gene therapy by modifying autologous hematopoietic stem cells (HSCs) offers an attractive alternative to allogeneic hematopoietic stem cell transplantation (HSCT), the current standard of care to treat severe IEI. This approach does not require availability of a suitable allogeneic donor and eliminates the risk of graft versus host disease (GvHD). Gene therapy can be attempted by using a viral vector to add a copy of the therapeutic gene (viral gene addition) or by using programmable nucleases (gene editing) to precisely correct mutations, disrupt a gene or introduce an entire copy of a gene at a specific locus. However, gene therapy comes with its own challenges such as safety, therapeutic effectiveness and access. For viral gene addition, a major safety concern is vector-related insertional mutagenesis, although this has been greatly reduced with the introduction of safer vectors. For gene editing, the risk of off-site mutagenesis is a main driver behind the ongoing search for modified nucleases. For both approaches, HSCs have to be manipulated ex vivo, and doing this efficiently without losing stemness remains a challenge, especially for gene editing.
介绍先天性免疫缺陷（IEI）基因治疗的里程碑式成就和最新技术。
在基因治疗首次应用于 IEI 三十年后，仅有一款产品获得市场许可，而其他一些产品的疗效已在正在进行的临床试验中得到证实或正在测试中。使用可编程核酸酶的基因编辑方法正在进行临床前研究，对于需要严格调控表达、获得功能突变和显性负突变的基因可能具有益处。
通过修饰自体造血干细胞（HSCs）的基因治疗为治疗严重 IEI 的首选方法——异基因造血干细胞移植（HSCT）提供了一种有吸引力的替代方案。这种方法不需要合适的异体供体，并且消除了移植物抗宿主病（GvHD）的风险。可以通过使用病毒载体添加治疗基因的副本（病毒基因添加）或使用可编程核酸酶（基因编辑）来精确纠正突变、破坏基因或在特定基因座引入整个基因副本来尝试基因治疗。然而，基因治疗也存在自身的挑战，如安全性、治疗效果和可及性。对于病毒基因添加，主要的安全问题是载体相关的插入突变，尽管随着更安全载体的引入，这种情况已经大大减少。对于基因编辑，脱靶突变的风险是不断寻找修饰性核酸酶的主要驱动力。对于这两种方法，都需要对 HSCs 进行体外操作，而在不失去干性的情况下高效地进行操作仍然是一个挑战，尤其是对于基因编辑。
