Arduini Ariana, Katiyar Harshita, Liang Chen
Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada.
Viruses. 2025 May 31;17(6):802. doi: 10.3390/v17060802.
Lentiviral vectors (LVs) have become a fundamental tool in gene therapy due to their unique ability to transduce both dividing and non-dividing cells, transfer large genes of up to 10 kb, and facilitate stable, long-term expression of therapeutic genes into target cells. A key application of LVs is the ex vivo genetic modification of patient-derived cells, such as the production of CAR-T cells by transducing isolated T cells with LVs to express the CAR gene, enabling them to target and destroy cancer cells once infused back into the patient. However, these ex vivo gene therapy drugs are often dismally unaffordable due to the complex procedures involved, including cell isolation, genetic modification, and expansion, along with the significant risks associated with immune conditioning to ensure successful engraftment. To overcome these barriers, direct in vivo transgene delivery to physiologically relevant cells has been explored, bypassing the need for ex vivo manipulations and reducing costs. Yet, a major challenge in this approach is engineering LV cell tropism to ensure the precise targeting of specific cells while avoiding off-target effects. Recent advances in modifying LV surface proteins have shown promise, including the successful in vivo generation of CAR T cells and ensuing clinical trials. This review is aimed at providing an up-to-date account of the progress in engineering LV tropism, covering the utility of different heterologous viral envelopes and their engineering to achieve cell-type-specific delivery and host immune evasion, and highlighting the potential of in vivo gene therapy to improve the affordability and accessibility of life-saving treatments.
慢病毒载体（LVs）已成为基因治疗中的一种基本工具，因为它们具有独特的能力，能够转导分裂细胞和非分裂细胞，转移长达10 kb的大基因，并促进治疗性基因在靶细胞中稳定、长期表达。LVs的一个关键应用是对患者来源的细胞进行体外基因改造，例如通过用LVs转导分离的T细胞来表达CAR基因，从而生产CAR-T细胞，使它们在重新注入患者体内后能够靶向并摧毁癌细胞。然而，由于涉及细胞分离、基因改造和扩增等复杂程序，以及与免疫预处理相关的重大风险以确保成功植入，这些体外基因治疗药物往往价格高得令人望而却步。为了克服这些障碍，人们探索了将转基因直接体内递送至生理相关细胞的方法，从而绕过了体外操作的需求并降低了成本。然而，这种方法的一个主要挑战是改造LV细胞嗜性，以确保精确靶向特定细胞，同时避免脱靶效应。修饰LV表面蛋白的最新进展已显示出前景，包括在体内成功生成CAR T细胞以及随后的临床试验。本综述旨在提供关于改造LV嗜性进展的最新情况，涵盖不同异源病毒包膜的效用及其工程改造以实现细胞类型特异性递送和宿主免疫逃避，并强调体内基因治疗在提高挽救生命治疗的可负担性和可及性方面的潜力。
