Abstract
Lentiviral vectors are the most frequently used tool to stably transfer and express genes in the context of gene therapy for monogenic diseases. The vast majority of clinical applications involves an ex vivo modality whereby lentiviral vectors are used to transduce autologous somatic cells, obtained from patients and re-delivered to patients after transduction. Examples are hematopoietic stem cells used in gene therapy for hematological or neurometabolic diseases or T cells for immunotherapy of cancer. We review the design and use of lentiviral vectors in gene therapy of monogenic diseases, with a focus on controlling gene expression by transcriptional or post-transcriptional mechanisms in the context of vectors that have already entered a clinical development phase.
Highlights
Replication-defective retroviral vectors have been used as a convenient tool for efficient and stable gene transfer in human cells for almost three decades
This type of strategy has been applied to the design of gene expression cassettes for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by mutations in the CYBB gene encoding the gp91phox catalytic subunit of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, a crucial gene for the function of monocyte-macrophages
lentiviral vectors (LVs) have proven their safety and efficacy as flexible gene delivery vectors in clinical applications of gene therapy for genetic diseases. Their ability to transduce both dividing and non-dividing cells and to integrate in the transduced cell genome offers the unique possibility of inserting and expressing therapeutic genes in tissues or organs maintained by dividing stem and progenitor cells, such as blood, skin, microglia or liver
Summary
Replication-defective retroviral vectors have been used as a convenient tool for efficient and stable gene transfer in human cells for almost three decades now. Genetically modified cells represent “medicinal products”, produced under good manufacturing practices (GMP) and clinically developed under the same phased scheme used for conventional drugs The first of this class of products, Strimvelis® , received marketing authorization in Europe in 2016 for the treatment of patients with severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID). A number of seminal clinical studies addressing primary immunodeficiencies [7,8,9,10], hemoglobinopathies [11,12], stem cell deficiencies [13] and neurometabolic diseases [14,15,16,17] proved the therapeutic efficacy and safety of lentiviral vectors, which eventually allowed the commercial registration of Zynteglo® for gene therapy of β-thalassemia (https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo, accessed on 1 August 2021) and Libmeldi® for metachromatic leukodystrophy (MLD).
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