please revise the following text (for submission): Introduction: Gene Therapy

Gene therapy (GT) is a revolutionary approach to treating genetic diseases by targeting and correcting genetic mutations. It encompasses the introduction of genomic sequences in human cells to treat disease. This is mostly achieved by autologous transplant of CD34+ modified stem cells extracted from a patient. Corrected stem cells regenerate and promote expansion of progenitors. The two main GT approaches include gene addition (GA), entailing the exogenous delivery of a desired gene into the genome, whereas gene editing (GE) involves correction of a mutated gene. GA typically utilizes integrating viral vectors, mainly gamma retroviral (gRv) or lentiviral (Lv) vectors, which serve as a ‘delivery vehicle’ for the gene of interest. The viral vector enables its survival within the cell, integrate in the genome delivering an extra-copy of the functional gene of interest, and ultimately facilitating its constitutive expression.

GT is particularly attractive in the field of inborn errors of immunity (IEIs). There are currently over 500 IEIs, the vast are monogenic genetic defects, predisposing affected individuals to life-threatening infections, autoimmunity and lymphoproliferation. In many IEIs, the definitive therapy remains hematopoietic stem cell transplantation (HSCT). However, HSCT holds significant risks such as graft vs host disease (GvHD), and lower survival rates in the absence of a human leukocyte antigen (HLA)-matched donor. 

Indeed, clinical trials that have pioneered the way toward safer and more efficacious GT trials were conducted in patients with IEI. The first human GT was conducted in 1990, in two patients with adenosine deaminase (ADA) deficiency, causing Severe Combined Immunodeficiency (SCID), characterized by lack of all lymphocyte subsets (T-B-NK- SCID) as well as extra-hematopoietic manifestations such as lung, liver, and CNS which are not amenable to correction by hematopoietic stem cell transplantation (HSCT). Autologous T-cells were transduced ex-vivo with a gRv containing cDNA of ADA. Corrected CD8+ T-cells persisted, but the SCID was not corrected. In 1999 twenty X-SCID patients were treated with GT using gamma retrovirus (gRv). X-SCID, caused by mutation in IL2RG encoding the common gamma chain is the most common cause of SCID worldwide, characterized as T-B+NK- phenotype. T-cell engraftment was retained and X-SCID was the first disease corrected by GT. Additional non-SCID IEIs have been treated with gene addition, such as Wiskott-Aldrich (WAS) patients, Chronic Granulomatous Disease (CGD), Leukocyte Adhesion Defect and others. However, setbacks due to insertional oncogenesis were observed. Six X-SCID patients developed T-cell malignancies 2-14 years post-GT as a result of the integration of the inserted genes in the vicinity of oncogenes LIM-domain only protein 2 (LMO-2) and G1/S-specific cyclin D2 (CCND2). The enhancer located in the 5’ untranslated region (LTR) caused their transactivation ultimately leading to leukemo- and lymphoma-genesis. 6 WAS patients developed T-cell malignancies and myelodysplastic features due to transactivation of LMO2 and MECOM. As a result, self-inactivating (SIN) viral vectors were developed in which the enhancer was deleted, including second generation gRvs and LVs, which have been proven to be safer. Altogether, over 400 patients were treated with GT utilizing gene addition during the past three decades, most of them with IEI, as well as metabolic disorders, hemoglobinopathies, and bone marrow failure syndromes. The generation of safer and more potent vectors have increased the efficacy and application of GT.