Research review paperThe approved gene therapy drugs worldwide: from 1998 to 2019
Introduction
As early as 1972, the concept of gene therapy for human diseases was put forward clearly by Theodore Friedmann and Richard Roblin after Stanfield Rogers came up with the use of ‘good’ deoxyribonucleic acid (DNA) to replace defective DNA as a treatment for inherited disease in 1970 (Athanasopoulos et al., 2017; Friedmann and Roblin, 1972). Gene therapy could radically treat the causes of monogenic disorders and other genetically defined diseases by regulating the malfunctioning genes (Gruntman and Flotte, 2018; Hanna et al., 2017; High and Roncarolo, 2019). The United States (U.S.) Food and Drug Administration (FDA) defined that gene therapy was a technique that modified a person’s genes to treat or cure disease and that gene therapy could work by several mechanisms: i) replacing a disease-causing gene with a healthy copy of the gene; ii) inactivating a disease-causing gene that was not functioning properly; iii) introducing a new or modified gene into the body to help treat a disease (FDA, 2019a). Meanwhile, the FDA defined that human gene therapy sought to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use (FDA, 2019b). Gene therapy drugs, regarded as a revolution in the health sciences and pharmaceutical fields, were pharmaceutical products approved by drug regulatory agencies for treatment, prevention or diagnosis in the clinical practice of gene therapy (Gruntman and Flotte, 2018; Hanna et al., 2017). Gene therapy drugs were also biological medicinal products which were administered as nucleic acids, lipid complexes, viruses, or genetically engineered micro-organisms for a therapeutic, prophylactic or diagnostic effect (EMA, 2019a; Goswami et al., 2019). Therefore, the worldwide approved plasmid DNAs, anti-sense oligonucleotides, small interfering RNA (siRNA)-lipid complex, viruses, and genetically engineered cellular therapy products were summarized as gene therapy drugs in this review.
Section snippets
Summary of approved gene therapy drugs
The death of Jesse Gelsinger in 1999 shocked the entire gene therapy field, and gene therapy fell into a trough in the early 2000s due to its safety issues, especially in U.S. and Europe (Friedmann, 2004; Wilson, 2009). However, four gene therapy drugs were approved before 2010, and three of them were authorized to treat cancers in Asia.
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The FDA approved the first drug of gene therapy in 1998 which was named Vitravene (Fomivirsen) (Stein and Castanotto, 2017). Vitravene was a kind of antisense
Naked plasmids
Gene therapy had emerged as a novel approach to increase revascularization in patients with CLI caused by peripheral artery disease (Forster et al., 2018; Shimamura et al., 2014). Although viral vectors showed high efficiency of gene transfer, viral vectors-mediated gene transfer of proangiogenic factors (for example, vascular endothelial growth factor, VEGF) induced hemangioma formation in murine hearts (Sanada et al., 2015; Shimamura et al., 2014). Moreover, hemangioma formation was also
A non-viral vector loading RNAi drug
RNAi was an endogenous mechanism for post-transcriptional regulation of gene expression (Adams et al., 2018; Fellmann and Lowe, 2014). siRNA is a class of double-stranded RNA molecules with typically 20-22 nucleotides in length (Bernstein et al., 2001; Fellmann and Lowe, 2014; Fitzgerald et al., 2014). After binding to the RNA-induced silencing complex, siRNA enabled gene silencing by the cleavage of target mRNA (Adams et al., 2018; Chavez-Pena and Kamen, 2018). Therefore, siRNA had been
Viral vectors
The virus was first used as a gene vector for human gene therapy because it exhibited good infection efficiency and had the potential for permanent expression in target cells in vitro and in vivo (Keeler et al., 2017). Even now, viral vectors were still the mainstream tools for human cellular and gene therapy products (Dunbar et al., 2018). Viral vectors occupied the first place in the clinical trials of gene therapy, and more than 70% of gene therapy programs employed viral vectors (Ginn et
Patient-derived (autologous) cellular gene therapy products
Cell therapy represented the most recent phase of the biotechnology revolution in medicine (Mount et al., 2015). Cell therapy, also termed cellular therapy or cytotherapy, was a therapy in which intact and living cells were used to regenerate the biological function of damaged tissue or organs (Gage, 1998; Golchin and Farahany, 2019). FDA defined that patient-derived cellular gene therapy products are cells removed from the patient, genetically modified (often using a viral vector) and then
Conclusions and perspectives
Gene therapy represents the most recent advances of the biotechnology revolution in medicine. In the past half century, gene therapy has been promptly absorbing almost all advanced biotechnologies to develop promising gene therapy drugs for human use. Since 1998, twenty-two gene therapy drugs including naked nucleic acids, a non-viral vector, viral vectors and cell-mediated gene therapy products have been approved for treatment of human diseases (Fig. 7). These gene therapy drugs definitely
Declaration of CompetingConflict of interest
The authors have no conflict of interest to declare.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (grant number 81602699); the National Natural Science Fund for Distinguished Young Scholar (grant number 31525009); the National High-Tech R&D Program of China (grant numbers 2015AA020309, 2014AA020708); the Sichuan Science and Technology program (grant numbers 2018GZ0311, 2019YFG0266); the China Postdoctoral Science Foundation funded project (grant number 2015M570791); the Salubris Academician Workstation
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These authors contributed equally to this work.