![]() ![]() 8 The interrupted trials were therefore allowed to reopen, pending the case-by-case re-evaluation of the risk/benefit ratio for every study and the appropriate revision of the monitoring plans and of the information provided to prospective patients before obtaining informed consent. Following a temporary hold on gene therapy trials using retroviral vectors to transduce hematopoietic stem cells, the US Food and Drug Administration and the NIH Recombinant DNA Advisory Committee judiciously concluded that this pair of SAEs did not constitute ground for the cessation of gene therapy investigation. 7 These two SAEs imposed a re-evaluation of the safety concerns associated with gene transfer and of the risk benefit ratio of gene therapy in the context of SCID as well as other diseases. 6 The consternation brought upon by this serious adverse event (SAE), which shook the medical community and the concerned regulatory agencies, was compounded, but also mitigated, when a second case was reported 6 months later – in the same trial. ![]() This reassuring point of view was challenged last year when the first-ever case of iatrogenic malignant transformation was reported in a gene therapy patient treated for X-linked severe combined immune deficiency (SCID). 5 Based on these experimental data, gene therapists and their patients have justifiably assumed that the risk of insertional oncogenesis would be very low. 4 Yet, there have been extremely few reports documenting insertional oncogenesis in rodent, dog and non-human primate gene transfer studies. 1, 2, 3 The earliest analyses of the therapeutic potential of gene transfer have thus recognized the risk of insertional oncogenesis as inherent to the use of integrating vectors. The propensity of transposable elements to induce experimental tumors in animals has long been exploited to study the genetic basis of cancer. The acquisition of the malignant phenotype may follow tumor suppressor gene inactivation, typically a recessive event, or oncogene trans-activation, which is likely to exert a dominant effect. The gravest concern associated with such mutations is the risk of cell transformation. Whether it involves an integrating virus, a transposable element, a replication-defective viral vector or plasmid DNA, the ectopic chromosomal integration of DNA is a mutagenic event that may disrupt chromatin or gene structure, thereby altering gene transcription, regulation and/or coding sequences. Insertional mutagenesis is an unavoidable consequence of the transposition of genetic material. ![]()
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