Editorial [Hot topic: Gene Therapy Continues to Make Progress: Clinical and Regulatory Perspectives (Guest Editors: Maria G. Castro and Pedro R. Lowenstein)]

Gene therapy, defined as the use of genetic elements to treat diseases, is increasingly being used, with more than 1,300 clinical trials approved during the last decade [1]. These trials involve direct gene transfer into the target affected tissues, or the use of in vitro genetically engineered and expanded bone marrow stem cells. Deadly diseases such as adenosine deaminase deficiency (ADA) [2, 3], chronic granulomatous disease [4], and X-linked severe combined immunodeficiency (X-SCID) [5-7] have been successfully treated using autologous bone marrow cells transduced with retroviral vectors encoding the mutated genes. In spite of the biochemical, immunological, and clinical improvements in patient's lives, the development of leukemia in 5 out of 20 treated patients in the SCID-X1 gene therapy trials, involving the use of CD34+ autologous bone marrow cells transduced with retrovirus encoding the common γ-chain of cytokine receptors, called into question the overall safety of this therapeutic approach [8, 9]. It was later demonstrated that the development of leukemia in these patients was due to the insertion of the therapeutic gene in the vicinity of the LMO2 oncogene, and the unopposed growth advantage of transduced cells [10]. Importantly, out of the 5 patients who developed leukemia, one died in spite of treatment for leukemia, and 4 were in remission following chemotherapy, with a reconstituted immune system as a result of gene therapy. Thus, out of 20 patients who would have otherwise been restricted to life in a sterile bubble, 19 are able to have a normal life or a 95% success rate in an otherwise incurable disease. Since in the overall majority of the treated patients, the leukemia was successfully treated with chemotherapy, this highlights the tremendous success of gene therapy in treating a deadly disease, albeit at the expense of putative serious but treatable side effects. The events described above highlight the critical importance of very carefully assessing the possible risk vs. benefit ratios before attempting the clinical implementation of a novel therapeutic strategy, and the importance of learning lessons from clinical trials that will surely lead to improved genetic therapies. Another recently very highly publicized trial involved a Phase I-II gene therapy trial for rheumatoid arthritis [11] utilizing tgAAC94, adeno-associated vector (AAV), in which one of the patients enrolled in the trial died. Although the death was initially suspected to be potentially related to gene therapy, detailed investigations concluded that the most likely cause of death was disseminated, recrudescent fungal infection with Histoplasma capsulatum [12]. As these investigations regarding the details surrounding this patient's death unraveled, a number of questions were posed, i.e., should this patient have been enrolled in this trial given the substantial immunosuppressive treatment this patient was receiving to control her disease, were the inclusion-exclusion criteria sufficiently stringent, was the risk vs. benefit ratio properly evaluated, were the channels of communication between all parties involved appropriate? Curiously however, the fact that the gene therapy was being developed to selectively treat the affected joints, without having to expose patients to the very high incidence of serious adverse events caused by the systemic immune suppressants needed, was mostly missed by all reports.