Guest editorial: recent progress in gene therapy

Abstract

After the occurrence of leukemia owing to insertional mutagenesis following hematopoietic stem cell gene therapy for severe immunodeficiencies using retroviral vectors, clinical trials of gene therapy remained stagnant for many years. However, clinical gene therapy has been revived because a number of successful clinical trials have been reported recently. For example, gene therapy of Leber’s congenital amaurosis, Parkinson’s disease, and hemophilia B, showed adeno-associated virus (AAV) vectors were safe and clinically effective gene delivery vehicles. AAV vectors can transduce non-dividing, terminally differentiated cells efficiently, and long-term transgene expression can be obtained after single gene transfer. Another superior gene delivery vector is the lentiviral vector, which was successfully used for hematopoietic stem cell gene therapy of X-linked adrenoleukodystrophy. Even in the case of classical hematopoietic stem cell gene therapy of severe immunodeficiencies, safety was much improved using selfinactivating retroviral vectors. Regarding cancer gene therapy, targeting technology is important to improve its efficacy. In this regard, there has been increasing focus on chimeric antigen receptor (CAR) technology when using engineered T cell therapy for hematological malignancies. CD19-targeted CAR-T gene therapy has had surprising clinical efficacy against chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this ‘‘Progress in Hematology’’ issue, four excellent review articles [1–4] cover recent topics in the field of gene therapy. The first two articles deal with targeted cancer gene therapy, i.e., CAR technology [1] and mesenchymal stem cells (MSCs) with tumor-homing ability [2]. The third article describes gene therapy for hemophilia B [3], which is considered one of the best targets for AAV vectormediated gene therapy. The last article discusses hematopoietic stem cell gene therapy, the most representative and classical gene therapy for treatment of genetic diseases [4]. Davila et al. [1] provide a review on adoptive immunogene therapy using CAR-expressing T cells for hematological malignancies. Recent clinical trials of CD19-targeted CAR-T gene therapy revealed this therapeutic strategy is promising for the treatment of relapsed/refractory B cell malignancies, including CLL, ALL, and nonHodgkin lymphoma (NHL). Interestingly, robust and rapid anti-leukemia activity of CAR-T cells was observed in patients with B-ALL, while outcomes have been more modest in patients with CLL or NHL. Davila et al. also discuss the application of CAR technology for the treatment of multiple myeloma and acute myeloid leukemia. Another interesting targeting technology is the use of MSCs that accumulate at tumor sites. Uchibori et al. [2] reviewed the characteristics of MSCs and their potential as cellular vehicles for targeted cancer gene therapy. Since MSCs themselves may support tumor growth, genetical manipulation such as the addition of cytokine genes or suicide genes is required to provide them with anti-cancer activity. This review also discusses the molecular K. Ozawa (&) Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan e-mail: kozawa@ms2.jichi.ac.jp