Gene therapy on the move

Abstract

The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders.

Keywords: clinical trials; iPS; monogenic disorders; stem cell therapy; viral vectors.

Figure 1. In vivo and ex vivo gene therapy concepts

For the in vivo application of gene-based drugs, the therapeutic gene is introduced directly into the body (e.g. muscle, liver) of the patient, while for ex vivo applications, patient cells are first isolated from the body, genetically modified outside the body and reintroduced into the patient as an autologous transplant (see text for details). BM, bone marrow.

Figure 2. Haematopoiesis and main diseases in focus of ex vivo HSC gene therapy

The haematopoietic stem cell (HSC) has the ability to give rise to all terminally differentiated haematopoietic effector cells by passing through various intermediate precursor stages. Lineage fate is determined mainly by cytokine profiles which drive development from multipotent progenitors (MPP) to either oligopotent committed lymphoid or myeloid progenitors (CLP and CMP, respectively). CLP eventually provide mature B- and T-lymphocytes, natural killer (NK) cells and dendritic cells (DC). DC can also descend from the myeloid lineage. CMP give rise to megakaryocyte–erythrocyte progenitors (MEP) and granulocyte–monocyte-progenitor (GMP) eventually resulting in either erythrocytes (Ery) and platelet-producing megakaryocytes (Mk) or monocytes (M) and the different entities of granulocytes (G), respectively (adapted from Doulatov et al, 2012). Primary immunodeficiencies (PID) discussed in the text (black) can manifest at several of these stages as indicated, resulting in defects affecting only certain cell types or in complete absence of an entire lineage branch. Gene-transfer in HSC also offers cell replacement or cross-correction of storage diseases of the brain, e.g. due to invading monocytes differentiating into microglia.

Figure 3. HSC gene therapy timeline

History of gene therapy and the milestones that contributed to the implementation of gene therapy for monogeneic disorders using haematopoietic cells (adapted from Appelbaum, ; Wirth et al, 2013). Milestones in HSCT are highlighted in light blue whereas major contributions in the field of gene transfer are coloured violet. Although no haematological disorder can be treated with Glybera® (dark blue), its market approval is a milestone for the entire field of gene therapy. BMT, bone marrow transplantation; disease abbreviations as in the text.

Figure 4. Proposed concept of designer nuclease-mediated correction of patient-specific iPSC for autologous transplantation

Patient-specific iPSC can be generated from somatic cells (e.g. fibroblasts, blood cells) and reprogrammed into pluripotent stem cells as discussed in the text. Targeted gene correction can be mediated via either zinc-finger nucleases (ZFN), transcription activator like effector nucleases (TALEN) or RNA guided-nucleases of patient-derived cells either before or after reprogramming to iPSC. Disease-corrected somatic cells can be derived from the iPSC and reintroduced into the patient as an autologous transplant.