Update on Clinical Ex Vivo Hematopoietic Stem Cell Gene Therapy for Inherited Monogenic Diseases

Abstract

Gene transfer into autologous hematopoietic stem progenitor cells (HSPCs) has the potential to cure monogenic inherited disorders caused by an altered development and/or function of the blood system, such as immune deficiencies and red blood cell and platelet disorders. Gene-corrected HSPCs and their progeny can also be exploited as cell vehicles to deliver molecules into the circulation and tissues, including the central nervous system. In this review, we focus on the progress of clinical development of medicinal products based on HSPCs engineered and modified by integrating viral vectors for the treatment of monogenic blood disorders and metabolic diseases. Two products have reached the stage of market approval in the EU, and more are foreseen to be approved in the near future. Despite these achievements, several challenges remain for HSPC gene therapy (HSPC-GT) precluding a wider application of this type of gene therapy to a wider set of diseases while gene-editing approaches are entering the clinical arena.

Keywords: chemotherapy; gene editing; genetic disease; hematopoietic stem/progenitor cells; lentiviral vector; retroviral vector; transplantation.

Graphical abstract

Figure 1

Gene Therapy for Primary Immunodeficiencies Schematic representations of each hematopoietic cell lineage. Blue boxes denote the cell type(s) most affected in the various primary immunodeficiencies. The color of genes indicates approved gene products (red), products under clinical trial (orange), and products in preclinical studies (green). HSC, hematopoietic stem cell; MPP, multilineage progenitor; CMP, common lymphoid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte-erythroid progenitor; GMP, granulocyte-monocyte progenitor; MKB, megakaryoblast; MK, megakaryocyte; RBC, red blood cell; PLT, platelet; Neu, neutrophil; Bas, basophil; Eos, eosinophil; Mono, monocyte; B, B cell; T, T cell; NK, NK cell; nTreg, natural T regulatory cell.

Figure 2

Summary of Representative Conditioning Regimens Preparatory for Gene Therapy and the HSPC Sources Conditioning regimens are designed based on the target disease and gene-corrected chimerism, presence of selective advantage, need for immune suppression, or ablation of resident brain myeloid cells. The first ADA-SCID HSPC-GT trials resulted in low or absent engraftment due to no preconditioning. In the subsequent trials, a minimal dose intensity conditioning with busulfan intravenously (i.v.), corresponding to ∼25% of the standard dose used in allogeneic HSCT (Bu-low), was introduced, allowing good levels of multilineage engraftment of corrected cells. The rationale of combining busulfan at a reduced intensity dose (Bu-medium) and fludarabine (Flu) in the WAS trials was to minimize toxicity and fully exploit the selective growth advantage of gene-corrected cells (role of busulfan), deplete the lymphoid compartment of potentially autoreactive lymphocytes (role of Flu and anti-CD20), and prevent lymphoproliferative disorders due to EBV reactivation (role of anti-CD20). For the LSDs and hemoglobinopathies, a myeloablative dose of alkylating agents (Bu-high or Treo/TT) is required to cross the BBB and obtain high engraftment levels, which is necessary due to the absence of a natural selective advantage for the gene-corrected cells. In the MPS IH trial Flu and anti-CD20 were foreseen to achieve a level of immunosuppression able to reduce or abolish an anti-IDUA B and T cell response that may jeopardize the survival of the gene-modified cells. HSPC collection can be performed through a BM harvest or apheresis from a peripheral vein after mobilization with G-CSF alone or in combination with plerixafor. BBB, brain-blood barrier; BM, bone marrow; Bu, busulfan; Flu, fludarabine; HSCT, hematopoietic stem cell transplantation; LSD, lysosomal storage disease; Treo, treosulfan; TT, thiotepa.