Gene therapy for blood cell diseases with autologous hematopoietic stem cells

Abstract

Gene therapy is under development to treat genetic diseases of blood cells, including primary immune deficiencies (PID), lysosomal storage and related metabolic disorders, and hemoglobinopathies. Based on the experience with allogeneic hematopoietic stem cell (HSC) transplantation to successfully cure these disorders, gene therapy using autologous HSC holds the potential for safer treatments, avoiding immune complications. The key technical challenge is to achieve highly efficient gene correction in HSC, without impairing the long-term reconstituting capacity of the stem cells nor causing genotoxicity by the genetic manipulations. Initial trials using gamma-retroviral vectors showed clinical efficacy for ADA-deficient SCID, X-SCID, X-Chronic Granulomatous Disease and Wiskott-Aldrich Syndrome, although insertional oncogenesis led to leukoproliferative complications in the latter three conditions. Subsequent trials using retroviral or lentiviral vectors from which the long-terminal repeat enhancers are deleted (SIN vectors) have led to further demonstration of efficacy for these PID and no clinical genotoxic events. X-linked Adrenoleukodystrophy was the first disorder approached using lentiviral vectors to transduce HSC and results in have been were equivalent to those with allogeneic HSCT, without GVHD. Autologous HSC gene therapy for Metachromatic Leukodystrophy produced outcomes that were better than those previously observed using allogeneic HSCT, with over-expression of the relevant gene product (arylsulfatase A) leading to cross-correction and clinically meaningful neuroprotection and excellent development outcomes. For hemoglobinopathies, early reports from clinical trials for beta-thalassemia and sickle cell disease indicate some degree of efficacy, although it remains uncertain whether current vector designs yield sufficient beta-globin gene transfer and expression to ameliorate severe forms of the diseases. The potential game-changer in this area is correction of the underlying defective gene in HSC, using site-specific endonucleases (ZFN, TALEN, Meganucleases and CRISPR/Cas9) to augment homology-driven gene repair. There have been rapid advances in this approach, although the frequency of engrafting HSC that are gene-corrected and without off-target effects are not yet up to levels that would be therapeutic for most disorders. One disorder at a time, autologous HSC gene therapy is advancing to provide effective and safe therapies for genetic diseases of blood cells.