Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects

Abstract

Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous 'natural' genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID--current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed.

Primary immunodeficiencies: a decade of shifting paradigms, the current status and the emergence of cutting-edge therapies and diagnostics

“…This difference may be explained by delayed transplantation in non-SCID versus immediate Diagnosis & treatment of primary immunodeficiencies Review informahealthcare.com transplantation in SCID patients shortly after diagnosis. Serious adverse events after transplantation, including prolonged steroid resistance, steroid-dependent GVHD and overwhelming infections during the immunocompromised state of posttransplantation before full immune reconstitution, may be observed in those who do not have a well-matched donor or present with pre-existing comorbidities [90].…”

“…Clinical gene therapy approaches rely on ex vivo manipulation and re-infusion of engineered HSCs and integration of an additional copy (or copies) of cDNA delivered by viral vectors [90]. In vivo experiments indicated that the severity of some diseases could be attenuated by genetic corrections.…”

“…Transient benefit from autologous gene-modified CD34 + stem cells has been reported. However, long-term persistence of corrected neutrophils has not been established [90].…”

“…Lentiviral-mediated correction is being used in studies and could replace poor donor-matched allogeneic HSCT [90].…”

Genetisch modifizierte Zellen zur Therapie verschiedener Erkrankungen

“…B. Lymphozyten) das eingeschleuste Gen tragen und exprimieren. Die Modifizierung von HSCs ist daher ein besonders erfolgversprechender Gentherapieansatz.Tatsächlich wird dieser Ansatz zur Behandlung einer ganzen Reihe von Erbkrankheiten angewendet [1,2]. Das Vorgehen ist dabei immer ähnlich: Aus dem Knochenmark oder aus Apheresematerial des Patienten werden die CD34-positiven HSCs isoliert, mit einem Zytokincocktail stimuliert, ex vivo mithilfe eines integrierenden Vektors genetisch modifiziert und dann in den Blutkreislauf des Patienten (gegebenenfalls nach angemessener Konditionierung) reinfundiert.…”