Gene therapy for primary immunodeficiencies: current status and future prospects.

[wiskott-aldrich syndrome]

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 .

Diseases
Validation

Diseases presenting "primary immunodeficiencies" symptom

22q11.2 deletion syndrome

junctional epidermolysis bullosa

omenn syndrome

severe combined immunodeficiency

wiskott-aldrich syndrome

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