Gene therapy for chronic granulomatous disease and leukocyte adhesion deficiency

W. S. Goebel, A. Kume, M. C. Dinauer

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Recent advances in molecular genetics have identified gene defects responsible for a variety of primary leukocyte dysfunctions, and genetic correction of these disorders has been envisioned with the advent of somatic gene transfer. Much of the work aimed at molecular therapy for inherited leukocyte disorders has focused on chronic granulomatous disease (CGD) and leukocyte adhesion deficiency type 1 (LAD-1). CGD patients lack the nicotinamide dinucleotide phosphate (NADPH) oxidase enzyme complex required for the production of reactive oxygen intermediates in phagocytes. The absence of phagocyte oxidants causes recurrent infections and inflammatory granulomas in affected patients, which can be associated with significant morbidity and mortality. Patients with LAD-1 are deficient in the β2 integrins, which are required for leukocytes to bind to vascular endothelium and transmigrate to the site of infection, as well as for leukocyte activation by the complement fragment C3. Consequently, patients with LAD-1 also suffer from recurrent, often life-threatening infections. Allogeneic bone marrow transplantation (BMT) can cure these disorders, but transplant-related toxicity and lack of matched donors have limited its wider use. Recently, CGD and LAD-1 have emerged as promising candidates for gene therapy targeted at the hematopoietic system. CGD mouse models have been developed by gene disruption, and preclinical studies on these animals using recombinant retroviral vectors have demonstrated reconstitution of functionally normal neutrophils and increased resistance against pathogens such as Aspergillus, B. cepacia and S. aureus. Current human phase I clinical studies in CGD patients have yet to produce clinically beneficial numbers of corrected neutrophils for extended periods. CD18-deficient mice also have been developed, but the animals do not precisely mirror the human LAD-1 phenotype. Thus far, preclinical studies of LAD-1 gene therapy have been limited to in vitro studies with patient cells.

Original languageEnglish (US)
Pages (from-to)359-372
Number of pages14
JournalInternational Journal of Pediatric Hematology/Oncology
Volume7
Issue number5-6
StatePublished - Dec 1 2001

Keywords

  • Chronic granulomatous disease (CGD)
  • Gene therapy
  • Leukocyte adhesion deficiency type 1 (LAD-1)

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Cancer Research

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