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Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells
Published on: February 15, 2019
Gene therapy for chronic granulomatous disease
Elizabeth M Kang1, Harry L Malech
1Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Methods in Enzymology
|February 28, 2012
Summary
Gene therapy using autologous stem cells offers a life-saving treatment for patients with Chronic Granulomatous Disease (CGD) who have severe infections and lack a donor. This approach successfully restored immune function in two out of three patients, resolving infections.
Area of Science:
- Immunology
- Hematology
- Gene Therapy
Background:
- Chronic Granulomatous Disease (CGD) results from mutations in phagocyte NADPH oxidase, leading to recurrent infections.
- Hematopoietic stem cell (HSC) transplantation can cure CGD but is limited by donor availability.
- Existing therapies for CGD are often insufficient for patients with severe, untreatable infections.
Purpose of the Study:
- To evaluate the safety and efficacy of ex vivo autologous HSC gene transfer as a salvage therapy for X-linked CGD (X-CGD) patients with life-threatening infections.
- To assess the long-term durability of gene marking and oxidase function following gene therapy.
- To determine the clinical benefit of gene therapy in CGD patients lacking a suitable HSC donor.
Main Methods:
- Three patients with X-CGD and incurable infections received nonmyeloablative busulfan conditioning followed by infusion of autologous HSCs genetically modified with an amphotropic MFGS-gp91phox retroviral vector.
- Gene marking and oxidase function in circulating neutrophils were assessed post-transduction.
- Clinical outcomes, including infection resolution, blood counts, and bone marrow examinations, were monitored long-term.
Main Results:
- Successful gene marking and oxidase function correction were observed in circulating neutrophils (24%, 5%, and 4% in the three subjects).
- Two of the three patients achieved complete resolution of infections and maintained gene marking for at least 5 years, with 0.7% and 0.03% oxidase-normal neutrophils, respectively.
- One patient lost gene marking early and succumbed to infection; the surviving patients showed normal blood counts and bone marrow exams without evidence of clonal dominance.
Conclusions:
- Ex vivo autologous HSC gene therapy can provide life-saving clinical benefit as a salvage treatment for severe, infection-prone CGD patients lacking a suitable donor.
- The study demonstrates the potential for sustained immune function restoration and infection resolution through gene therapy in CGD.
- Future directions include developing lentiviral vectors and exploring gene-targeting strategies with induced pluripotent stem cells for next-generation CGD gene therapy.
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