What is the role of gene therapy in the treatment of pediatric chronic granulomatous disease (CGD)?

Updated: Aug 07, 2019
  • Author: Lawrence C Wolfe, MD; Chief Editor: Cameron K Tebbi, MD  more...
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Answer

Gene therapy for chronic granulomatous disease is attractive for numerous reasons. The exact genetic defect can usually be identified. The cells lacking the functional gene product and their precursors are accessible in blood or bone marrow. Because carriers of X-CGD are rarely symptomatic, unless less than 10% of phagocytes express the normal gene for gp91, stable correction of only 5-10% of circulating phagocytes may be adequate to substantially improve the clinical outcome.

The primary disadvantage of chronic granulomatous disease as a candidate disease for gene therapy is that the gene-modified cells do not have a selective advantage over defective host cells. This is because the phox genes are required only in the terminally differentiated phagocyte.

Published results of gene therapy in chronic granulomatous disease have come from animal studies, in vitro studies of cells derived from human bone marrow, and a reports of adoptive transfer of ex vivo modified cells into human patients. A report in two patients who underwent reduced-intensity transplant conditioning and gene transfer led to improvement in phagocyte superoxide generating activity. [23] Long-term follow up studies are required to document the safety of the gene insertion and the possibility of deleterious effects.

With current techniques, partial temporary correction of the phagocyte defect may be possible as an adjunct to medical therapy of acute or chronic infection. However, durable clinically significant correction of chronic granulomatous disease with gene therapy awaits improved methods for gene transfer, targeting of hematopoietic stem cells, and control of genetic expression. When these problems are solved, safe practical gene therapy will become the treatment of choice for chronic granulomatous disease.


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