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Gene therapy for primary immunodeficiency

Francisco A Bonilla, MD, PhD
Section Editor
Jennifer M Puck, MD
Deputy Editor
Elizabeth TePas, MD, MS


Gene therapy is one of two modalities with the potential to cure genetic disease [1-4], the other modality being hematopoietic cell transplantation (HCT), which provides to an affected patient healthy, tissue-matched hematopoietic stem cells (HSCs) that will differentiate into mature functional immune cells. The goal of gene therapy trials has been to correct the inherited immune deficiency by introducing a functional copy of the patient's defective gene into the appropriate cells. This has been accomplished by removing HSCs from an affected patient, adding ex vivo a correct gene copy that integrates into chromosomal DNA, and then returning the cells to the patient as an autologous HCT. However, potential alternatives or adjunctive approaches to gene addition therapy or HCT are under development, including mutation-targeted drug treatment [5] and autologous cell gene correction [6]. Pharmacogenetic agents may temporarily or permanently correct genetic mutations at the nuclear level.

Allogeneic HCT and medical therapy of immunodeficiencies are discussed separately. (See "Hematopoietic cell transplantation for primary immunodeficiency" and "Primary immunodeficiency: Overview of management".)


Gene therapy has the potential to cure genetically based diseases. In gene addition therapy, the gene copy must be introduced into a sufficient number of cells and also be adequately expressed for its product to correct the deficiency. Hematopoietic stem cells (HSCs), the blood-forming cells that reside in bone marrow and differentiate into all blood elements, can be targeted for correction for defects in genes whose expression is primarily or exclusively important in developing hematopoietic lineages. Integration of a vector carrying the correct gene copy into the chromosomal DNA is needed to assure that the HSC correction is conferred on future generations of stem cells and their differentiated progeny to effect a permanent cure.

Genetically engineered viruses are the vectors used to carry the DNA of interest into host cells [4,7,8]. Viral genes required for virus propagation are deleted and replaced with a working copy of the human gene of interest. Viral DNA signals cause the DNA to be inserted into the host genome when retroviral or lentiviral vectors are used. Although initial success was more likely with expression of genes that confer a development or survival advantage over untransduced cells, protocols no longer rely on this in vivo selective advantage.

Gene therapy has been complicated by technical difficulties and risks of side effects from genomic manipulation. These barriers to wide application have been intensely researched, leading to safer, more effective therapies that promise to become standard therapies [4,6,9-12].

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Literature review current through: Oct 2017. | This topic last updated: Dec 13, 2016.
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