Gene therapy for primary immunodeficiency
- Francisco A Bonilla, MD, PhD
Francisco A Bonilla, MD, PhD
- Section Editor — Immunology and Immunodeficiency
- Associate Professor of Pediatrics
- Harvard Medical School
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  and autologous cell gene correction . 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].
- Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Gene therapy for primary immunodeficiencies. Immunol Allergy Clin North Am 2010; 30:237.
- Pessach IM, Notarangelo LD. Gene therapy for primary immunodeficiencies: looking ahead, toward gene correction. J Allergy Clin Immunol 2011; 127:1344.
- Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Gene therapy for primary adaptive immune deficiencies. J Allergy Clin Immunol 2011; 127:1356.
- Kuo CY, Kohn DB. Gene Therapy for the Treatment of Primary Immune Deficiencies. Curr Allergy Asthma Rep 2016; 16:39.
- Hu H, Gatti RA. New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals. Curr Opin Allergy Clin Immunol 2008; 8:540.
- Chang CW, Lai YS, Westin E, et al. Modeling Human Severe Combined Immunodeficiency and Correction by CRISPR/Cas9-Enhanced Gene Targeting. Cell Rep 2015; 12:1668.
- Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol 2008; 15:375.
- Qasim W, Gaspar HB, Thrasher AJ. Update on clinical gene therapy in childhood. Arch Dis Child 2007; 92:1028.
- Cavazzana M, Six E, Lagresle-Peyrou C, et al. Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand? Hum Gene Ther 2016; 27:108.
- Ylä-Herttuala S. ADA-SCID Gene Therapy Endorsed By European Medicines Agency For Marketing Authorization. Mol Ther 2016; 24:1013.
- Cicalese MP, Ferrua F, Castagnaro L, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 2016; 128:45.
- De Ravin SS, Wu X, Moir S, et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 2016; 8:335ra57.
- Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993; 73:147.
- Notarangelo LD, Giliani S, Mella P, et al. Combined immunodeficiencies due to defects in signal transduction: defects of the gammac-JAK3 signaling pathway as a model. Immunobiology 2000; 202:106.
- Thrasher AJ, Hacein-Bey-Abina S, Gaspar HB, et al. Failure of SCID-X1 gene therapy in older patients. Blood 2005; 105:4255.
- Chinen J, Puck JM. Perspectives of gene therapy for primary immunodeficiencies. Curr Opin Allergy Clin Immunol 2004; 4:523.
- Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002; 346:1185.
- Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M. Gene therapy of X-linked severe combined immunodeficiency. Int J Hematol 2002; 76:295.
- Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 2004; 364:2181.
- Chinen J, Davis J, De Ravin SS, et al. Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency. Blood 2007; 110:67.
- Hacein-Bey-Abina S, Hauer J, Lim A, et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010; 363:355.
- Hacein-Bey-Abina S, Pai SY, Gaspar HB, et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014; 371:1407.
- Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008; 118:3132.
- "The Pink Sheet". Gene therapy trial clinical hold will be topic of FDA, NIH meetings. January 20, 2003; 65:7.
- Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 2003; 3:477.
- The American Society of Gene Therapy is a non-profit medical, scientific, and professional organization devoted to the research and development of therapies that involve the introduction of genetic material and/or cells into the body to treat or prevent disease. Resources include news releases regarding reported side effects in gene therapy trials. www.asgt.org/ (Accessed on January 06, 2009).
- Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348:255.
- Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302:415.
- McCormack MP, Rabbitts TH. Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2004; 350:913.
- Woods NB, Bottero V, Schmidt M, et al. Gene therapy: therapeutic gene causing lymphoma. Nature 2006; 440:1123.
- Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 2009; 360:447.
- Rans TS, England R. The evolution of gene therapy in X-linked severe combined immunodeficiency. Ann Allergy Asthma Immunol 2009; 102:357.
- Vassilopoulos G, Trobridge G, Josephson NC, Russell DW. Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors. Blood 2001; 98:604.
- Throm RE, Ouma AA, Zhou S, et al. Efficient construction of producer cell lines for a SIN lentiviral vector for SCID-X1 gene therapy by concatemeric array transfection. Blood 2009; 113:5104.
- Moiani A, Paleari Y, Sartori D, et al. Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts. J Clin Invest 2012; 122:1653.
- Cesana D, Sgualdino J, Rudilosso L, et al. Whole transcriptome characterization of aberrant splicing events induced by lentiviral vector integrations. J Clin Invest 2012; 122:1667.
- Thrasher AJ, Goldman J, de Alwis M, et al. Gene therapy for primary immunodeficiency. Biochem Soc Trans 1997; 25:537.
- ID bases are locus-specific databases for immunodeficiency-causing mutations. The aim of the website is to establish database for every immunodeficiency or provide links to those maintained elsewhere. http://bioinf.uta.fi/base_root/ (Accessed on January 06, 2009).
- Lai CH, Chun HH, Nahas SA, et al. Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc Natl Acad Sci U S A 2004; 101:15676.
- Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447:87.
- Dietz HC. New therapeutic approaches to mendelian disorders. N Engl J Med 2010; 363:852.
- Du L, Pollard JM, Gatti RA. Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides. Proc Natl Acad Sci U S A 2007; 104:6007.
- Urnov FD, Miller JC, Lee YL, et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 2005; 435:646.
- van Deutekom JC, Janson AA, Ginjaar IB, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 2007; 357:2677.
- GENE THERAPY
- X-linked SCID
- Adenosine deaminase deficiency
- Chronic granulomatous disease
- Other disorders
- Limitations of gene therapy
- MUTATION-TARGETED THERAPY
- Nonsense mutations
- Splice-site mutations
- Frameshift mutations
- Missense and in-frame mutations
- SOCIETY GUIDELINE LINKS