Gene Therapy for Primary Immunodeficiency


Primary immunodeficiencies represent a spectrum of disorders characterised by impaired development and function of the immune system with the more severe forms being lethal in infancy. Haematopoietic stem cell transplant is a curative treatment for many of these conditions but is limited by the availability of suitable donors and toxicities associated with cytoreductive chemotherapy and human leucocyte antigen disparity. Gene therapy strategies offer an alternative management option and have been developed for a number of disorders, with clinical trials underway for adenosine deaminase‐deficient‐severe combined immune deficiency (SCID), X‐linked SCID, X‐linked chronic granulomatous disease and Wiskott–Aldrich Syndrome. Initial trials using gammaretroviral vector‐mediated gene transfer showed impressive efficacy but were complicated by vector insertion driven leukaemia in some patients. Newer designs using modified vectors are likely to have an improved safety profile and the results of ongoing clinical trials may pave the way for gene therapy as a feasible management option for some children with PIDs.

Key Concepts:

  • In gene therapy, a patient's own haematopoietic stem cells are harvested, transduced with a viral vector containing a corrected copy of the defective gene and then returned to the patient.

  • A gene therapy procedure can be curative for patients with specific forms of severe combined immune deficiency (SCID), namely adenosine deaminase‐deficient SCID (ADA‐SCID) or X‐linked SCID.

  • Gene therapy also potentially offers definitive treatment for some non‐SCID PIDs including CGD and WAS although clinical trials are at early stages and those performed using gammaretroviral vectors offered only transient clinical benefit, if any.

  • Owing to the nature of the gammaretroviral vectors used in early trials several patients treated developed leukaemias or myelodysplasia.

  • Lentiviral vectors with an improved biosafety profile have since been developed, which reduce the risk of this happening again.

  • Targeted gene correction where the gene of interest is corrected in situ using meganuclease technology is currently being investigated as a future strategy, which may improve both the safety and efficacy of gene therapy procedures.

Keywords: primary immunodeficiency; severe combined immune deficiency; gene therapy; chronic granulomatous disease; Wiskott–Aldrich syndrome; lentiviral vectors; gene correction

Figure 1.

A gene therapy procedure takes several days, beginning with stem cell harvest from the patient (direct from bone marrow or mobilised peripheral blood) followed by CD34+ stem cell enrichment using a magnetic bead system. Depending on the specific disease protocol, CD34+ cells are kept in culture with cytokines for a period before incubation with the viral vector containing the corrective transgene. After cell entry, the transgene is incorporated into the host genome, allowing expression of the relevant protein. Washed cells are infused back into the patient via a venous route. The process is subject to stringent quality assurance and control and the procedure is carried out in a dedicated gene therapy laboratory under good manufacturing practice conditions. Adapted with permission from Booth et al., . © Wolters Kluwer Health.



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Further Reading

Aiuti A, Bacchetta R, Seger R, Villa A and Cavazzana‐Calvo M (2012) Gene therapy for primary immunodeficiencies: Part 2. Current Opinion in Immunology 24(5): 585–591.

Cavazzana‐Calvo M, Fischer A, Hacein‐Bey‐Abina S and Aiuti A (2012) Gene therapy for primary immunodeficiencies: Part 1. Current Opinion in Immunology 24(5): 580–584.

Porteus M (2011) Homologous recombination‐based gene therapy for the primary immunodeficiencies. Annals of the New York Academy of Sciences 1246: 131–140.

Rahman SH, Maeder ML, Joung JK and Cathomen T (2011) Zinc‐finger nucleases for somatic gene therapy: the next frontier. Human Gene Therapy 22(8): 925–933.

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Booth, Claire, Gaspar, H Bobby, and Thrasher, Adrian J(Jun 2013) Gene Therapy for Primary Immunodeficiency. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024635]