Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

Management of Immunodeficiency: Gene Therapy

  • Jennifer W. LeidingEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_83-1

The use of gene-modified cells as a source of hematopoietic stem cell transplantation (HSCT) has grown significantly in the last 10 years. Although advances in supportive care, prevention of infections, improved HLA typing, and improved conditioning regimens have improved survival, HSCT can be complicated in those who lack well-matched donors or who have preexisting infections.

The ability to develop viral vectors that stably integrate modified genes into cells occurred in the 1980s and 1990s. The first gene therapy trial occurred with a 4-year-old girl with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). The patient received several infusions of a gamma retroviral vector containing normal ADA cDNA which led to endogenous production of ADA.

The sequence of events for gene modification therapy is as follows:
  1. 1.

    Stem cells collected from affected patient.

     
  2. 2.

    Stem cells cultured in vitro with modified virus carrying the corrective gene sequence.

     
  3. 3.

    Preconditioning chemotherapy is given to create bone marrow space.

     
  4. 4.

    Genetically modified stem cells are infused into the patient.

     

Gene Therapy for ADA SCID

ADA deficiency is an autosomal recessive disorder that manifests as T, B, and NK cell deficiency and dysfunction. The ADA enzyme is ubiquitously expressed, and deficiency of ADA leads to the buildup of toxic metabolites in lymphocytes and other cells. Enzyme replacement with pegylated ADA provides detoxification and some immune reconstitution, and over time the effects of pegylated ADA become blunted. HSCT is the treatment of choice for ADA deficiency, but for those without optimal donors, gene therapy is becoming standard of care. The gene therapy trials for ADA SCID are described below:
  • The first trial used a murine gamma retroviral vector with patients maintained on enzyme replacement therapy. Although ADA expression developed, it was not high enough to confer significant benefit.

  • The next trials used Moloney murine leukemia-derived replication-deficient recombinant retroviruses. Non-myeloablative doses of busulfan or melphalan were also used to create space in the bone marrow compartment. Enzyme replacement was stopped either shortly before or at time of infusion. The majority of patients treated were able to discontinue IVIG and/or enzyme replacement therapy.

Overall, more than 100 patients have been treated with gene modification therapy with ADA SCID with 100% survival (Aiuti et al. 2009).

Gene Therapy for X-Linked SCID

X-linked SCID is caused by mutations in the IL2RG gene found on the X chromosome. IL2RG encodes for the common gamma chain that is responsible for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signaling. Defects in IL2RG lead to defective T and NK cell production with present B cells.

The first clinical trial for gene therapy for X-SCID occurred in 1999 in Paris and was followed closely in 2001 in London. X-SCID patients without an HLA-identical donor were treated without chemotherapy; hematopoietic stem cells were treated with a murine gamma retroviral vector in which the common gamma chain was under control of U3 region enhancers. Stable immune reconstitution was obtained and all patients had control of infections and increased growth. However, 31–68 months after gene therapy, five patients developed T cell acute lymphoblastic leukemia. In four patients, the gamma retroviral vector was integrated near and activated the LIM domain-only 2 (LMO2) proto-oncogene. Four of the five survived after receiving chemotherapy and bone marrow transplantation (Hacein-Bey Abina et al. 2008).

Subsequently, modifications were made to the gamma retrovirus vector, removing the enhancer sequences. This new self-inactivating gamma retroviral expressing IL2RG has been used in nine boys. Eight of the nine are still alive, and there have been no leukemic events following gene therapy. This trial is still open and enrolling (Hacein-Bey-Abina et al. 2014).

A newer approach using lentiviral vectors combined with low-exposure targeted busulfan has resulted in multilineage engraftment of functional T cells and B cells in 8 infants (reference Mamcarz E et al. “Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1” NEJM. 2019.

Gene Therapy for X-Linked Chronic Granulomatous Disease

X-linked CGD is caused by mutations in CYBB which encodes for gp91phox, a major component of the NADPH oxidase in neutrophils. Defects in the NADPH oxidase results in immunodeficiency characterized by severe bacterial and fungal infections and autoinflammation.

The first clinical trials used gamma retroviral vectors to deliver normal CYBB, some with and some without preconditioning regimens. Despite the presence of gene-corrected cells, these numbers decreased significantly in the first year after gene therapy. During these times of low but present gene-corrected neutrophils, severe life-threatening infections were able to improve or were cured. In an additional subset of patients, there was insertional activation of growth-promoting genes that led to myelodysplasia and monosomy 7 in two patients (Kang et al. 2010). Because of these problems with gamma retroviral vectors, use of a lentivirus vector to deliver CYBB is now being investigated (Farinelli et al. 2016). Initial results show >20% genetically modified neutrophils with resolution of infections and inflammatory disease in participants (Kohn et al. 2018) (Table 1).
Table 1

Gene therapy trials for primary immunodeficiency diseases

Disease

Center

Status

NCT

Vector

ADA SCID

UCLA

Recruiting

NCT03765632

LV

London

Recruiting

NCT01380990

LV

Los Angeles, Bethesda, London

Complete

NCT0127972071, NCT02022696

LV

Milan, Jerusalem

Complete

NCT00599781; NCT00598481

γ-RV

Bethesda

Complete

NCT00018018

γ-RV

London

Complete

NCT01279720

γ-RV

X-linked SCID

London

Recruiting

NCT01175239

SIN-γ-RV

Paris

Recruiting

NCT01410019

SIN- γ-RV

Memphis, San Francisco, Seattle

Recruiting

NCT01512888

LV

Boston, Los Angeles

Recruiting

NCT03311503

LV

Beijing

Recruiting

NCT03217617

LV

Bethesda

Recruiting

NCT03315078

LV

Bethesda

Recruiting

NCT01306019

LV

London

Recruiting

NCT03601286

LV

Boston, Cincinnati, London, Los Angeles, Paris

Complete

NCT01175239

SIN- γ-RV

Bethesda

Complete

NCT00028236

RV

Bethesda, Cincinnati, Los Angeles

Complete

NCT01129544

γ-RV

X-CGD

Frankfurt

Recruiting

NCT01906541

γ-RV

Frankfurt, London, Paris, Zurich

Recruiting

NCT01855685

LV

Bethesda, Boston, Los Angeles

Recruiting

NCT02234934

LV

Paris

Recruiting

NCT02757911

LV

Zurich

Complete

NCT00927134

γ-RV

Bethesda

Complete

NCT00001476

γ-RV

Seoul

Complete

NCT00778882

γ-RV

Bethesda

Complete

NCT00394316

γ-RV

WAS

London

Recruiting

NCT01347242

LV

Milan

Recruiting

NCT03837483

LV

Boston

Recruiting

NCT01410825

LV

Milan

Complete

NCT01515462

LV

Paris

London

Complete

NCT01347346

LV

 

Paris

Complete

NCT02333760

LV

RV retrovirus, LV lentivirus

Gene Therapy for Wiskott–Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia, and susceptibility to infections. WAS protein is required for functional leukocyte migration. The first clinical trial for gene therapy for WAS started in 2006. Ten patients received non-myeloablative doses of busulfan and hematopoietic stem cells corrected with a Wiskott-Aldrich Syndrome protein (WASP) expressing gamma retrovirus (Hacein-Bey Abina et al. 2015). Immune reconstitution occurred in nine patients, along with increases in platelet count (Farinelli et al. 2016). Unfortunately, vector site insertion analysis showed clustering at sites of proto-oncogenes. Between 14 months and 5 years post gene therapy, seven of nine developed hematologic malignancy. All were treated with chemotherapy and HSCT, but two died of leukemia (Boztug et al. 2010).

In response, gene therapy trials using a self-inactivated lentiviral vector was developed. A total of 21 patients have been treated with stable engraftment of gene-marked cells. Patients had clinical benefit with decreased bleeding episodes and decreased incidence of infections, autoimmunity, and eczema. Platelet recovery has been variable (Braun et al. 2014).

There have been tremendous advances in gene therapy for treatment of primary immunodeficiency in the last 30 years, providing a new standard for treatment of patients. Newer technology to improve gene therapy strategies using genome editing tools to cause site-specific gene editing is underway8.

References

  1. Aiuti A, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009;360(5):447–58.CrossRefGoogle Scholar
  2. Boztug K, Schmidt M, Schwarzer A, et al. Stem-cell gene therapy for the Wiskott- Aldrich syndrome. N Engl J Med. 2010;363(20):1918–27.CrossRefGoogle Scholar
  3. Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich syn- drome–long-term efficacy and genotoxicity. Sci Transl Med. 2014;6(227):227–33.CrossRefGoogle Scholar
  4. Farinelli G, Jofra Hernandez R, Rossi A, Ranucci S, Sanvito F, Migliavacca M, Brombin C, Pramov A, Di Serio C, Bovolenta C, Gentner B, Bragonzi A, Aiuti A. Lentiviral vector gene therapy protects XCGD Mice from Acute Staphylococcus aureus Pneumonia and Inflammatory Response. Mol Ther. 2016;24(10):1873–80.CrossRefGoogle Scholar
  5. 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(9):3132–42.CrossRefGoogle Scholar
  6. Hacein-Bey Abina S, Gaspar HB, Blondeau J, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich Syndrome. JAMA. 2015;313(15):1550.CrossRefGoogle Scholar
  7. Hacein-Bey-Abina S, Pai S-Y, Gaspar HB, et al. A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency. N Engl J Med. 2014;371(15):1407–17.CrossRefGoogle Scholar
  8. Kang EM, Choi U, Theobald N, et al. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010;115(4):783–91.CrossRefGoogle Scholar
  9. Kohn DBB C, Kang EM, Pai SY, Shaw KL, Kuo CY, Terrazas DR, Wang LD, Armant M, Santilli G, Bucklandd K, Rico DL, Snell K, De Ravin S, Choi U, Mavilio F, Galy A, Newburger P, Bushman FD, Gaspar HB, Williams DA, Malech HL, Thrasher AJ. Gene therapy for X-linked chronic granulomatous disease. Molecular Therapy. 2018;26(5S1):157–8.Google Scholar
  10. Kohn. Consensus approach for the management of secvere combined immunodeficiency caused by ADA deficiency. JACI. 2019;143(3):852–863.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Allergy and ImmunologyUniversity of South Florida at Johns Hopkins – All Children’s HospitalSt. PetersburgUSA

Section editors and affiliations

  • Elena E. Perez
    • 1
  1. 1.Allergy Associates of the Palm BeachesNorth Palm BeachUSA