Gene therapy for the treatment of adenosine deaminase-deficient severe combined immune deficiency

ABSTRACT

Introduction: Adenosine deaminase (ADA) deficiency was the first human disease treated with gene therapy. Initial trials established proofs of concepts, but did not lead to cure of the severe combined immune deficiency that is the hallmark of this disease. A breakthrough trial combined gammaretroviral gene therapy with non-myeloablative conditioning of subjects unable to benefit from enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA). Three additional trials have confirmed the ability of gene therapy to cure the clinical immune defect of ADA deficiency.

Areas covered: This article reviews the development of gene therapy for ADA-SCID, compares the four trials that have been reported and discusses open questions remaining in the field.

Expert opinion: Gene therapy may be regarded as standard of care for the majority of patients with ADA deficiency, along with allogeneic hematopoietic cell transplantation (HCT) or ERT. The appropriate sequencing of these treatments remains uncertain. While gammaretroviral gene therapy has been approved in Europe, remaining concerns about potential genotoxicity have led to further development, including the use of lentivirus vectors and modification of peri-transplant management. The ability of gene therapy to completely correct both the immunologic and non-immunologic  manifestations of ADA deficiency remains to be demonstrated.

KEYWORDS:

• Adenosine deaminase deficiency
• gene therapy
• severe combined immune deficiency
• viral vectors

Article highlights

• ADA-SCID is considered to be an ideal disease for treatment with marrow-directed gene therapy.

• Initial studies of gene therapy for ADA deficiency had limited success.

• The first major success for gene therapy of ADA-SCID occurred in a study of children unable to benefit from PEG-ADA who underwent non-myeloablative chemotherapy conditioning before the infusion of genetically corrected cells.

• No child has suffered severe genotoxicity after gammaretroviral gene therapy of ADA-SCID, but concerns for insertional oncogenesis have contributed to the perceived need for further refinement of gene therapy for ADA-SCID.

• A commercial product has been approved in Europe for gene therapy of ADA-SCID in patients up to 6.1 years of age who lack an HLA-identical sibling donor.

This box summarizes key points contained in the article.

Acknowledgments

This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

F Candotti receives support from the UNIL-CHUV research fund, the National Science Foundation, Gebert Rüf Stiftung and Horizon 2020. R Sokolic is funded by the United States Food and Drug Administration.