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.