Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency

Abstract

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

“…Therapeutic small molecules and monoclonal antibodies are now revolutionizing care for many autoimmune diseases, taking the place of steroids because they have fewer systemic side effects. Gene therapy, accomplished by lentiviral addition of a cloned, correct copy of a gene into HSCs of a patient harboring a gene defect, has proven so successful for ADA SCID and X‐linked SCID that it is poised to become standard therapy . Similar gene addition trials are in progress for other PIDs.…”

“…Gene therapy, accomplished by lentiviral addition of a cloned, correct copy of a gene into HSCs of a patient harboring a gene defect, has proven so successful for ADA SCID and X-linked SCID that it is poised to become standard therapy. [14][15][16][17] Similar gene addition trials are in progress for other PIDs. Although low doses of chemotherapy appear to be required to make space in bone marrow niches for engraftment of corrected HSC, the difficulties with allogeneic HCT, rejection and GVHD, are avoided.…”

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…The first disease linked to a defect in adenosine deaminase function, severe combined immunodeficiency (SCID), was described in the 1970s. Extensive multidisciplinary research conducted over more than four decades elucidated its pathogenesis and led to the development of both enzyme replacement and gene therapy . Inspired by the experience with ADA1 deficiency, our goal is to review the discovery and characterization of ADA2 and its gene in humans and invertebrates, the discovery only 5 years ago of ADA2 deficiency in humans, and to update current understanding of its clinical heterogeneity.…”

“…Extensive multidisciplinary research conducted over more than four decades elucidated its pathogenesis and led to the development of both enzyme replacement and gene therapy. 8,9 Inspired by the experience with ADA1 deficiency, our goal is to review the discovery and characterization of ADA2 and its gene in humans and invertebrates, the discovery only 5 years ago of…”

Gene therapy for severe combined immunodeficiencies and beyond

“…The enzyme ADA is involved in purine metabolism. A lack of ADA activity leads to the accumulation of toxic deoxyadenosine and dATP (within the cell), and thus the premature death of lymphocyte progenitor cells (Kohn et al, 2019). It is noteworthy that ADA is expressed ubiquitously; hence, ADA deficiency is associated with a number of additional, nonimmune features, such as lung and brain disease (Kohn et al, 2019).…”