Gene Therapy for ADA-Deficient Severe Combined Immunodeficiency

Abstract

Source: Reinhardt B, Habib O, Shaw KL, et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood. 2021 Oct 14;138(15):1304-1316; doi:10.1182/blood.2020010260Investigators from multiple institutions conducted a study to evaluate long-term outcomes in children with severe combined immunodeficiency (SCID) caused by lack of adenosine deaminase activity (ADA) who were treated with autologous hematopoietic stem cell transplant (HSCT) of gene-corrected cells (gene therapy [GT]). Participants were children diagnosed with SCID with absence of ADA activity, an absolute lymphocyte count of <200 cells/mm3, and no suitable sibling donor for allogeneic HSCT who were being treated with ADA enzyme replacement therapy (ERT). These patients had CD34+ cells harvested by bone marrow aspirate that were transduced with a gamma-retroviral vector encoding for a functional human ADA cDNA sequence. The transduced cells were infused into the patient. Study patients were followed at annual visits at which interval histories were obtained along with blood specimens for multiple laboratory assays. Previously, short-term outcomes (up to 2 years post-GT treatment) were reported. For the current study, long-term outcomes, including occurrence of severe or unusual infections, leukoproliferative events or malignancies, ADA enzyme activity, need for ERT, lymphocyte counts, and immunoglobulin levels were assessed 8-11 years after treatment.Data were analyzed on 10 children with ADA SCID who received GT treatment between 2009 and 2012. At the time of treatment, the study patients ranged in age from 3 months to 15 years. At follow-up, no severe, persistent, or opportunistic infections, or leukoproliferative events or malignancies, occurred in any of the study patients. In 8 of the 10 study participants, peripheral blood mononuclear cell (PBMC) ADA activity was maintained in the normal range. In 1 child, with low PBMC ADA activity, ERT was resumed 6 months after GT; no other patient required ERT following treatment with GT. Patients who received GT at the youngest ages (3 months) had the highest PBMC ADA activity. Absolute lymphocyte counts remained relatively stable in study patients over the follow-up period, although levels were ≤ the 10th percentile for healthy children. Lymphocyte counts were higher in children receiving GT at 3 months of age and, overall, counts were highly correlated with ADA activity. Four patients had Immunoglobulin G (IgM) levels in the normal range. These children were taken off immunoglobulin replacement therapy, and 2 of these responded to vaccines. The other patients had IgM levels near or below the lower limit of normal.The authors conclude that in this group of children with ADA SCID, the long-term outcomes demonstrate enduring efficacy of GT.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.ADA deficiency results from an autosomal recessive inheritance of mutations in the ADA gene, accounting for up to 15% of severe combined immunodeficiency cases and affecting 1:200,000 to 1:1,000,000 live births worldwide.1 Lack of ADA results in buildup of adenosine, 2’-deoxyadenosine, and deoxyadenosine, which is toxic to lymphocytes, bone, brain, lungs, and other organs. Within 6-12 months of age, infants develop life-threatening sinopulmonary and gastrointestinal infections with failure to thrive.2Abnormal newborn screening with reduced T cell receptor excision circles should prompt immediate testing of serum T, B, and NK lymphocytes and immunoglobulins.1 Referral to pediatric immunology, genetics, and a pediatric HSCT center will help expedite confirmatory enzyme and genetic testing while providing prophylactic antimicrobials and intravenous immunoglobulin.2 When an ideal HLA-matched healthy sibling HSCT donor is not available, enzyme replacement therapy (ERT) with intramuscular injections of polyethylene glycol-conjugated ADA helps provide some lymphocyte recovery until a possible unrelated donor or GT of autologous CD34+ HSCT.3The current study’s strengths include a standard replicable therapy protocol with consistent long-term follow-up of clinical and microscopic characteristics.3 Since the initial treatment of these individuals, advances in GT include improvements in vectors, transduction, and cryopreservation.3 Thus far, more than 100 affected individuals have undergone GT on 11 different clinical trials worldwide with excellent immunocompetent results.4 However, randomized controlled trials comparing ideal sibling HSCT or variations in GT have not been done.4 Long-term safety monitoring for malignant transformation or loss of immunocompetence can be difficult due to the diversity of treatment sites, data collection, and patient retention.5Infusion of autologous hematopoietic stem cells transduced with ADA-gammaretroviral vector gene therapy has provided long-term immune reconstitution in children with ADA deficiency.