Gene Therapy for Inborn Errors of Immunity: Severe Combined Immunodeficiencies.

Severe combined immune deficiency (SCID) causes profound deficiency in T cells and variable deficiencies in B and NK cells. Untreated, the condition is fatal within the first 2 years of life. HSCT has traditionally been the only curative approach; however, success rates are suboptimal in those lacking an HLA-matched donor and conditioning regimens can cause significant toxicity. Gene therapy was pioneered for adenosine deaminase (ADA-SCID) over 3 decades ago and has produced highly successful results. Encouraging data for X-SCID and preclinical work for Artemis-SCID and RAG1-SCID are paving the way for the therapy to become a viable curative treatment option.

Teeth or no teeth: exploring punitive measures for adults smoking in cars containing children in Aotearoa/New Zealand.

This viewpoint welcomes the recent announcement of the Government of Aotearoa/New Zealand to ban smoking in cars with children. However, it notes that the thorny issue of enforcement and punishment remains. Internationally there is a deficit on research on this issue. The experiences of the UK and Ireland are examined, where there was little or no enforcement of such laws, as well as a comparison with the State of Victoria in Australia, where the law was more robustly enforced. This viewpoint argues that enforcement is an important element in safeguarding the health and wellbeing of children.

Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.

BACKGROUND: X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. OBJECTIVES: Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. METHODS: CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. RESULTS: In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. CONCLUSIONS: These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.