Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency

Progress and prospects: gene therapy for inherited immunodeficiencies

“…In these studies, three older (aged 10-14 years) patients who had previously undergone allogeneic HSCT, but had poor immunological recovery, were treated by retroviral gene therapy targeting mobilized CD34 + stem cells from peripheral blood. 8 The MFG vector used was pseudotyped with the Gibbon Ape Leukaemia virus and was similar to that used in the London study. All patients had evidence of gene marking, but only one had improvement (albeit limited) of T-cell function, and there was no evidence of clonal expansion or insertional mutagenesis.…”

“…All patients had evidence of gene marking, but only one had improvement (albeit limited) of T-cell function, and there was no evidence of clonal expansion or insertional mutagenesis. 8 Rescue treatment of such patients, particularly for older children, is extremely challenging and is probably related to agerelated thymic involution resulting in limited thymopoiesis despite satisfactory stem cell transduction.…”

Antigen-specific humoral tolerance or immune augmentation induced by intramuscular delivery of adeno-associated viruses encoding CTLA4-Ig-antigen fusion molecules

“…32 Surprisingly, tolerance in this study was induced independently of CTLA4-Ig binding with B7 molecules as shown by mutating the MYPPPY-binding motif of the vector construct. CTLA4 also operates independently of B7 binding, 43,44 and it will be interesting to determine whether tolerance can be induced by a vector encoding an Ig fusion molecule that lacks CTLA4, that is, rAAV-Ig-MSP4/5. Such a finding would create interesting parallels with other models of humoral tolerance either through B-lymphocyte expression of antigens fused to the N-terminus of IgG heavy chains, [45][46][47] or where the antibody isotype of the Ig fusion molecule is key to determine immunity or tolerance.…”

Gene Therapy for Primary Immunodeficiencies

“…Immune reconstitution was limited in these patients despite good engraftment, with only a slight improvement of T-cell function in the youngest child. This unexpectedly reduced efficacy of gene therapy is likely explained by the age-related decreased plasticity and loss of thymopoietic capacity in older subjects particularly those in whom thymopoiesis has been absent for extended periods (Chinen et al, 2007).…”