Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency

Abstract

Patients lacking functional adenosine deaminase activity suffer from severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy-GT). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a Phase II clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND-ADA gamma-retroviral vector (gRV) and infused following busulfan reduced intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8-11 years. Nine of ten patients have sufficient immune reconstitution to protect against serious infections, and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of nine evaluable patients with the highest gene marking and B cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells, and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID, but risks of genotoxicity with gRVs. (Clinicaltrials.gov #NCT00794508)

IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy

“…Correction of glycogen content was achieved at a VCN in bone marrow as low as 3 after lentiviral gene therapy with LV -IGF2.GAAco . In a direct comparison at subtherapeutic conditions, the clinically acceptable MND promoter 59 , 60 , 61 showed similar efficacy in reducing glycogen levels compared with the SF promoter ( Figure S10 ).

Figure 3 Gene therapy with LV- IGF2.GAAco results in correction in skeletal muscles (A–D) Total glycogen content in skeletal muscles after different doses of gene therapy with LV- IGF2.GAAco or LV- GAAco .

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“…To address this, we have tested alternative promoters. This identified the clinically acceptable MND promoter 59 , 60 , 61 to have the same efficacy as the SF promoter ( Figure S10 ), indicating that a lentiviral vector expressing the IGF2 . GAA transgene under the control of the MND promoter may well be suitable for clinical translation.…”

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

“…T cell GT for IEIs could benefit from the rapidly expanding infrastructure to manufacture genetically engineered T cell products ( 47 ). Correction of HSCs enables long-term correction due to modification of a self-renewing population of cells ( 48 ); however, increasing data suggests that genetically engineered CAR-T cells can also persist long term if sufficient numbers of central and effector memory T cells are modified and transferred ( 49 ). Clinical proof of principle of T cell GT for IEIs already exists from the early retroviral T cell GT trials for adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID), which demonstrated persistence of gene marking 10 years after patients received gene-modified T cells ( 50 ).…”

Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency—Improved Outcomes in the Modern Era

“…Both OS, particularly since 2007, and EFS in our cohort are comparable to those recently reported for GT for ADA deficiency [ 16 , 17 ]. Although initial data reported no leukemic change in recipients of gammaretroviral GT [ 8 ], a recent report has documented the development of T-cell leukemia in a gammaretroviral GT recipient [ 18 ], and persisting prominent clones with vector integration adjacent to proto-oncogenes have been demonstrated in several other patients [ 19 ]. Lentiviral GT has demonstrated excellent survival outcomes and safety to date [ 13 ], but access to this novel therapeutic modality remains a major limitation.…”