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This will include complete clinical evaluation of any AEs resulting from the gene transfer procedure.

Evaluate the overall, long-term safety of lentiviral gene transfer.

Studies on sorted cells will also include deep sequencing with an automated sequencer to characterize insertion sites, and expression array analysis of T-cell clones to assay for gene expression alterations within 100 kb of the insertion sites. Vector copy number in sorted T-cells will be evaluated as a potential safety measure and will be reported to the FDA if the vector copy number is greater than 5 copies per T cell in any patient at any time. Sorted T-cells, B-cells, NK cells, granulocytes and monocytes will be evaluated for vector copy number.

Determine the vector copy number and the location of vector-integration sites in sorted blood cells.

Evaluation will include flow cytometry evaluation of NK cell numbers.

Evaluate NK cell numbers in long term follow-up of protocol patients.

Evaluation will include γc expression in circulating B-cells, measurement of serum IgG, IgA, and IgM concentration, measurement of antibody responses to vaccination, evaluation of IgG production after cessation of intravenous gamma globulin therapy in patients with clinical indications to discontinue IVIG.

Evaluate B-cell function during longterm follow-up of protocol patients.

Evaluate the efficacy of busulfan dose-targeting with busulfan administration every 24 hours for a total of 2 doses in order to achieve a cumulative busulfan area under the curve of 22 mg*hr/L.

Correlate busulfan and its metabolite pharmacokinetics with toxicity, efficacy, engraftment of vector-transduced cells, and event-free survival and overall survival.

≥ 200 autologous CD4+ CD45RA T-cells/μl in the peripheral blood.

≥ 500 autologous CD4+ T-cells/μl in the peripheral blood.

≥ 1000 autologous CD3+ T-cells/μl in the peripheral blood.

The development of T-cell proliferative responses to phytohemagglutinin (PHA) that are ≥ 50% the value seen in normal controls.Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present:

Primary Objective 2: Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks (± 4 weeks) after transplantation. Primary Objective 1: Evaluate the safety and feasibility of infusing at least 1 million transduced CD34+ cells per kilogram of body weight in SCID-X1 infants.

This study will evaluate the first use of a SIN lentiviral vector for the treatment of SCID-X1 and may lead to a new form of therapy that could be applied to the majority of newly diagnosed patients.Īssess the safety, feasibility and efficacy of lentiviral gene transfer in newly diagnosed SCID-X1 patients transplanted with autologous CD34+ cells that have been transduced with a self-inactivating lentiviral vector (CL20-i4-EF1α-hγc-OPT) expressing a γc gene. Continued and detailed evaluation of all aspects of immune reconstitution, protocol-related toxicity, and retroviral integration sites will also be performed. The primary endpoint assessing the efficacy of this approach will be T-cell immune reconstitution 52 weeks (± 4) weeks after transplantation. Participants will be monitored for hematopoietic recovery from busulfan and for severe adverse events for 42 days post gene therapy. Why Should I Register and Submit Results?īone marrow CD34+ cells will be obtained in the operating room, transduced with the lentiviral vector that contains a normal copy of the γc gene, and reinfused without any myeloreductive conditioning.