Lentiviral Gene Therapy and Genome Editing for X-linked Severe Combined Immunodeficiency

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PROJECT SUMMARY – PROJECT 3 The overall goal of this project is to determine if lentiviral gene therapy combined with subablative busulfan conditioning can be used to treat a broad spectrum of patients with severe combined immunodeficiency (XSCID). This catastrophic disease of childhood is caused by mutations in the IL2RG gene that lead to profound defects in T cell, NK cell, and B-cell mediated immunity. Allogeneic transplant is the standard therapy, but results in suboptimal outcomes in patients that lack matched sibling donors. While prior gene therapy trials with gamma- retroviral vectors showed clinical benefit, incomplete immune reconstitution and vector-related leukemia was seen in a significant number of cases. We propose a new approach using a safety-modified lentiviral vector and reduced intensity conditioning in order establish long-term correction via bone marrow engraftment of transduced hematopoietic stem cells. During the past funding period, we opened the first clinical lentiviral trials with subablative busulfan for XSCID and have obtained remarkable success in 12 cases treated thus far. The LVXSCID-OC trial at the NIH Clinical Center has enrolled eight XSCID patients who had waning immunity despite having undergone a prior allogeneic transplant. These cases have shown high levels of myeloid marking that are unprecedented in prior XSCID gene therapy trials and complete immune reconstitution in some cases. In particular, B cell function was restored in the first two cases leading to independence from gamma-globulin replacement therapy, which has not been obtained in prior gene therapy trials. We have also opened a newly diagnosed protocol (LVXSCID-ND) at St. Jude, UCSF, and Seattle and have treated four infants with transduced bone marrow cells following targeted subablative conditioning over the past seven months. Gene marking in blood and bone marrow myeloid cells has been very high and has been associated with rapid reconstitution of T and NK cell numbers and function. B cell marking levels have averaged 0.8 copies/cell and have been noted with preliminary evidence of endogenous gamma-globulin production in one case. Based on these results, we now seek support to complete both of these Phase I studies by validating more GMP-grade vector batches, completing enrollment on both protocols, and performing detailed, long term analyses of immune reconstitution, vector marking/clonality studies, and clinical safety in these cases. We anticipate that these studies will provide a new therapy for XSCID and leading to commercialization of this gene therapy approach so that this treatment can be made widely available.