This project involves the conduct of therapeutic clinical trials for the treatment of X-linked chronic granulomatous disease (CGD) with autologous blood stem cell targeted gene therapy. Patients with CGD have defective circulating blood neutrophils that fail to produce microbicidal hydrogen peroxide. They suffer from recurrent life threatening infections and premature mortality. In 1997, we completed a clinical trial of gene therapy for the inherited deficiency of the phagocytic cell immune system known as the X-linked form of chronic granulomatous disease (X-CGD). In some of our gene therapy treated patients up to 1 in 400 circulating neutrophils in the peripheral blood demonstrated functional correction following the gene therapy. This peak level of correction occurred at 3 to 6 weeks after therapy and the effect could be sustained for over a year in three of five patients treated with multiple infusions of autologous ex vivo gene corrected CD34+ progenitor cells. These gene therapy studies demonstrated that it is possible to provide a low level partial and transient correction of the CGD defect in patients by gene therapy. In 2004, the results of a similar gene therapy trial for CGD was reported by a group from Germany that treated X-CGD patients; however they also included the chemotherapy agent busulfan at a dose of 8mg/kg to make room in the bone marrow and therefore improve engraftment. They achieved initial levels of 20% in the peripheral blood however, there was also an outgrowth of gene corrected myeloid cells resulting in increasing levels. This outgrowth was however associated with oligoclonality and over-representation of clones in which the gene therapy vector had by insertional mutagenesis activated MDS1 and other genes associated with myeloid cell development. Although the patients in this trial were not cured, and the first patient actually expired from sepsis, both patients appeared to have some clinical benefit from the treatment as they each had an underlying infection at the time of their transplant, which resolved in the initial peritransplant period prior to the clonal outgrowth and ultimate silencing of the transduced cells. We therefore initiated a clinical trial in 2006 to treat patients with XCGD and an underlying infection, protocol number 07-I-0017. Based on preclinical data in the rhesus as well as clinical data in a patient, we used busulfan at a dose of 10mg/kg prior to infusion of the genetically modified cells. We treated three patients, the first a 28 year old male with multiple liver abscesses, not amenable to surgical or radio frequency ablative approaches. The patient initially had a level of 24% positive cells and at 7 months post treatment had resolution of his liver abscesses, with 1.2% detectable marking persisting in the peripheral bloodthere was no evidence of clonal outgrowth and the level of oxidase expression on a per cell basis continued to be at almost normal levels with a reduction in infection rate compared to his prior history. The patient howevere developed a progressive pulmonary process which despite an attempt at allogeneic transplant, led to his demise in 2016. The second patient treated on this trial appeared to develop an immune reaction against the transduced cells, with rapid clearance of these cells after initially having 5% marking in the peripheral blood. The third patient was treated for a fungal lung infection and had an initial marking level of 4% with a subsequent decline to 0.03% where it has remained stable until he underwent a matched unrelated donor transplant due to continued infections. He is now three years out doing well. We have now been enrolling patients in a collaborative trial- Protocol 15-I-0008 using a lentiviral vector produced by Genethon. The first patient was treated in Boston in December 2015, and has done relatively well with persistent marking in the 20-25% range. The second patient on the trial was treated at NIH in July 2016, and this patient continues to have marking in the 20-30% range more than a year out with no adverse events. The second NIH patient (fourth on the trial) is now over two months post transplant with significant improvement in his infection for which he was treated. Our third patient was treated early August and the fourth will be treated in September. All patients on the trial (total of 5 treated to date) have good marking and no adverse events from the therapy. We are now working to obtain additional vector to continue treating patients given the very exciting results we have seen to date as we have used all of our available slots on the multicenter study. We are also working on amendments to improve the ease and applicability of this therapy including the use of freezing the transduced cells. We have also initiated accrual of plerixafor/GCSF mobilized peripheral blood cells on Protocol 10-I-0016, to assess the impact, if any, of plerixafor on gene transduction of these mobilized cells. Finally, we are continuing our collaboration with David Rawlings at the University of Washington and investigators at St Judes to initiate a clinical gene therapy trial for patients with Wiskott-Aldrich Syndrome. Results from this study should be helpful for improving our gene therapy for CGD patients as well.

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Straughan, David M; McLoughlin, Kaitlin C; Mullinax, John E et al. (2018) The Changing Paradigm of Management of Liver Abscesses in Chronic Granulomatous Disease. Clin Infect Dis 66:1427-1434
Keller, Michael D; Notarangelo, Luigi D; Malech, Harry L (2018) Future of Care for Patients With Chronic Granulomatous Disease: Gene Therapy and Targeted Molecular Medicine. J Pediatric Infect Dis Soc 7:S40-S44
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