{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T12:09:13Z","timestamp":1787400553478,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["119187"],"award-info":[{"award-number":["119187"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015982","name":"Midwest Athletes Against Childhood Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Fabry disease is an X\u2010linked lysosomal storage disorder due to a deficiency of \u03b1\u2010galactosidase A (\u03b1\u2010gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for \u03b1\u2010gal A into their CD34+ hematopoietic stem\/progenitor cells (HSPCs). Overexpression of \u03b1\u2010gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene\u2010augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this \u2018first\u2010in\u2010the\u2010world\u2019 Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5\u2010year \u2018End\u2010of\u2010Study\u2019 results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of \u03b1\u2010gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. \u03b1\u2010Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso\u2010Gb3 levels in urine and plasma were assessed by mass spectrometry. qPCR assays measured vector copy number in PB leucocytes. Antibody titers were measured by ELISA. Body weight, blood pressure, urinary protein levels, eGFR, troponin levels, and LVMI were tracked.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating \u03b1\u2010gal A activity was observed at Day 6\u20138 in each patient following infusion and has remained durable for 5+ years. LV marking of peripheral blood cells has remained durable and polyclonal. All 5 patients were eligible to come off biweekly enzyme therapy; 3 patients did so. Plasma lyso\u2010Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti\u2010\u03b1\u2010gal A antibodies. Patient weight was stable in 4 of the 5 patients. All blood pressures were in the normal range. Kidney symptoms were stabilized in all patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This treatment was well tolerated as only two SAEs occurred (during the treatment phase) and only two AEs were reported since 2021. We demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>This was the first gene therapy clinical trial to be completed for Fabry disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>There were no adverse events of any grade attributable to the cellular gene therapy \tintervention or host conditioning throughout the follow\u2010up interval of 5 years.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>After reduced\u2010intensity melphalan treatment, all patients engrafted their autologous modified \u03b1\u2010gal A expressing cells.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>All patients synthesized and secreted \u03b1\u2010gal A throughout the course of the study.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Expression of \u03b1\u2010gal A resulted in a decrease in plasma lyso\u2010Gb3 in four of five patients and stabilization of kidney symptoms in all patients.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70073","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T22:55:04Z","timestamp":1736549704000},"source":"Crossref","is-referenced-by-count":16,"title":["Lentivirus\u2010mediated gene therapy for Fabry disease: 5\u2010year End\u2010of\u2010Study results from the Canadian FACTs trial"],"prefix":"10.1002","volume":"15","author":[{"given":"Aneal","family":"Khan","sequence":"first","affiliation":[{"name":"M.A.G.I.C. (Metabolics and Genetics in Canada) Clinic  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwayne L.","family":"Barber","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"McKillop","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Anthony","family":"Rupar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Auray\u2010Blais","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics CIUSS de l'Estrie\u2010CHUS Hospital Fleurimont University de Sherbrooke  Sherbrooke Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Fraser","sequence":"additional","affiliation":[{"name":"Department of Oncology McMaster University and Juravinski Hospital and Cancer Centre  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Rapa Therapeutics  Rockville Maryland 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