Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial
Abstract Background Fabry disease is an X‐linked lysosomal storage disorder due to a deficiency of α‐galactosidase A (α‐gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α‐gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs)....
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2025-01-01
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| Online Access: | https://doi.org/10.1002/ctm2.70073 |
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| author | Aneal Khan Dwayne L. Barber William M. McKillop C. Anthony Rupar Christiane Auray‐Blais Graeme Fraser Daniel H. Fowler Alexandra Berger Ronan Foley Armand Keating Michael L. West Jeffrey A. Medin |
| author_facet | Aneal Khan Dwayne L. Barber William M. McKillop C. Anthony Rupar Christiane Auray‐Blais Graeme Fraser Daniel H. Fowler Alexandra Berger Ronan Foley Armand Keating Michael L. West Jeffrey A. Medin |
| author_sort | Aneal Khan |
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| description | Abstract Background Fabry disease is an X‐linked lysosomal storage disorder due to a deficiency of α‐galactosidase A (α‐gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α‐gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α‐gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene‐augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this ‘first‐in‐the‐world’ Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5‐year ‘End‐of‐Study’ results. Methods Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α‐gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α‐Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso‐Gb3 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. Results Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α‐gal A activity was observed at Day 6–8 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‐Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti‐α‐gal 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. Conclusions 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. Highlights This was the first gene therapy clinical trial to be completed for Fabry disease. There were no adverse events of any grade attributable to the cellular gene therapy intervention or host conditioning throughout the follow‐up interval of 5 years. After reduced‐intensity melphalan treatment, all patients engrafted their autologous modified α‐gal A expressing cells. All patients synthesized and secreted α‐gal A throughout the course of the study. Expression of α‐gal A resulted in a decrease in plasma lyso‐Gb3 in four of five patients and stabilization of kidney symptoms in all patients. |
| format | Article |
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| institution | Kabale University |
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| publishDate | 2025-01-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-b915b7d5ce12426b9c6a650fd475e50b2025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70073Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trialAneal Khan0Dwayne L. Barber1William M. McKillop2C. Anthony Rupar3Christiane Auray‐Blais4Graeme Fraser5Daniel H. Fowler6Alexandra Berger7Ronan Foley8Armand Keating9Michael L. West10Jeffrey A. Medin11M.A.G.I.C. (Metabolics and Genetics in Canada) Clinic Calgary Alberta CanadaDepartment of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario CanadaDepartment of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin USADepartment of Pathology and Laboratory Medicine Western University London Ontario CanadaDepartment of Pediatrics, Division of Medical Genetics CIUSS de l'Estrie‐CHUS Hospital Fleurimont University de Sherbrooke Sherbrooke Quebec CanadaDepartment of Oncology McMaster University and Juravinski Hospital and Cancer Centre Hamilton Ontario CanadaRapa Therapeutics Rockville Maryland USAPrincess Margaret Cancer Centre University Health Network Toronto Ontario CanadaDepartment of Pathology and Molecular Medicine McMaster University and Juravinski Hospital and Cancer Centre Hamilton Ontario CanadaDepartment of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario CanadaDivision of Nephrology, Department of Medicine Dalhousie University Halifax Nova Scotia CanadaDepartment of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin USAAbstract Background Fabry disease is an X‐linked lysosomal storage disorder due to a deficiency of α‐galactosidase A (α‐gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α‐gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α‐gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene‐augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this ‘first‐in‐the‐world’ Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5‐year ‘End‐of‐Study’ results. Methods Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α‐gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α‐Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso‐Gb3 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. Results Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α‐gal A activity was observed at Day 6–8 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‐Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti‐α‐gal 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. Conclusions 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. Highlights This was the first gene therapy clinical trial to be completed for Fabry disease. There were no adverse events of any grade attributable to the cellular gene therapy intervention or host conditioning throughout the follow‐up interval of 5 years. After reduced‐intensity melphalan treatment, all patients engrafted their autologous modified α‐gal A expressing cells. All patients synthesized and secreted α‐gal A throughout the course of the study. Expression of α‐gal A resulted in a decrease in plasma lyso‐Gb3 in four of five patients and stabilization of kidney symptoms in all patients.https://doi.org/10.1002/ctm2.70073clinical trial resultshaematopoietic stem cellslysosomal storage disordersmelphalan conditioningprogenitor cells |
| spellingShingle | Aneal Khan Dwayne L. Barber William M. McKillop C. Anthony Rupar Christiane Auray‐Blais Graeme Fraser Daniel H. Fowler Alexandra Berger Ronan Foley Armand Keating Michael L. West Jeffrey A. Medin Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial Clinical and Translational Medicine clinical trial results haematopoietic stem cells lysosomal storage disorders melphalan conditioning progenitor cells |
| title | Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial |
| title_full | Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial |
| title_fullStr | Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial |
| title_full_unstemmed | Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial |
| title_short | Lentivirus‐mediated gene therapy for Fabry disease: 5‐year End‐of‐Study results from the Canadian FACTs trial |
| title_sort | lentivirus mediated gene therapy for fabry disease 5 year end of study results from the canadian facts trial |
| topic | clinical trial results haematopoietic stem cells lysosomal storage disorders melphalan conditioning progenitor cells |
| url | https://doi.org/10.1002/ctm2.70073 |
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