The trial, known as the FACTs (Fabry Disease Clinical Research and Therapeutics) study, was carried out in Halifax, Toronto and Calgary and started in 2016 with five Canadian men who were treated with a novel gene therapy that enabled their bodies to produce the missing enzyme that causes Fabry disease. The findings were published in the journal Clinical and Translational Medicine.
Life-changing results
The results were life-changing: four of five patients showed significant biomarker improvements, and three were able to stop their enzyme replacement therapy (ERT) entirely, suggesting the possibility of a "one-and-done" treatment.
"This trial marks a critical step forward in demonstrating the safety and efficacy of LV-mediated gene therapy for Fabry disease," says Dr. Michael West, a Dal professor and nephrologist at the QEII Health Sciences Center, who was a co-investigator in the study that was the first gene therapy trial for Fabry.
"The continued therapy response over five years and the positive impact on patients' quality of life, particularly the ability to discontinue ERT, offers hope that gene therapy can significantly change the landscape of treatment options for individuals affected by this rare disease."
Fabry disease causes certain fat molecules to accumulate in the cells of various tissues, because the body is unable to produce the correct version of an enzyme that breaks down these fatty materials. It can cause some people to experience pain in their hands and feet, intestinal problems, chronic fatigue, kidney disease, heart failure and strokes.
A working copy
The therapy uses engineered patient blood stem cells to deliver a working copy of the faulty gene. Results showed lasting enzyme production and stabilized kidney function in one patient with advanced kidney disease. Researchers are excited by the therapy's safety profile, with only two temporary severe adverse events reported.
The study revealed that all five patients had sustained persistence of LV-marked blood cells and continual enzyme production. As a result, three patients could stop biweekly ERT (every two weeks), with a saving of roughly $3.7 million in costs for provincial health-care programs.
"I had about four years with no ERT, and I gained back all that time with my family," said 44-year-old Ryan Deveau of Dartmouth, who was one of the five patients treated with the LV therapy.
"At one point, my wife and I realized we were forgetting I had Fabry at all."
Dr. West said the goal now is to create a similar study with 25 to 30 patients, including women, over a two- to three-year period.
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Khan A, Barber DL, McKillop WM, Rupar CA, Auray-Blais C, Fraser G, Fowler DH, Berger A, Foley R, Keating A, West ML, Medin JA. Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial. Clin Transl Med. 2025 Jan;15(1):e70073. doi: 10.1002/ctm2.70073. PMID: 39794302; PMCID: PMC11726700.
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.
Khan A, Barber DL, McKillop WM, Rupar CA, Auray-Blais C, Fraser G, Fowler DH, Berger A, Foley R, Keating A, West ML, Medin JA. Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial. Clin Transl Med. 2025 Jan;15(1):e70073. doi: 10.1002/ctm2.70073. PMID: 39794302; PMCID: PMC11726700.
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.
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