PMID- 33633114
OWN - NLM
STAT- MEDLINE
DCOM- 20210311
LR  - 20210402
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 12
IP  - 1
DP  - 2021 Feb 25
TI  - Lentivirus-mediated gene therapy for Fabry disease.
PG  - 1178
LID - 10.1038/s41467-021-21371-5 [doi]
LID - 1178
AB  - Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments 
      are expensive and require intrusive biweekly infusions; they are also not 
      particularly efficacious. In this pilot, single-arm study (NCT02800070), five 
      adult males with Type 1 (classical) phenotype Fabry disease were infused with 
      autologous lentivirus-transduced, CD34(+)-selected, hematopoietic stem/progenitor 
      cells engineered to express alpha-galactosidase A (alpha-gal A). Safety and toxicity 
      are the primary endpoints. The non-myeloablative preparative regimen consisted of 
      intravenous melphalan. No serious adverse events (AEs) are attributable to the 
      investigational product. All patients produced alpha-gal A to near normal levels 
      within one week. Vector is detected in peripheral blood and bone marrow cells, 
      plasma and leukocytes demonstrate alpha-gal A activity within or above the reference 
      range, and reductions in plasma and urine globotriaosylceramide (Gb(3)) and 
      globotriaosylsphingosine (lyso-Gb(3)) are seen. While the study and evaluations 
      are still ongoing, the first patient is nearly three years post-infusion. Three 
      patients have elected to discontinue enzyme therapy.
FAU - Khan, Aneal
AU  - Khan A
AD  - Department of Medical Genetics, Metabolics and Pediatrics, Alberta Children's 
      Hospital, Cumming School of Medicine, Research Institute, University of Calgary, 
      Calgary, AB, Canada.
FAU - Barber, Dwayne L
AU  - Barber DL
AUID- ORCID: 0000-0001-5528-8150
AD  - University Health Network, Toronto, ON, Canada.
AD  - Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Toronto, ON, Canada.
FAU - Huang, Ju
AU  - Huang J
AD  - University Health Network, Toronto, ON, Canada.
FAU - Rupar, C Anthony
AU  - Rupar CA
AD  - Department of Pathology and Laboratory Medicine, Western University, London, ON, 
      Canada.
AD  - Department of Pediatrics, Western University, London, ON, Canada.
AD  - Children's Health Research Institute, London, ON, Canada.
FAU - Rip, Jack W
AU  - Rip JW
AD  - Department of Pathology and Laboratory Medicine, Western University, London, ON, 
      Canada.
FAU - Auray-Blais, Christiane
AU  - Auray-Blais C
AD  - Division of Medical Genetics, Department of Pediatrics, CIUSSS de l'Estrie-CHUS 
      Hospital Fleurimont, Universite de Sherbrooke, Sherbrooke, QC, Canada.
FAU - Boutin, Michel
AU  - Boutin M
AD  - Division of Medical Genetics, Department of Pediatrics, CIUSSS de l'Estrie-CHUS 
      Hospital Fleurimont, Universite de Sherbrooke, Sherbrooke, QC, Canada.
FAU - O'Hoski, Pamela
AU  - O'Hoski P
AD  - Department of Pathology and Molecular Medicine, McMaster University and 
      Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada.
FAU - Gargulak, Kristy
AU  - Gargulak K
AD  - Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
FAU - McKillop, William M
AU  - McKillop WM
AD  - Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
FAU - Fraser, Graeme
AU  - Fraser G
AD  - Department of Oncology, McMaster University and Juravinski Hospital and Cancer 
      Centre, Hamilton, ON, Canada.
FAU - Wasim, Syed
AU  - Wasim S
AD  - Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, 
      Canada.
FAU - LeMoine, Kaye
AU  - LeMoine K
AD  - Nova Scotia Health Authority, QEII Health Sciences Centre, Canadian Fabry Disease 
      Initiative, Nova Scotia Fabry Disease Program, Halifax, NS, Canada.
FAU - Jelinski, Shelly
AU  - Jelinski S
AD  - Alberta Children's Hospital and Foothills Medical Centre, Calgary, AB, Canada.
AD  - Tom Baker Cancer Centre, Alberta Health Services, Calgary, AB, Canada.
FAU - Chaudhry, Ahsan
AU  - Chaudhry A
AD  - Departments of Oncology and Medicine, Alberta Blood and Marrow Transplant 
      Program, University of Calgary, Calgary, AB, Canada.
FAU - Prokopishyn, Nicole
AU  - Prokopishyn N
AD  - Department of Pathology and Laboratory Medicine, Cumming School of Medicine, 
      University of Calgary, Calgary, AB, Canada.
FAU - Morel, Chantal F
AU  - Morel CF
AD  - Fred A. Litwin Family Centre in Genetic Medicine, Department of Medicine, 
      University Health Network, Toronto, ON, Canada.
FAU - Couban, Stephen
AU  - Couban S
AD  - Division of Hematology, Department of Medicine, Dalhousie University, Halifax, 
      NS, Canada.
FAU - Duggan, Peter R
AU  - Duggan PR
AUID- ORCID: 0000-0002-1615-2274
AD  - Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
FAU - Fowler, Daniel H
AU  - Fowler DH
AD  - Rapa Therapeutics, Rockville, MD, USA.
FAU - Keating, Armand
AU  - Keating A
AD  - University Health Network, Toronto, ON, Canada.
AD  - University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada.
FAU - West, Michael L
AU  - West ML
AD  - Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, 
      NS, Canada.
FAU - Foley, Ronan
AU  - Foley R
AD  - Department of Pathology and Molecular Medicine, McMaster University and 
      Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada.
FAU - Medin, Jeffrey A
AU  - Medin JA
AUID- ORCID: 0000-0001-8165-8995
AD  - University Health Network, Toronto, ON, Canada. jmedin@mcw.edu.
AD  - Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. 
      jmedin@mcw.edu.
AD  - Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA. 
      jmedin@mcw.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT02800070
GR  - 119187/CIHR/Canada
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210225
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Antigens, CD34)
RN  - 0 (Trihexosylceramides)
RN  - 71965-57-6 (globotriaosylceramide)
RN  - EC 3.2.1.22 (GLA protein, human)
RN  - EC 3.2.1.22 (alpha-Galactosidase)
SB  - IM
MH  - Adult
MH  - Antigens, CD34
MH  - Bone Marrow Cells
MH  - Fabry Disease/*enzymology/genetics/*therapy
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Hematopoietic Stem Cells
MH  - Humans
MH  - Lentivirus/*genetics
MH  - Leukocytes
MH  - Male
MH  - Middle Aged
MH  - Trihexosylceramides/blood/urine
MH  - alpha-Galactosidase/*genetics/*therapeutic use
PMC - PMC7907075
COIS- A.K. received grants, consulting fees, revenue distribution agreement, speaker 
      fees and travel support with AVROBIO, Inc. as well as revenue distribution 
      agreement with University Health Network regarding gene therapy using technology 
      from this work. D.L.B. and J.H. were partially paid from a Sponsored Research 
      Agreement-AVROBIO, Inc. C. A. Rupar has the following financial relationships to 
      disclose: the Biochemical Genetics clinical diagnostic laboratory at his home 
      institution is contracted by AVROBIO, Inc. to assay enzymes on a fee for service 
      basis. He is the laboratory director but receives no personal compensation. 
      C.A.-B. has received a service contract and honoraria for biomarker analysis with 
      AVROBIO, Inc., grant from CIHR. K.G. had travel paid for by AVROBIO, Inc. S.W. 
      has received nonfinancial support from Sanofi-Genzyme, nonfinancial support from 
      Takeda Pharmaceuticals (formerly Shire HGT), personal fees and nonfinancial 
      support from Amicus Therapeutics. K.L. has received travel grant and honorarium 
      from Amicus Therapies; travel grant and speaker fees from Sanofi-Genzyme; travel 
      grant, consulting fees and speaker fees from Takeda Pharmaceuticals; medical 
      advisor to the Canadian Fabry Disease Association. C.F.M. has received grants, 
      personal fees, and nonfinancial support from Takeda Pharmaceuticals (previously 
      Shire HGT), grants, personal fees and nonfinancial support from Sanofi-Genzyme, 
      nonfinancial support from Amicus Therapeutics. A.K. has received consultancy fees 
      from AVROBIO, Inc. unrelated to this study. M.L.W. has received research grants, 
      consulting fees, speaker fees and travel support with Amicus Therapeutics, 
      Protalix, Sanofi-Genzyme and Takeda, revenue distribution agreement with 
      University Health Network regarding gene therapy using technology from this work. 
      J.A.M. has the following financial relationships to disclose: SAB-Rapa 
      Therapeutics. Honoraria-Sanofi-Genzyme, Shire. Co-Founder-AVROBIO, Inc. 
      Shareholder-AVROBIO, Inc. Grants from Canadian Institutes of Health Research and 
      Kidney Foundation of Canada and AVROBIO, Inc. M.B., A.C., P.R.D., R.F., D.H.F., 
      G.F., S.J., W.M.M., P.O., N.P., and J.W.R. have no financial relationships to 
      disclose in relation to this trial.
EDAT- 2021/02/27 06:00
MHDA- 2021/03/12 06:00
PMCR- 2021/02/25
CRDT- 2021/02/26 05:55
PHST- 2020/05/05 00:00 [received]
PHST- 2021/01/25 00:00 [accepted]
PHST- 2021/02/26 05:55 [entrez]
PHST- 2021/02/27 06:00 [pubmed]
PHST- 2021/03/12 06:00 [medline]
PHST- 2021/02/25 00:00 [pmc-release]
AID - 10.1038/s41467-021-21371-5 [pii]
AID - 21371 [pii]
AID - 10.1038/s41467-021-21371-5 [doi]
PST - epublish
SO  - Nat Commun. 2021 Feb 25;12(1):1178. doi: 10.1038/s41467-021-21371-5.