PMID- 31501599
OWN - NLM
STAT- MEDLINE
DCOM- 20191112
LR  - 20220417
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 25
IP  - 9
DP  - 2019 Sep
TI  - Successful engraftment of gene-corrected hematopoietic stem cells in 
      non-conditioned patients with Fanconi anemia.
PG  - 1396-1401
LID - 10.1038/s41591-019-0550-z [doi]
AB  - Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 
      22 FA genes discovered to date(1,2). Mutations in FANCA account for more than 60% 
      of FA cases worldwide(3,4). Clinically, FA is associated with congenital 
      abnormalities and cancer predisposition. However, bone marrow failure is the 
      primary pathological feature of FA that becomes evident in 70-80% of patients 
      with FA during the first decade of life(5,6). In this clinical study 
      (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 
      2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene 
      therapy reproducibly confers engraftment and proliferation advantages of 
      gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with 
      FA subtype A. Insertion-site analyses revealed the multipotent nature of 
      corrected HSCs and showed that the repopulation advantage of these cells was not 
      due to genotoxic integrations of the therapeutic provirus. Phenotypic correction 
      of blood and bone marrow cells was shown by the acquired resistance of 
      hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. 
      Additionally, an arrest of bone marrow failure progression was observed in 
      patients with the highest levels of gene marking. The progressive engraftment of 
      corrected HSCs in non-conditioned patients with FA supports that gene therapy 
      should constitute an innovative low-toxicity therapeutic option for this 
      life-threatening disorder.
FAU - Rio, Paula
AU  - Rio P
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Navarro, Susana
AU  - Navarro S
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Wang, Wei
AU  - Wang W
AD  - Division of Translational Oncology, German Cancer Research Center and National 
      Center for Tumor Diseases, Heidelberg, Germany.
AD  - GeneWerk, Heidelberg, Germany.
FAU - Sanchez-Dominguez, Rebeca
AU  - Sanchez-Dominguez R
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Pujol, Roser M
AU  - Pujol RM
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
AD  - Servicio de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
AD  - Instituto de Investigaciones Biomedicas, Hospital de la Santa Creu i Sant Pau, 
      Barcelona, Spain.
FAU - Segovia, Jose C
AU  - Segovia JC
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Bogliolo, Massimo
AU  - Bogliolo M
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
AD  - Servicio de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
AD  - Instituto de Investigaciones Biomedicas, Hospital de la Santa Creu i Sant Pau, 
      Barcelona, Spain.
FAU - Merino, Eva
AU  - Merino E
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Servicio de Hematologia y Oncologia Pediatrica, Fundacion de Investigacion 
      Biomedica, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.
FAU - Wu, Ning
AU  - Wu N
AD  - Division of Translational Oncology, German Cancer Research Center and National 
      Center for Tumor Diseases, Heidelberg, Germany.
FAU - Salgado, Rocio
AU  - Salgado R
AD  - Servicio de Hematologia, Hospital Universitario Fundacion Jimenez Diaz, Instituto 
      de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, Spain.
FAU - Lamana, Maria L
AU  - Lamana ML
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Yanez, Rosa M
AU  - Yanez RM
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Casado, Jose A
AU  - Casado JA
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Gimenez, Yari
AU  - Gimenez Y
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Roman-Rodriguez, Francisco J
AU  - Roman-Rodriguez FJ
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Alvarez, Lara
AU  - Alvarez L
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Alberquilla, Omaira
AU  - Alberquilla O
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Raimbault, Anna
AU  - Raimbault A
AD  - Universite de Paris (IRSL, INSERM, CNRS), Paris, France.
AD  - Hopital Saint-Louis, Paris, France.
FAU - Guenechea, Guillermo
AU  - Guenechea G
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Lozano, M Luz
AU  - Lozano ML
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Cerrato, Laura
AU  - Cerrato L
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Hernando, Miriam
AU  - Hernando M
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - Galvez, Eva
AU  - Galvez E
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Servicio de Hematologia y Oncologia Pediatrica, Fundacion de Investigacion 
      Biomedica, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.
FAU - Hladun, Raquel
AU  - Hladun R
AD  - Servicio de Oncologia y Hematologia Pediatricas, Hospital Universitari Vall 
      d'Hebron, Barcelona, Spain.
AD  - Vall d'Hebron Institut de Recerca, Barcelona, Spain.
FAU - Giralt, Irina
AU  - Giralt I
AD  - Vall d'Hebron Institut de Recerca, Barcelona, Spain.
FAU - Barquinero, Jordi
AU  - Barquinero J
AD  - Vall d'Hebron Institut de Recerca, Barcelona, Spain.
FAU - Galy, Anne
AU  - Galy A
AD  - Genethon, Evry, France.
FAU - Garcia de Andoin, Nagore
AU  - Garcia de Andoin N
AD  - Hospital Universitario Donostia, San Sebastian, Spain.
FAU - Lopez, Ricardo
AU  - Lopez R
AD  - Osakidetza Basque Health Service, Pediatric Oncology and Hematology Unit, Cruces 
      University Hospital, Barakaldo, Spain.
FAU - Catala, Albert
AU  - Catala A
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Servicio de Hematologia y Oncologia, Hospital Sant Joan de Deu, Barcelona, Spain.
FAU - Schwartz, Jonathan D
AU  - Schwartz JD
AD  - Rocket Pharma, New York, NY, USA.
FAU - Surralles, Jordi
AU  - Surralles J
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
AD  - Servicio de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
AD  - Instituto de Investigaciones Biomedicas, Hospital de la Santa Creu i Sant Pau, 
      Barcelona, Spain.
FAU - Soulier, Jean
AU  - Soulier J
AD  - Universite de Paris (IRSL, INSERM, CNRS), Paris, France.
AD  - Hopital Saint-Louis, Paris, France.
FAU - Schmidt, Manfred
AU  - Schmidt M
AD  - Division of Translational Oncology, German Cancer Research Center and National 
      Center for Tumor Diseases, Heidelberg, Germany.
AD  - GeneWerk, Heidelberg, Germany.
FAU - Diaz de Heredia, Cristina
AU  - Diaz de Heredia C
AD  - Servicio de Oncologia y Hematologia Pediatricas, Hospital Universitari Vall 
      d'Hebron, Barcelona, Spain.
AD  - Vall d'Hebron Institut de Recerca, Barcelona, Spain.
FAU - Sevilla, Julian
AU  - Sevilla J
AUID- ORCID: 0000-0002-6852-1860
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
AD  - Servicio de Hematologia y Oncologia Pediatrica, Fundacion de Investigacion 
      Biomedica, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.
FAU - Bueren, Juan A
AU  - Bueren JA
AUID- ORCID: 0000-0002-3228-7013
AD  - Hematopoietic Innovative Therapies Division, Centro de investigaciones 
      Energeticas, Medioambientales y Tecnologicas, Madrid, Spain. 
      juan.bueren@ciemat.es.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain. 
      juan.bueren@ciemat.es.
AD  - Instituto de Investigaciones Sanitarias de la Fundacion Jimenez Diaz, Madrid, 
      Spain. juan.bueren@ciemat.es.
LA  - eng
SI  - ClinicalTrials.gov/NCT03157804
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190909
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Fanconi Anemia Complementation Group A Protein)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Bone Marrow Cells/cytology
MH  - Child
MH  - Child, Preschool
MH  - Fanconi Anemia/genetics/physiopathology/*therapy
MH  - Fanconi Anemia Complementation Group A Protein/*genetics
MH  - Female
MH  - *Genetic Therapy
MH  - Genetic Vectors/genetics
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Hematopoietic Stem Cells/metabolism
MH  - Humans
MH  - Infant
MH  - Lentivirus/genetics
MH  - Male
MH  - Mutation/genetics
MH  - Spain/epidemiology
MH  - Targeted Gene Repair
MH  - Transduction, Genetic
MH  - Young Adult
EDAT- 2019/09/11 06:00
MHDA- 2019/11/13 06:00
CRDT- 2019/09/11 06:00
PHST- 2018/06/22 00:00 [received]
PHST- 2019/07/18 00:00 [accepted]
PHST- 2019/09/11 06:00 [entrez]
PHST- 2019/09/11 06:00 [pubmed]
PHST- 2019/11/13 06:00 [medline]
AID - 10.1038/s41591-019-0550-z [pii]
AID - 10.1038/s41591-019-0550-z [doi]
PST - ppublish
SO  - Nat Med. 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 
      9.