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Targeting NSG Mice Engrafting Cells with a Clinically Applicable Lentiviral Vector Corrects Osteoclasts in Infantile Malignant Osteopetrosis

Moscatelli, Ilana LU ; Löfvall, Henrik LU orcid ; Schneider Thudium, Christian ; Rothe, Michael ; Montano, Carmen LU ; Kertész, Zsuzsanna LU ; Sirin, Mehtap ; Schulz, Ansgar ; Schambach, Axel and Henriksen, Kim , et al. (2018) In Human Gene Therapy 29(8). p.938-949
Abstract
Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by nonfunctional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to develop a clinically applicable lentiviral vector expressing TCIRG1 to correct osteoclast function in IMO. Two mammalian promoters were compared: elongation factor 1α short (EFS) promoter and chimeric myeloid promoter (ChimP). EFS promoter was chosen for continued experiments, as it performed better. IMO osteoclasts corrected in vitro by a TCIRG1-expressing lentiviral vector driven by EFS (EFS-T) restored Ca2+ release to 92% and the levels of the bone degradation... (More)
Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by nonfunctional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to develop a clinically applicable lentiviral vector expressing TCIRG1 to correct osteoclast function in IMO. Two mammalian promoters were compared: elongation factor 1α short (EFS) promoter and chimeric myeloid promoter (ChimP). EFS promoter was chosen for continued experiments, as it performed better. IMO osteoclasts corrected in vitro by a TCIRG1-expressing lentiviral vector driven by EFS (EFS-T) restored Ca2+ release to 92% and the levels of the bone degradation product CTX-I to 95% in the media compared to control osteoclasts. IMO CD34+ cells from five patients transduced with EFS-T were transplanted into NSG mice. Bone marrow was harvested 9–19 weeks after transplantation, and human CD34+ cells were selected, expanded, and seeded on bone slices. Vector-corrected IMO osteoclasts had completely restored Ca2+ release. CTX-I levels in the media were 33% compared to normal osteoclasts. Thus, in summary, evidence is provided that transduction of IMO CD34+ cells with the clinically applicable EFS-T vector leads to full rescue of osteoclasts in vitro and partial rescue of osteoclasts generated from NSG mice engrafting hematopoietic cells. This supports the continued clinical development of gene therapy for IMO. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Gene Therapy
volume
29
issue
8
pages
938 - 949
publisher
Mary Ann Liebert, Inc.
external identifiers
  • pmid:28726516
  • scopus:85051361142
ISSN
1043-0342
DOI
10.1089/hum.2017.053
project
Improving our understanding of osteoclasts in bone metabolic diseases through novel osteoclast models
language
English
LU publication?
yes
id
b97d8be3-7f0e-44f1-8666-b2781840208c
date added to LUP
2018-01-22 11:37:00
date last changed
2022-04-25 05:12:12
@article{b97d8be3-7f0e-44f1-8666-b2781840208c,
  abstract     = {{Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by nonfunctional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to develop a clinically applicable lentiviral vector expressing TCIRG1 to correct osteoclast function in IMO. Two mammalian promoters were compared: elongation factor 1α short (EFS) promoter and chimeric myeloid promoter (ChimP). EFS promoter was chosen for continued experiments, as it performed better. IMO osteoclasts corrected in vitro by a TCIRG1-expressing lentiviral vector driven by EFS (EFS-T) restored Ca2+ release to 92% and the levels of the bone degradation product CTX-I to 95% in the media compared to control osteoclasts. IMO CD34+ cells from five patients transduced with EFS-T were transplanted into NSG mice. Bone marrow was harvested 9–19 weeks after transplantation, and human CD34+ cells were selected, expanded, and seeded on bone slices. Vector-corrected IMO osteoclasts had completely restored Ca2+ release. CTX-I levels in the media were 33% compared to normal osteoclasts. Thus, in summary, evidence is provided that transduction of IMO CD34+ cells with the clinically applicable EFS-T vector leads to full rescue of osteoclasts in vitro and partial rescue of osteoclasts generated from NSG mice engrafting hematopoietic cells. This supports the continued clinical development of gene therapy for IMO.}},
  author       = {{Moscatelli, Ilana and Löfvall, Henrik and Schneider Thudium, Christian and Rothe, Michael and Montano, Carmen and Kertész, Zsuzsanna and Sirin, Mehtap and Schulz, Ansgar and Schambach, Axel and Henriksen, Kim and Richter, Johan}},
  issn         = {{1043-0342}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{938--949}},
  publisher    = {{Mary Ann Liebert, Inc.}},
  series       = {{Human Gene Therapy}},
  title        = {{Targeting NSG Mice Engrafting Cells with a Clinically Applicable Lentiviral Vector Corrects Osteoclasts in Infantile Malignant Osteopetrosis}},
  url          = {{http://dx.doi.org/10.1089/hum.2017.053}},
  doi          = {{10.1089/hum.2017.053}},
  volume       = {{29}},
  year         = {{2018}},
}