Targeting NSG Mice Engrafting Cells with a Clinically Applicable Lentiviral Vector Corrects Osteoclasts in Infantile Malignant Osteopetrosis
(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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- author
- organization
- publishing date
- 2018
- 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}}, }