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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


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.


  • Ilana Moscatelli
  • Henrik Löfvall
  • Christian Schneider Thudium
  • Michael Rothe
  • Carmen Montano
  • Zsuzsanna Kertész
  • Mehtap Sirin
  • Ansgar Schulz
  • Axel Schambach
  • Kim Henriksen
  • Johan Richter
Enheter & grupper
Externa organisationer
  • Nordic Bioscience AS
  • Hannover Medical School
  • University Hospital of Ulm

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Sidor (från-till)938-949
TidskriftHuman Gene Therapy
Tidigt onlinedatum2017 okt 3
StatusPublished - 2018
Peer review utfördJa

Relaterad forskningsoutput

Löfvall, H., 2018, Lund: Lund University, Faculty of Medicine. 114 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Related projects

Henrik Löfvall, Johan Richter, Kim Henriksen & Christian S. Thudium


Projekt: Forskning

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