Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero

Annalisa Frattini, Harry C. Blair, Maria Grazia Sacco, Francesco Cerisoli, Francesca Faggioli, Enrica Mira Catò, Alessandra Pangrazio, Antonio Musio, Francesca Rucci, Cristina Sobacchi, Allison C. Sharrow, Sara E. Kalla, Maria Grazia Bruzzone, Roberte Colombo, Maria Cristina Magli, Paolo Vezzoni, Anna Villa

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Autosomal recessive osteopetrosis (ARO) is a paradigm for genetic diseases that cause severe, often irreversible, defects before birth. In ARO, osteoclasts cannot remove mineralized cartilage, bone marrow is severely reduced, and bone cannot be remodeled for growth. More than 50% of the patients show defects in the osteoclastic vacuolar-proton-pump subunit, ATP6a3. We treated ATP6a3-deficient mice by in utero heterologous hematopoietic stem cell (HSC) transplant from outbred GFP transgenic mice. Dramatic phenotype rescue by GFP osteoclasts was obtained with engraftment, which was observed in most cases. Engraftment survived for variable periods. Recipients were not immunosuppressed, and graft-versus-host disease was not observed in all pups born after in utero treatment. Thus, differentiation of unmatched HSC transplanted in utero is sufficient to prevent fatal defects in ARO and may prevent complications of ARO unresponsive to conventional bone marrow transplantation. The presence of defective cells is not a barrier to the rescue of the phenotype by donor HSC.

Original languageEnglish
Pages (from-to)14629-14634
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number41
DOIs
Publication statusPublished - Oct 11 2005

Fingerprint

Osteopetrosis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Osteoclasts
Phenotype
Proton Pumps
Inborn Genetic Diseases
Graft vs Host Disease
Bone Marrow Transplantation
Transgenic Mice
Cartilage
Bone Marrow
Tissue Donors
Transplants
Bone and Bones
Growth

Keywords

  • Autosomal recessive osteopetrosis
  • Bone marrow transplant
  • Prenatal therapy

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero. / Frattini, Annalisa; Blair, Harry C.; Sacco, Maria Grazia; Cerisoli, Francesco; Faggioli, Francesca; Catò, Enrica Mira; Pangrazio, Alessandra; Musio, Antonio; Rucci, Francesca; Sobacchi, Cristina; Sharrow, Allison C.; Kalla, Sara E.; Bruzzone, Maria Grazia; Colombo, Roberte; Magli, Maria Cristina; Vezzoni, Paolo; Villa, Anna.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 41, 11.10.2005, p. 14629-14634.

Research output: Contribution to journalArticle

Frattini, Annalisa ; Blair, Harry C. ; Sacco, Maria Grazia ; Cerisoli, Francesco ; Faggioli, Francesca ; Catò, Enrica Mira ; Pangrazio, Alessandra ; Musio, Antonio ; Rucci, Francesca ; Sobacchi, Cristina ; Sharrow, Allison C. ; Kalla, Sara E. ; Bruzzone, Maria Grazia ; Colombo, Roberte ; Magli, Maria Cristina ; Vezzoni, Paolo ; Villa, Anna. / Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 41. pp. 14629-14634.
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