What Is Happening at the University of Minnesota Regarding Research on Osteopetrosis?
The first bone marrow transplant for osteopetrosis was performed at the University of Minnesota. Currently Dr. Paul Orchard is leading the research and treatment investigations at the University of Minnesota. Dr. Orchard has an interest in the use of transplantation for osteopetrosis, as well as the biology and genetics of this disorder; his publications relating to osteopetrosis are listed below. As the primary organizer of the “International Symposium on Osteopetrosis: Biology and Therapy” at the National Institutes of Health on October 24, 2003, Dr. Orchard brought researchers together in the first meeting of its kind to discuss what is currently known regarding this disorder and what remains to be determined regarding the genetics and treatment of osteopetrosis.
At the University of Minnesota, Orchard has developed a transplant protocol using less aggressive therapy in an attempt to decrease the toxicity associated with transplant. In addition, he has developed a research protocol to investigate the function of osteoclasts from individuals with osteopetrosis with collaborators Dr. Blair, in Pittsburgh and Dr. Schlesinger, in St. Louis. He has also worked on the genetic basis of osteopetrosis along with Dr. Villa and Dr. Vezzoni in Milan, Italy.
Currently at the University of Minnesota the ability to test for the two most common genes causing osteopetrosis is in development, and should be available for patient testing in early 2005. This testing will allow evaluation of other family members to determine carrier status, and will be invaluable as a research tool to determine the implications of genetic findings in the prognosis and treatment of these patients. Dr. Orchard can be contacted at 612-626-4812 or 612-626-2961. His email is orcha001@umn.edu
References Regarding Osteopetrosis
1.Orchard PJ, Dickerman JD, Mathews CHE, Frierdich S, Hong R, Trigg ME, Shahidi NT, Finlay JL, Sondel PM: Haploidentical bone marrow transplantation for osteopetrosis. The American Journal of Pediatric Hematology/Oncology 9: 335-340, 1987.
2.Orchard PJ, Dahl N, Aukerman SL, Blazar BR, Key LL: Circulating macrophage colony-stimulating factor is not reduced in malignant osteopetrosis. Experimental Hematology 20: 103-105, 1992.
3.Yamamoto N, Naraparaju VR, Srinivaula SM, Orchard PJ. Defective lymphocyte glycosidases in the macrophage activation cascade of juvenile osteopetrosis. Blood 88: 1473-1478, 1996.
4.Eapen M, Davies SM, Ramsay NKC, Orchard PJ. Hematopoietic Stem Cell Transplantation for Infantile Osteopetrosis. Bone Marrow Transplantation 22(10):941-946, 1998.
5.Frattini A*, Orchard PJ*, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson A-K, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 Subunit of the Vacuolar Proton Pump are Responsible for a Subset of Human Autosomal Recessive Osteopetrosis. Nature Genetics 25:343-346, July 2000. *Coprincipal authors.
6.Sobacchi C, Frattini A, Orchard PJ, Porras O, Tezcan I, et al. The Mutational Spectrum of Human Malignant Autosomal Recessive Osteopetrosis. Human Molecular Genetics 10(17):1767-1773, 2001.
7.Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A. Chloride Channel CICN7 Mutations are Responsible for Severe Recessive, Dominant, and Intermediate Osteopetrosis. Journal of Bone and Mineral Research 18(10):1740-1747, November 10, 2003.
8.Blair HC, Borysenko CW, Villa A, Schlesinger PH, Kalla SE, Yaroslavskiy BB, Garcίa -Palacios V, Oakley JI, Orchard PJ. In Vitro Differentiation of CD14 Cells from Osteopetrotic Subjects: Contrasting Phenotypes with TCIRG1, CLCN7, and Attachment Defects. Journal of Bone and Mineral Research 19(8):1329-1338, Aug. 2004.
9.Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savariravan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F. TCIRG1-Dependent Recessive Osteopetrosis: Mutation Analysis, Functional Identification of the Splicing Defects and in vitro Rescue by U1 snRNA. Human Mutation 24:225-235, Sep. 2004.
10.Orchard P, Whyte M, Eapen M, Kasow K, Tolar J, Yang S, Mundy G, Key L. Proceedings of the First International Symposium on Osteopetrosis. Journal of Bone and Mineral Research 19:1356-1375, 2004.
11.Tolar J, Teitelbaum S, Orchard PJ. Molecular Etiology of Human Osteopetrosis. New England Journal of Medicine. New England Journal of Medicine 2004; 351:2839-49.
12.Steward CG, Blair A, Moppett J, Clarke E, Virgo P, Lankester A, Burger SR, Flanagan AM, Pamphilon D, Orchard P. High Peripheral Blood Progenitor Cell Counts Enable Autologous Back-up Before Stem Cell Transplantation for Malignant Infantile Osteopetrosis. Biology of Blood and Marrow Transplantation. In press..