Targeting the hematopoietic stem cell to correct osteopetrosis
type: CreativeWork
description: This thesis focuses on developing stem cell targeted gene therapy for the severe hereditary disorder Infantile Malignant Osteopetrosis (IMO) as well as increasing the understanding of how the genetic defect present in IMO affects the hematopoietic stem cells and hematopoiesis in general. IMO is a rare congenital disorder associated with an increased number of non-functional osteoclasts and the absence of bone resorption results in accumulation of sclerotic bone leading to abnormal bone marrow cavity formation insufficient to support hematopoiesis. The most common mutation is in the TCIRG1 gene seen in over 50% of the patients. The children suffer from bone marrow failure, anemia, thrombocytopenia, hepatosplenomegaly, immune dysfunction and recurrent infections. Furthermore, the impaired remodeling of the developing bone results in compression of cranial nerves which leads to neurological impairment, affecting especially vision and hearing which may progress to blindness and deafness. The only curative treatment available today for IMO is bone marrow transplantation. However, this can only be performed if the patient has a suitable stem cell donor. If untreated, the children die around the age of five. Currently no alternative treatment exists, thus IMO is a candidate disease for development of gene therapy. The first two papers are based on studies conducted with the oc/oc mouse model that has a mutation in the homologous gene and shares the same osteopetrotic phenotype as seen in humans. Paper one focuses on developing a clinically relevant model for cell therapy in the oc/oc mouse by replacing radiation conditioning with low-dose busulfan conditioning prior to neonatal bone marrow transplantation and optimizing the administration procedure. In paper two, neonatal oc/oc mice were treated with bone marrow transplantation without any prior conditioning, which showed a rapid reversal of the severe osteopetrotic phenotype despite low level of engraftment and lack of se…
abstract: This thesis focuses on developing stem cell targeted gene therapy for the severe hereditary disorder Infantile Malignant Osteopetrosis (IMO) as well as increasing the understanding of how the genetic defect present in IMO affects the hematopoietic stem cells and hematopoiesis in general. IMO is a rare congenital disorder associated with an increased number of non-functional osteoclasts and the absence of bone resorption results in accumulation of sclerotic bone leading to abnormal bone marrow cavity formation insufficient to support hematopoiesis. The most common mutation is in the TCIRG1 gene seen in over 50% of the patients. The children suffer from bone marrow failure, anemia, thrombocytopenia, hepatosplenomegaly, immune dysfunction and recurrent infections. Furthermore, the impaired remodeling of the developing bone results in compression of cranial nerves which leads to neurological impairment, affecting especially vision and hearing which may progress to blindness and deafness. The only curative treatment available today for IMO is bone marrow transplantation. However, this can only be performed if the patient has a suitable stem cell donor. If untreated, the children die around the age of five. Currently no alternative treatment exists, thus IMO is a candidate disease for development of gene therapy. The first two papers are based on studies conducted with the oc/oc mouse model that has a mutation in the homologous gene and shares the same osteopetrotic phenotype as seen in humans. Paper one focuses on developing a clinically relevant model for cell therapy in the oc/oc mouse by replacing radiation conditioning with low-dose busulfan conditioning prior to neonatal bone marrow transplantation and optimizing the administration procedure. In paper two, neonatal oc/oc mice were treated with bone marrow transplantation without any prior conditioning, which showed a rapid reversal of the severe osteopetrotic phenotype despite low level of engraftment and lack of se…
author: Flores Bjurström, Carmen
language: eng
keywords: Hematology, Hematopoietic stem cells, bone marrow transplantation, gene therapy, osteoclasts, infantile malignant osteopetrosis
date published: 2012
date modified: 2026-07-24T02:59:49Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Division of Molecular Medicine and Gene Therapy