Cellular Therapy for Osteogenesis Imperfecta

University Of Connecticut Sch Of Med/Dnt, Farmington CT

Investigators

Abstract

ABSTRACT Osteogenesis imperfecta (OI) is a genetic disease that causes abnormal type I collagen production leading to bone fragility. Current pharmacological approaches result in an increase in the amount of defective matrix, without addressing the underlying collagen defect. An alternate approach is cell therapy. Cell therapy is based on transplanting stem/progenitor cells which can subsequently differentiate into osteoblasts and produce normal collagen. To date, preclinical and clinical studies attempting systemic transplantation of mesenchymal stem cells (MSC) in OI have had very limited success. We evaluated direct intra-bone transplantation of MSCs following total body irradiation as a therapeutic approach. Utilizing a set of stringent criteria for detection and evaluation of successful engraftment, we showed that donor MSC/progenitor cells are capable of differentiating into osteoblasts and osteocytes resulting in an increase in bone mass and improved mechanical properties of transplanted bone. Use of irradiation proved to be a critical for achieving successful engraftment. We hypothesize that by understanding mechanism of irradiation on local bone directed transplantation of MSCs we would be able to achieve a long- term successful therapy for OI. This approach of directed therapy to individual bones has the potential to improve bone growth and the outcome of the surgical procedures performed on the transplanted bones. Our study has three specific aims focusing on increasing a long-term functional engraftment of selected MSCs in the OI. Aim 1 we will evaluate different populations of cells that are accessible and can be utilized as progenitor sources for transplantation studies. In 2 aim we will determine the mechanisms by which irradiation improves engraftment. We will test the effects of irradiation on multiple lineages within the bone marrow-bone and endosteal niche. Effects on hematopoietic lineage, vascularization, mesenchymal progenitors will be examined. Understanding these mechanisms has the potential to facilitate development of optimal host preconditioning approaches for direct intra bone marrow transplantation. In Aim 3 we will test alternative methods to total body irradiation such as myeloablation. To avoid whole-body irradiation, cells will be transplanted into a femur following focal limb irradiation and effects of transplantation will be assessed with or without fracture. Our approach of targeted cellular therapy to individual bones has potential to improve the bone growth and the outcome of surgical procedures performed in OI patients. This work is prerequisite for success of any ex vivo gene-therapy attempts and our results will define a translational approach to improve treatment of OI.