Treatment of very young dogs suffering from muscular dystrophy by allogeneic stem cell transplantation
10 / 2002 - 01 / 2006
Duchenne muscular dystrophy (DMD) is a fatal X-linked hereditary disease for which no effective treatment exists. The disease is caused by mutations in the dystrophin gene which result in progressive wasting of both skeletal and heart muscle. It was recently discovered that transplantation of bone marrow cells from normal donors to dystrophin-deficient mdx mice results in the appearance of donor-derived, dystrophin-expressing myocytes in skeletal and cardiac muscle tissue. As mdx mice are clinically only marginally affected, they are not suited to study the effect of bone marrow transplantation on the disease pattern in DMD. However, dogs with DMD show a clinical pattern of disease that is very similar to human DMD. We propose to investigate the infiltration of donor derived muscle progenitor cells following stem cell transplantation in this canine model of DMD. In addition, we will study whether stem cell transplantation may alter the disease pattern in DMD dogs. In the present project, we propose to investigate the role of stem cell transplantation in very young, pre-symptomatic dogs with DMD. We focus on very young (1-2 months old), clinically asymptomatic dogs, as it can be expected that early infiltration of donor-derived muscle cells, before the onset of irreversible fibrosis and necrosis, may prevent or ameliorate clinical symptoms. E.g., we will investigate whether stem cell transplantation results in infiltration of donor derived cells in cardiac and skeletal muscle and whether skeletal and cardiac functions improve after transplantation. The kinetics of the infiltration of donor-derived cells will be studied by sequential analysis in transplanted dogs. If our studies show that stem cell transplantation can diminish the disease pattern in DMD dogs, a clinical study to the effect of stem cell transplantation in patients with DMD may be initiated. In addition, the model for stem cell transplantation in very young dogs may be extended to study the role of genetically modified, autologous stem cells, in which a functional copy of the dystrophin gene is being expressed. In the pilot year of the project, an experimental set-up for stem cell transplantation in very young, healthy non-DMD dogs (less than 2 months of age) will be developed. In addition, baseline investigations in DMD dogs will be carried out. These pilot studies are aimed to confirm that BMT in DMD dogs will be feasible at our institution. In the second year, very young dogs with DMD will be transplanted, and the effects will be analysed.