Krabbe's disease is a life threatening, inherited glycogen storage disease resulting from mutations in the enzyme galactocerebrosidase (GALC). The only available therapy is heterologous bone marrow transplantation during the earliest months of life to produce the active form of GALC through out the body. Bone marrow transplantation is complicated by graft versus host disease, a severe immunological disorder characterized by engrafted cytotoxic T lymphocytes destruction of host tissues including the skin epithelium, intestinal mucosa, and kidneys. The complications of GVHD extend hospitalizations, increase medical costs, and have a high degree of associated morbidity and mortality. If the clinical diagnosis of Krabbe's disease is made later than the first few months, there is no effective treatment option for patients, as bone marrow transplant is no longer effective. Our Preliminary data indicates that GALC is expressed not only by hematopoietic stem cells but also by adipose derived stem cells. Based on these important observations, we propose to test the following overarching hypothesis: That adipose derived stem cells (ASC) have the potential to serve as a cell therapeutic expressing GALC for Krabbe's disease without the complicating destructive consequences of hematopoietic stem cell therapy. This proposal constitutes the initial proof of concept step in the translational and regenerative medical strategy outlined below. The murine studies are the first step in this process. Eventually, the nonhuman primate model will allow the analysis of our novel therapeutic interventions by permitting multiple biopsies, MRI analysis of animals and unique avenues, such as the ability to perform both cognitive and behavioral testing that cannot be done in lower order animal models. Additionally, the analysis of therapies in nonhuman primates permits the testing to be performed in a manner nearly identical to a human clinical trial. Our investigations are directed towards the only available nonhuman primate model of a human genetic disease, and will provide essential information that cannot be ethically obtained in a human clinical setting, and are of direct importance for the treatment of human fetuses and infants compromised by this devastating disease.
The grant is resubmitted in response to PAR-06-198 """"""""NINDS Exploratory / Developmental Projects in Translational Research"""""""". This R21 proposal rests on the hypothesis that adipose derived stem cells (ASC) have the potential to serve as a cell therapeutic expressing GALC for Krabbe's disease without the complicating destructive consequences of hematopoietic stem cell therapy. This proposal constitutes the initial proof of concept step in a comprehensive translational and regenerative medical strategy. Specifically, murine studies will serve as the first step in this process. Subsequent proof of principle studies in a nonhuman primate model will allow the analysis of our novel therapeutic interventions by permitting multiple biopsies, MRI analysis of animals and unique avenues, such as the ability to perform both cognitive and behavioral testing, that cannot be done in lower order animal models.
