Stem Cell-Based Therapy for Canavan Disease



 DESCRIPTION (provided by applicant): Human neural stem cells hold considerable potential for the treatment of neurodegenerative disease. This proposal outlines a series of experiments designed to validate stem cell transplantation as a viable therapeutic option for treatment of the currently intractable inherited pediatric leukodystrophy Canavan disease (CD). In collaboration with Stem Cells Inc. we have generated preliminary data demonstrating the successful engraftment of human neural stem cells (HuCNS-SC) in an animal model of CD. Significantly, high levels of engraftment were observed in adult (3 month old) animals, which is considered to be of considerable clinical relevance. By comparing HuCNS-SC intervention side by side with murine oligodendrocyte progenitor (mOPC) intervention, we show that human material promotes phenotypic recovery by way of the support of endogenous oligodendrogenesis, and we hypothesize here that this effect is due to trophic effects exerted on the local microenvironment. On the basis of previously published work in this model system, we posit that HuCNS-SC effect this support by way of a reduction in damage resulting from oxidative stress, with a consequent improvement in oligodendrocyte viability. Accordingly, this study will quantify key metabolites in transplanted animals that have been previously shown by our group to be central to the CD phenotype. This point of focus differs significantly from current strategies in two important ways. Firstly, the fous on oxidative integrity is a significant departure from previous studies that have focused solely on strategies that seek to augment the loss of aspartoacylase function in CD. Secondly, we argue that any strategy seeking to treat symptomatic CD must account for the profound oligodendrocyte loss that is readily apparent in the model system to be employed in this project, and that the only truly viable strategies are those that can address this limiting feature of pathology directly. This study will provide graduate and undergraduate students at the host institution with the opportunity to work with an extremely promising therapeutic intervention under the mentorship of an investigator with a long standing commitment to translational CD research.