Correction of neural abnormalities in Hurler syndrome

DESCRIPTION (provided by applicant): Progressive neurological dysfunction and mental retardation are among the most devastating consequences of Hurler syndrome (mucopolysaccharidosis type I), the most common inherited disorder of glycosaminoglycan metabolism usually diagnosed in early childhood. These neuro-psychological abnormalities are not adequately corrected by hematopoietic stem cell transplantation (via bone marrow transplantation; BMT). The investigators recently enriched and expanded a non-hematopoietic, multipotent mesenchymal stem cell (MSC) from post-natal human bone marrow, which can be differentiated in vitro into various types of neuronal and glial cells as well as multiple mesodermal lineage cells. It may therefore be possible to reconstitute neuronal and diverse other tissues using such cells from the bone marrow. The long term goal of the studies is to develop a novel therapeutic strategy for the correction of neurological abnormalities by transplantation of MSC or their progeny into the central nervous system. Hurler syndrome will be used as a model for developing this strategy since (i) Hurler syndrome is the most common mucopolysaccharidosis, (ii) a large number of bone marrow samples are available because of referral of patients to the investigators' center for BMT, and (iii) the potential for clinical transnational studies in the investigators' large patient base. If successful, similar strategies may potentially be useful for treating other storage disorders of glycosaminoglycan metabolism in which BMT does not halt progressive neurological deterioration. The major advantages of using MSCs (rather than neuronal stem cells) for developing a therapeutic strategy are that these cells (i) can easily be obtained from a small bone marrow aspirate sample, (ii) can be transduced with genes with high efficiency without loss of stem cell capability, (iii) support sustained gene expression, and (iv) are not subject to ethical issues associated with the use of human embryonic stem cells or fetal neuronal stem cells. MSCs may thus be the ideal type of autologous cell for the clinical delivery of therapeutic genes in disorders such as Hurler syndrome. In this application, the investigators propose to initiate studies towards this goal. In the current Small Grant application, the investigators will focus on in vitro studies of human MSC derived from normal and Hurler bone marrow. They will compare the structure and binding properties of heparan sulfates from Hurler and normal MSC, identify the mechanism(s) by which abnormal glycosaminoglycas in Hurler cells lead to defective differentiation of neural cells derived from MSC, and examine if the presence of normal or gene corrected MSC can rectify these abnormalities. The investigators will also examine if MSC can be successfully implanted into brains of NOD/SCID mice. They have preliminary data supporting this hypothesis, and indicating that they can successfully perform the studies proposed. The investigators anticipate that data generated from these studies will lead to the subsequent submission of a traditional research grant application, in which they will extend these studies to animal models of Hurler syndrome such as the MPS-I mouse, as a prerequisite for future human trials.