Our laboratory is highly focused on developing gene therapy for MPS diseases, and with this grant from the Children’s Medical Research Foundation, has made significant advances during the past two years. This grand funds the work of Dr. Hong Zhao, who was the first to identify and characterize the gene causing Sanfilippo B Syndrome, while working in the laboratory of Dr. Elizabeth Neufeld (UCLA). The specific aims and accomplishments of Dr. Zhao and her colleagues illustrate the progress of a research concept as it develops from the laboratory bench toward potential clinical application.

Based on previous experience with mutation analysis methods developed in the laboratory of Dr. Whitley, Drs. Zhao and Elena Aronovich developed a method of rapid automated sequencing of the human NaGlu (Sanfilippo B gene) coding region, which allowed identification of the mutations responsible for defective NaGlu enzyme. While manual sequencing of a gene of this size normally requires several months’ work, the method developed by this group showed that it is possible to accomplish automated sequencing of a gene in as little as a week. Most importantly, this method provides the molecular genetic background to insert the normal gene sequence into a retrovirus vector, or other gene transfer vehicles, for subsequent investigations of therapeutic gene delivery and expression.

Initial gene therapy experiments would be to insert the NaGlu cDNA sequence into a virus-derived vector system and then study gene transfer into human blood cells. Investigators would then evaluate whether or not one or more such vectors will yield high levels of normal NaGlu enzyme. If so, such a vector could be used to provide a "super bone marrow transplant" which after modification of some of the currently used clinical approaches, could be used to transfer the normal gene into blood cells of affected individuals. The potential advantage would be the ability to provide high levels of enzyme in the blood, but without the problems and risks of "graft vs. host disease." Such vectors are currently in development.