Design of improved lentiviral vectors for gene delivery

 Xianyang Zhang PhD

We are working on the design of improved gene delivery systems, particularly recombinant viral vectors, to treat neurological disorders including lysosomal storage diseases.  Krabbe disease, or globoid cell leukodystrophy (GLD), is an inherited disorder affecting the central and peripheral nervous systems and is caused by a genetic defect in the gene encoding the lysosomal enzyme galactosylceramidase (GALC).  Insufficient GALC causes a series of pathological changes including demyelination of neurological tissues.  Like most chronic neurodegenerative disorders, effective treatments for Krabbe disease are impeded by the structural and functional complexity and relative inaccessibility of the central nervous system. Our goal is to develop improved lentivirus-based gene and protein transfer strategies for the central and peripheral nervous systems using the mouse model of Krabbe disease (twitcher mice). 

Our recent studies indicate that lentivirus vectors encoding a modified form of mouse GALC (containing a Tat protein transduction domain, PTD) allow sustained overproduction of GALC in mammalian cells infected with these vectors.  Inclusion of the Tat PTD motif facilitates the uptake of GALC by cells and its distribution between cells.  Indeed, complete correction of galactosylceramide accumulation in twitcher mouse fibroblasts lacking GALC activity was achieved by this lentivirus vector-mediated gene transfer.  With a view towards achieving more widespread distribution of  injected lentivirus vectors in the central and peripheral nervous systems, we are now using new lentivirus vectors that carry the glycoproteins of the Mokola and Rabies viruses.  Future approaches will involve the development of a further delivery system, ie. adeno-associated virus (AAV)-based vectors encoding modified mouse GALC, to test their therapeutic impact in twitcher mice.

Link to Dr. Zhang's Faculty page