In the area of development of virus vectors, we are designing new versions of herpes and retrovirus vectors that will increase the selectivity of gene delivery and provide for stable and regulated gene expression in vivo. Herpes vectors are being optimized for efficient, non-toxic gene delivery to neurons, as well as for therapeutic treatment of brain tumors. This includes coupling of amplicon and recombinant virus herpes vectors to allow conditional propagation and multiple transgene delivery; inclusion of DNA elements into amplicon vector that will promote integration and amplification in the host cell genome; and combining viral elements and DNA conjugates to develop synthetic vectors.
Our main target for gene therapy is glioblastomas using virus vectors bearing transgenes that can activate prodrugs to antineoplastic drugs. In experimental rodent models we are focusing on achieving gene delivery to disseminated tumor cells in the brain through on site vector generation, and administration through the cerebral spinal fluid and across the blood brain barrier. New recombinant prodrug activating enzymes are being developed which will act extracellularly and target selectively to tumor cells. In these efforts we are working closely with neurosurgeons, Drs. Griffith Harsh and E. Antonio Chiocca, and with neuro-oncologist, Dr. Fred Hochberg, to translate successful experimental models into phase 1 trials in humans.
Our laboratory has recently identified the gene responsible for early onset torsion dystonia, a movement disorder in humans inherited as an autosomal dominant trait. This is a non-degenerative disease of the basal ganglia which leads to a debilitating loss of motor control. The mutant protein is believed to disrupt dopaminergic neurotransmission, with consequent disturbance in postnatal development of the basal ganglia. Studies are underway to characterize the function of this protein using biochemical, immunological and neurobiologic analysis of cultured neurons and transgenic mice.