Research Interests:
INK family cell cycle inhibitors in melanoma.
Melanomas frequently have deletions of the ink4A/ink4B loci on chromosome 9. We have reintroduced p15/ink4B, with expression controlled by tetracycline, into melanoma cell lines to examine effects on phenotype, interactions with activated ras, and response to TGFb.
Regulated expression of a toxin gene.
Targeted ablation of specific cell populations would be valuable in various disease states. We have previously shown that such ablation can be achieved with considerable precision in mice using transcriptionally targeted transgenes encoding the A-chain of diphtheria toxin. We are further developing this approach with a view to both cancer therapy (targeting endothelial cells of vasculature) and AIDS therapy (targeting HIV infected cells) using AAV and other vectors for toxin gene delivery.
Parvoviruses as gene therapy agents.
Parvoviruses are small, single strand DNA viruses which preferentially replicate in, and kill, cancer cells. We are attempting to target these viruses as potential therapeutic agents against metastatic malignancies, including melanoma and breast cancer, by modification of viral transcriptional regulation and of the capsid proteins. We are also developing autonomous parvoviruses as gene delivery vectors.
Parvovirus basic virology.
Although parvoviruses appear structurally simple, the mechanisms involved in assembly of infectious virions, in completing the early stages of cell infection, and in host range determination, are poorly understood. We are investigating these processes by exploiting a transducing, recombinant parvovirus system that we have developed, which enables components of the virions to be independently mutagenized.