Jacquelyn Bower, PhD

Oxford-Harrington Rare Disease Scholar, Dr. Jacquelyn Bower, is working to develop potential therapies for a rare, aggressively metastasizing eye cancer—uveal melanoma (UVM). Difficult side effects accompany standard immunotherapy and radiation treatments, and eye removal doesn’t always stop the spread. Cruelly, UVM can strike again after a long remission. Dr. Bower hopes to develop a targeted gene therapy using a viral vector to help save sight and lives.

“In cell culture studies, we used an adeno-associated virus (AAV)-based vector to silence two mutated genes, GNAQ or GNA11— two closely related tumor drivers found in 90% of UVM patients,” Dr. Bower explains.

In early AAV studies using tumor cell cultures, Dr. Bower and her team decreased the survival of UVM cells—a big win. AAV effectively delivers nucleic acids that can target specific sequences of mutated genes, providing an advantage over chemical inhibition. The “G” family of proteins has been considered largely undruggable because chemical inhibitors have difficulty discerning between the normal and mutant proteins and therefore can be highly toxic in normal cells.

“With Harrington support, we are optimizing a combination of AAV-expressing shRNAs (artificial RNA molecules) targeting the mutant G proteins that drive 80-90% of UVM initiation and progression,” she says. “We’ll then test lead candidate vectors in genetically engineered UVM mice, targeting GNAQ and GNA11, as well as exploring additional gene therapy strategies for the remaining 10% of UVM cases.”

Survival rates for primary UVM tumors have improved with early diagnosis and treatment. But in about half of the patients the tumors return, and once metastasized, survival rates plummet to zero.

“Our number one hope is that AAV can treat both primary and metastatic tumors,”

Dr. Bower says.