Research is a key part of the Neurosurgery Department’s Residency Program at the U. To underscore its importance, dedicated time is given to each resident interested in doing investigative work.

Fourth-year neurosurgery resident Dominic Gessler, MD, PhD, is no stranger to such work. “Before I started my residency in Minnesota, I had been doing research for about eight years,” he said. “Part of it was in medical school; part was during my PhD research in gene therapy at the University of Massachusetts Medical School. I never really stopped doing it, which was possible because of Dr. Guangping Gao’s support and mentorship.” Gao is Director of the Gene Therapy Center and Co-Director of the Li Weibo Institute for Rare Diseases Research at UMass.

Focus on CNS disorders
Gessler’s work has focused on translational research for central nervous system (CNS) disorders, with an emphasis on a condition known as Canavan disease. “Canavan disease is a gene-linked neurological disorder in which the brain degenerates into spongy tissue riddled with microscopic fluid-filled spaces. Symptoms of Canavan disease usually appear in the first three to six months of life and progresses rapidly.”1 There is no cure.

Gessler’s other work focuses on mechanistic questions. He is trying to understand how different cells of the brain regulate brain energy metabolism and how it contributes to disease, and how that knowledge could be used as a therapy target, a concept known as metabolic rescue.

When the opportunity for his 18-month research stint arose during his residency at the U, Gessler knew he wanted to return to his mentor’s lab, who is a world-leader in gene therapy, and into a newly created Gene Therapy Fellowship.

UMN faculty support
“When I talked with Dr. [Michael] Park and other faculty members about it, they were all very supportive from the beginning,” said Gessler. “It’s not that easy for a program to enable a resident to go out of state. For the faculty to take the risk to support my interests is huge. It also highlights how the program at the U is trying to develop neurosurgeons who are passionate about what they do.”


Dominic Gessler

The fellowship enables Gessler (pictured here) to continue his lab work and get the opportunity to be involved in gene therapy clinical trials. “I am learning about what is required for a clinical trial, from an administrative as well as the clinical perspective, including what standards must be met, the regulatory process, patient monitoring and outcome assessment, and what and when information should be recorded,” he said. “It’s a lot of unknown territory for me.”

The two directors of the fellowship program are Miguel Sena Esteves, PhD, a basic scientist and world leader in gene therapy for CNS disorders with particular focus on Tay Sachs and Sandhoff disease; and Dean Terence R. Flotte, MD, who is a world-renowned gene therapy researcher and the first to use a recombinant adeno-associated virus in humans for gene therapy. “They are incredible mentors from which to learn,” said Gessler.

Multiple projects
The group is working on multiple projects. Gessler’s team focuses on Canavan disease. “It requires daily troubleshooting, developing new methods to answer our questions, and writing papers and grants,” he said. “On the clinical side, we meet weekly to discuss each patient who is enrolled in a gene therapy trial and look at their immune response, basic clinical biochemistry to see if they have signs of rising inflammation – indicated, for example, by heightened white blood cell count – or signs of liver injury and are with the patient when the gene therapy is being administered.”

The team must follow a strict regimen and protocols when they see trial participants in the clinic to determine if they’re doing okay or perhaps even improving, which is the goal, noted Gessler. “Many of these trials at UMass are Phase I/II with the focus on safety first and then on efficacy,” he noted. “We frequently check patients’ charts to see if there are any results that need to be discussed.”

The gene therapy for Canavan disease developed in his mentor’s lab is currently in Phase I/II trial, which is conducted at Massachusetts General Hospital in Boston. Part of the trial is starting patients at a lower dose of the therapy being tested to see how well it’s tolerated. “There is a specific range of doses that are part of each IND [Investigational New Drug] protocol,” said Gessler. “The expectation is that the closer we get to the target dose, the more treatment effect but also side-effects are likely to be seen. It depends on the subject’s age and the chronic nature of the CNS disease process. For Canavan patients, the gene therapy is delivered intravenously in a single dose to reach its target cells.”

Breaking the barrier
For other clinical trials, some genetically altered therapeutic viruses are delivered into the brain directly through burr holes and catheters, noted Gessler. When researchers want to deliver such viruses, they have an immediate obstacle to overcome — the blood-brain barrier that protects the brain. “What’s fascinating about recombinant adeno-associated virus is that it comes in many different types of ‘packages’ or serotypes,” said Gessler. “Depending on the packaging you choose, the virus has a propensity for one organ more than another, including the brain. There are several that have been well tested in animals and humans and they can safely cross the blood brain barrier. It makes for a versatile delivery tool.”

Ultimately, the research that Gessler is doing is designed to help patients and their families. “That’s the big promise of gene therapy for genetic diseases,” he said. “In some clinical trials, patients that would die early in childhood or never learn to walk are surviving now and walking. While the results are not perfect yet, the trials teach us a tremendous amount about safety and what we need to change to improve the efficacy. The families and patients are heroes to me – their commitment makes everything we do possible.”