UF gene therapy research enters new era with clinical-grade vector production facility

Gene therapy research at the University of Florida is taking a giant step forward, and UF doctors and their patients will reap the benefits.

This summer, UF’s new $3 million clinical-grade vector production laboratory began work on its first project, manufacturing a genetically modified virus that one day might bring relief to patients suffering from a damaging protein deficiency. UF researchers hope to begin a safety trial with the vector in a few months.

Known formally as the Human Applications Laboratory, the not-for-profit facility positions UF as one of the few academic institutions nationwide that produce gene therapy vectors suitable for use in people, said Richard O. Snyder, Ph.D., director of the human applications lab. It is located on the fifth floor of the Evelyn F. and William L. McKnight Brain Institute.

Clinical trials are one of the final links in a long chain of gene-therapy research UF has forged for two decades, which has included investigation of viruses for their suitability as vectors, methods of engineering the therapeutic genes into the viruses and studies in animal models, said Snyder, a UF assistant professor in the College of Medicine’s department of molecular genetics and microbiology. He also directs UF’s Vector Core, which produces research-grade vectors, and was recently named director of biotherapeutic programs for UF’s Office of Research and Graduate Programs.

"We’ve worked very hard to put something of high quality together here at the University of Florida," Snyder said. "But the real success is if we obtain beneficial effects for patients."

For long-time UF gene therapy researcher Nicholas Muzyczka, Ph.D., the human applications lab’s start-up is cause for celebration, and some anxiety. A professor and eminent scholar of molecular genetics and microbiology, Muzyczka developed the vector system the lab will manufacture in its initial project, by inserting copies of therapeutic genes into the adeno-associated virus. He hopes the vector lives up to expectations.

“We’ve been thinking about this for 20 years and what’s nice, and also scary in a way, is that we’re finally going to find out if this (vector) works — can you really correct somebody’s genetic defect?” Muzyczka said.

The human applications lab’s initial vector output will be used in a Phase 1 safety trial for adult patients suffering from alpha-1 antitrypsin deficiency disorder, a protein deficiency that causes emphysema and other diseases, said Terence Flotte, M.D., chairman of the UF department of pediatrics and the study's principal investigator. The trial will begin after the U.S. Food and Drug Administration gives its approval, expected late this year.

"The (gene therapy) is specifically designed to find a way to replace the current treatment, which is repeated intravenous infusions of the protein, by instead doing a one-time intramuscular injection of the gene vector," Flotte said. "This then allows the muscle cells to produce the normal protein and achieve a sustained release of the normal protein into the bloodstream."

Adeno-associated viral vectors are apparently harmless to humans and expresses corrective genes for long periods of time in animal models, said Barry Byrne, M.D., Ph.D., a UF professor of pediatrics and of molecular genetics and microbiology, and a veteran gene therapy researcher who pioneered intramuscular delivery of the virus.

UF researchers believe adeno-associated virus, which infects 90 to 95 percent of adults at some point in their lives and causes no known illness, is the most viable gene therapy vector available, said Byrne, who directs UF’s Powell Gene Therapy Center. Other vectors have produced harmful side effects or inadequate benefits.

Initial efforts to develop the vector production lab were led by Kye Flotte, M.S., former assistant director, research programs and services for the UF College of Medicine, Muzyczka said. During construction of the McKnight Brain Institute, Executive Director William Luttge, Ph.D., saw the opportunity to provide the needed lab space and dedicated about 2,800 square feet of the institute to the project.

Snyder arrived at UF from Harvard University in 2001 and has devoted most of his time to the effort. He credits a large group of UF entities with assisting in the lab’s development, including top administrators at the university and the College of Medicine, the McKnight Brain Institute, the Powell Gene Therapy Center, the Genetics Institute, the department of pediatrics, the department of molecular genetics and microbiology and the physical plant division.

The lab will primarily focus on producing vectors that meet U.S. Food and Drug Administration standards for Phase 1 safety trials and Phase 2 efficacy trials, handling one project at a time. The vectors are made in restricted-access clean rooms outfitted with high-tech ventilation systems and validated equipment, where operators gowned from head to toe manufacture the biopharmaceuticals following strict procedures.

Eight specially trained technicians will manufacture the vector and a five-person quality control team will test samples at various stages of the process to evaluate their safety, potency, purity and other attributes. For additional safety, an independent quality assurance unit will verify the vector meets FDA standards, as well as UF requirements.

“We’re part of a very large effort that includes basic researchers, translational researchers and clinical researchers, to ensure the safety of these patients,” Snyder said.