Phillip Tai, PhD, received a $1.6 million grant from the National Institute of General Medical Sciences to investigate the basic mechanisms of adeno-associated viral vectors (AAV) using high-resolution DNA sequencing technology. These findings could potentially lead to new vector designs that improve the safety of gene therapy treatments.
“If we can improve gene therapy vectors, even in a slight way, it’s going to have a tremendous benefit. We can tell patients and pharmaceutical companies that we have a better understanding of how these vectors work and that will open the doors for further research,” said Dr. Tai, assistant professor of genetic & cellular medicine.
Great strides have been made in delivering gene therapies to patients over the last 20 years. Physician–scientists can now deliver therapeutic genes safely and efficiently into human cells using engineered viral vectors, such as those based on AAV.
While these delivery systems have been proven to be safe for humans and have been given to thousands of patients over hundreds of clinical trials over the last ten years, some animal model studies have reported that a small number of these vectors can integrate into the host cell’s genome. A recent finding in a human clinical trial for severe mucopolysaccharidosis type I (MPSI, Hurler subtype) reported evidence of a neuroepithelial tumor with AAV integration following gene therapy. Although this finding remains an isolated incident, it has reraised concerns that integration of vector genomes can have an cancer-causing effect in patients.
Using the latest DNA sequencing technologies, Tai will investigate whether mutations in the small, highly structured ends of the AAV genomes called inverted terminal repeats (ITRs) are causing unexpected integration.
“Previous sequencing technologies weren’t able to resolve these small strands on the ends of the viral genome, which are highly important to the replication, manufacturing and production of AAV vectors,” said Tai. “They are also what give the viral vectors their stable structure.
“Because of the detail we’re able to get with long-read sequencing platforms, we can scan these genomic end pieces for mutations and then track them to see if they do, in fact, drive integration into the host-cell genome,” said Tai.
If these mutated ITRs are the cause of the unexplained vector genome integration in animal models, Tai and colleagues can develop ways to remove the mutations from vector production or engineer the vectors so they no longer mutate at high frequencies. These advances would further improve the safety of the AAV vector and reduce the risk of causing cancer.
“We know that AAVs are an ideal delivery system for gene therapies,” said Tai. “Using the latest technology to understand the fundamental biology behind these vectors, allows us to make them as safe as possible.”
Tai received his undergraduate degree from the University of California, Berkely, and his PhD from the University of Washington. He completed his postdoctoral studies in the labs of Gary Stein, PhD, at UMass Chan and the University of Vermont; and Guangping Gao, PhD, the Penelope Booth Rockwell Chair in Biomedical Research , director of the Horae Gene Therapy Center, director of the Li Weibo Institute for Rare Diseases Research and chair and professor of genetic & cellular medicine. He joined the faculty at UMass Chan in 2017.
About UMass Chan Medical School
UMass Chan Medical School, one of five campuses of the University of Massachusetts system, comprises the T.H. Chan School of Medicine; the Morningside Graduate School of Biomedical Sciences; the Tan Chingfen Graduate School of Nursing; ForHealth Consulting at UMass Chan Medical School, a public service health care consulting division; and MassBiologics, the only nonprofit, FDA-licensed manufacturer of vaccines, biologics and viral vector gene therapies in the United States; and a thriving Nobel-Prize-winning biomedical research enterprise.
UMass Chan is advancing together to improve the health and wellness of our diverse communities throughout Massachusetts and across the world by leading and innovating in education, research, health care delivery and public service. UMass Chan has built a reputation as a world-class destination for biomedical research. It is ranked among the best medical schools in the nation for primary care education and biomedical research by U.S. News & World Report. In 2021, the Medical School received a $175 million gift from The Morningside Foundation and was renamed UMass Chan Medical School. Learn more at www.umassmed.edu .