May 21, 2026 —
Phillip Tai, PhD, assistant professor of genetic & cellular medicine at UMass Chan Medical School, has received a $1.6 million grant from the National Institute of General Medical Sciences to investigate the basic mechanisms of adeno-associated viral vector behavior using high-resolution DNA sequencing technologies. The research aims to better understand how AAV vectors function at the genome level and may help inform the design of safer gene therapy vectors.
AAV vectors are among the most widely used delivery systems in gene therapy because they can efficiently deliver therapeutic genes into human cells and have been used across many clinical studies. However, while AAV vectors are generally considered predominantly non-integrating, some animal studies have reported that a small fraction of vector genomes can integrate into the host cell genome. More recently, a reported case of a neuroepithelial tumor with AAV integration after gene therapy for severe mucopolysaccharidosis type I has renewed interest in understanding whether and how rare integration events may contribute to safety risks.
Dr. Tai’s research will focus on the inverted terminal repeats, or ITRs, located at the ends of AAV genomes. These small, highly structured DNA elements are essential for AAV replication, vector manufacturing, and genome stability. Historically, their complex structure has made them difficult to resolve using conventional sequencing technologies. By applying long-read sequencing platforms, the research team aims to detect mutations in these regions and determine whether specific ITR alterations may be associated with unexpected vector genome integration.
If mutated ITRs are found to contribute to integration in preclinical models, the findings could guide new strategies to reduce risk. These may include improving vector production processes to remove ITR mutations, engineering more stable AAV genome designs, or developing improved quality control approaches to better characterize vector preparations before clinical use.
The grant supports a broader effort to strengthen the safety science behind gene therapy. As AAV-based treatments continue expanding into more diseases and patient populations, deeper understanding of vector biology, genome structure, and rare integration events will be essential for improving therapeutic design and maintaining confidence in long-term safety.
