Feb. 26, 2026

(NCATS)

PaVe-GT scientists underscore strategy, framework and early interaction with the FDA to align preclinical and clinical efforts in AAV gene therapy translation.

In a Human Gene Therapy article, the Platform Vector Gene Therapy (PaVe-GT) team shares its first-hand experience communicating with the U.S. Food and Drug Administration (FDA) and defining a framework early in the therapy development process. The PaVe-GT program, a collaboration between NCATS and the National Human Genome Research Institute (NHGRI), reflects NIH’s commitment to cross-institute partnership in solving complex challenges in translational science. PaVe-GT demonstrates how translational science can create durable frameworks that accelerate therapies across diseases — a central aim of NCATS’ strategic plan.

PaVe-GT shares insights on early planning, regulatory considerations and the ways the team dealt with FDA requirements, along with a regulatory package example — information that is often missing from the scientific literature. Regulatory approval remains challenging for adeno-associated virus (AAV) gene therapies because scientific and operational details are not fully disclosed publicly.

“This paper shows how thoughtful planning and early alignment with regulators can turn custom gene therapies into scalable solutions. PaVe-GT provides both a model and the templates to help transform one-off therapies into repeatable frameworks for rare disease treatment,” said Joni Rutter, Ph.D., NCATS director. “If we can standardize the path, we can speed it — not just for one disease, but for many.”

The article describes the value, traits and components of a target product profile (TPP) in preclinical drug development. A TPP defines key details of the expected drug and guides decisions and actions toward scientific and regulatory goals. A TPP can streamline drug development by informing the design of investigational new drug (IND)–enabling studies. The authors also outline what to consider when preparing for an INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs) meeting with the FDA.

“INTERACT helped us arrive at a strategy for our clinical study design,” said co-author and PaVe-GT team member Charles Venditti, M.D., Ph.D., chief of the Metabolic Medicine Branch at NHGRI. “The FDA advised us to start with adolescent patients and provide a detailed description about deciding patient age and recruiting clinical trial participants, even if our ideal target patient population was pediatric.”

Transparent data sharing and early planning are key to advancing treatments. “We highlight the importance of establishing a target product profile and the value of interactions with FDA early on to gain program-specific feedback,” said corresponding author Elizabeth Ottinger, Ph.D., director of the Therapeutic Development Branch at NCATS. “The INTERACT process and the discussion with the agency helped refine the TPP and the clinical plan. You must keep the end goal in mind from the start and maintain a clinical focus throughout development.”

The PaVe-GT website has such resources as templates for a TPP and an INTERACT package, with clear guidelines on the kinds of questions and supporting data to include. Earlier resources included application packages and templates that led to successful Orphan Drug and Rare Pediatric Disease designations for AAV9-hPCCA. Sharing these resources advances NCATS’ mission to create reusable tools that promote translational science and benefit the entire rare diseases community.

The FDA offered guidance on the animal model, tests for potency and immunogenicity, and companion diagnostics. It also tentatively agreed on the team’s proposed use of capsid-related biodistribution and anti-drug antibody level data for later relevant products.

“Getting the science right is necessary—but getting the operations right is what makes it reproducible. That’s the big value PaVe-GT delivers,” says Rutter.