# Exploitation of the natural biodiversity of AAV to identify “super transducers"

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $544,375

## Abstract

Project 3 - Project Summary:
 Liver is arguably the most permissive tissue for recombinant adeno-associated virus
(rAAV)-mediated in vivo gene delivery, and liver transduction can be achieved by a simple
systemic rAAV administration. However, liver-directed rAAV gene therapy for alpha-1-antitrypsin
(AAT) deficiency (AATD) has met multiple challenges, demanding more efficient gene delivery
and expression especially in the presence of pre-existing anti-AAV immunity. To address these
challenges, one potential solution is to develop new AAV capsids that allow for more efficient
gene delivery and/or transgene expression in the liver. We have recently employed single-
molecule, real-time (SMRT) sequencing to discover novel full-length cap sequences from
natural AAV proviral libraries from the human population to identify novel AAV variants with
desirable tissue tropisms and vector properties. In this project, we will employ a high-throughput
Illumina barcode sequencing approach to analyze a large collection of new AAV capsids
identified from NHP and human tissues. The new capsid variants identified from this project
collectively represent a valuable toolbox for liver-directed rAAV gene delivery to multiple species
with favorable immunological profiles, and therefore are expected to have broad utilization in
gene therapy applications. This project contains four specific aims designed to develop liver-
tropic AAV capsids from our primate-derived library to support preclinical AATD gene therapy
studies and clinical translation: Aim 1, To screen for mouse liver-targeting AAV capsid variants
in wild-type (WT) mice; Aim 2, To screen for ferret liver-targeting AAV capsid variants in WT
ferrets; Aim 3, To screen for human liver-targeting, NAB-escaping AAV capsid variants in
humanized mice; and Aim 4, Structural-functional studies of new capsid variants. There is
considerable interactivity between this project and the other three projects.

## Key facts

- **NIH application ID:** 10270094
- **Project number:** 1P01HL158506-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Dan Wang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $544,375
- **Award type:** 1
- **Project period:** 2021-08-09 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10270094

## Citation

> US National Institutes of Health, RePORTER application 10270094, Exploitation of the natural biodiversity of AAV to identify “super transducers" (1P01HL158506-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10270094. Licensed CC0.

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