# Develop humanized AAV vectors for liver targeting and neutralizing antibody evasion

> **NIH NIH R41** · BEDROCK THERAPEUTICS, INC. · 2020 · $249,310

## Abstract

Adeno-associated virus (AAV) vectors have been successfully applied in clinical trials in patients with
hemophilia. Two AAV based gene therapy drugs have been recently approved by the FDA. Luxturna has been
valued at $850,000 for a one-time treatment for a rare form of blindness and Zolgensma at $2,100,000 for
spinal muscle atrophy. Gene therapy with AAV vectors has shown a potentially huge market. Although
successful in clinical studies, two concerns restrict a broader AAV vector application for patients with
hemophilia who need systemic administration of AAV vector for effective liver targeting: low human hepatocyte
transduction and neutralizing antibody (Nab)-mediated blocking of AAV transduction. Several approaches have
been explored for AAV transduction enhancement or neutralizing antibody evasion. Engineering of the AAV
capsid represents a very powerful and popular technology, and has been extensively studied to develop novel
AAV vectors for transduction enhancement in pre-clinical animal models or Nab escape in vitro. It has been
demonstrated that the results from mouse experiments do not recapitulate those of large animals such as
primates and dogs, the data for AAV variants generated in animal cells and organs may not translate into
human application. Recently, a mouse model xenografted with human hepatocytes has been used to develop
AAV vectors for targeting gene therapy relative to human liver. We have isolated several AAV mutants from the
liver of chimeric mice xenografted with human hepatocytes in the presence of human neutralizing antibodies
(IVIG) using AAV shuffling library approach. In this application, we will study the ability of these mutants to
transduce human hepatocytes and evade Nabs. Following the identification of the best mutants with efficient
human hepatocyte transduction and high ability for Nab evasion, we will study the safety and long-term efficacy
of these mutants for hemophilia gene therapy in a mouse model with AAV Nabs after a single injection.
Successful validation of these mutants in hemophilic mice will provide a proof-of-concept for translation to
larger models of hemophilia in hopes of safely and effectively treating hemophilia patients with AAV Nabs
using a single dose.

## Key facts

- **NIH application ID:** 10079155
- **Project number:** 1R41HL152923-01A1
- **Recipient organization:** BEDROCK THERAPEUTICS, INC.
- **Principal Investigator:** Chengwen Li
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,310
- **Award type:** 1
- **Project period:** 2020-08-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079155

## Citation

> US National Institutes of Health, RePORTER application 10079155, Develop humanized AAV vectors for liver targeting and neutralizing antibody evasion (1R41HL152923-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10079155. Licensed CC0.

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