# Rational design of AAV vectors with human hepatocyte tropism and neutralizing antibody evasion

> **NIH NIH R41** · BEDROCK THERAPEUTICS, INC. · 2022 · $261,080

## Abstract

Adeno-associated virus (AAV) vectors have been successfully applied in clinical trials in patients with diverse
disorders. 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 priced at $2,100,000
for spinal muscle atrophy. As such, AAV vector based gene therapy is an increasingly attractive market.
Although successful in clinical studies, two concerns restrict broader AAV vector applications for patients
requiring liver targeted AAV gene therapy following systemic administration: low human hepatocyte
transduction and neutralizing antibody (Nab)-mediated inhibition of AAV transduction. Several approaches
have been explored for AAV transduction enhancement or capsid Nab evasion. Engineering of the AAV
capsid presents a very powerful and popular technology that has been extensively studied to develop novel
AAV vectors for enhanced transduction in animal models or Nab escape in vitro. However, it has been
demonstrated that the results from mouse experiments do not recapitulate those of large animals such as
primates and dogs. Thus, the data for AAV variants generated in animal cells and organs may not translate
into successful human applications. Recently, a mouse xenograft model with human hepatocytes has been
used to develop human liver targeted AAV vectors for gene therapy. In our previous studies, we have
successfully isolated several AAV mutants from the liver of chimeric mice with human hepatocyte xenografts in
the presence of human Nabs (IVIG) using the AAV shuffled capsid library approach. Specifically, BDRK001
(AAV mutant LP2-10) demonstrated a much higher ability to evade Nabs than any other AAV serotypes or
mutants. However, BDRK001 was not enhanced for transduction in human hepatocytes when compared to the
best natural serotype. In this application, we will use rational design strategy to generate novel AAV capsids by
variable region I (VRI) domain swapping of BDRK001 using natural serotypes or mutants with high human liver
tropism. This panel will then be evaluated in chimeric mice for human hepatocyte transduction (Aim 1) and
Nab evasion (Aim 2). Bedrock's long-term goal of this approach is low dose AAV gene therapy for the
successful treatment of a variety of liver diseases, independent of the patient's Nab prevalence.

## Key facts

- **NIH application ID:** 10546241
- **Project number:** 1R41DK133021-01A1
- **Recipient organization:** BEDROCK THERAPEUTICS, INC.
- **Principal Investigator:** Chengwen Li
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $261,080
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546241

## Citation

> US National Institutes of Health, RePORTER application 10546241, Rational design of AAV vectors with human hepatocyte tropism and neutralizing antibody evasion (1R41DK133021-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10546241. Licensed CC0.

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