# Rescue of multiorgan pathophysiology by adeno-associated virus 1 gene therapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $409,375

## Abstract

AAV vectors have great potential as gene therapeutic agents (3-5), in particular for cystic fibrosis (CF). Studies
originating from our group led to the first use of rAAV in humans (2). Many studies have shown that AAV vectors
can be used safely (5,6,9). The major challenge, however, is that they have not achieved a reproducible thera-
peutic effect, making it necessary to take a new approach to AAV gene therapy. In previous work, we have
identified three new strategies to alleviate these problems: 1) the use of AAV1, which is more tropic for the lung;
2) the use of 27-264, a truncated version of CFTR that corrects ∆F508 by a novel mechanism; and 3) the inclu-
sion of a powerful chicken β-actin (CBA) promoter. Given that CF is a multi-organ disease, a gene-based therapy
will have to target several organs whose cells normally turn over (3,4), making it advantageous to employ a virus
that can transduce multiple cell types if it is to be used in a single-treatment therapy. To further explore this
approach, we will use a ferret model bearing the G551D mutation, which responds to the CF potentiator VX-770.
We propose three overall Specific Aims:
Aim 1: To evaluate systemic vs. airway delivery of AAV1 gene therapy to transduce organs affected by
CF. For gene therapy to be effective for CF, it must correct defective CFTR function in several organs in the
body besides the airways. The question addressed here is whether transduction can occur in peripheral organs
following airway delivery of naturally occurring AAV1. Aim 2: To determine the duration of the therapeutic
effects of AAV1 vectors containing truncated CFTR. The overarching questions for CF gene therapy are
whether gene transduction can rescue the CF phenotype and how long the therapeutic effect will last before a
repeated dose is necessary. The answers to these practical questions have enormous clinical consequences for
the development of effective CF gene therapy. This Aim will address the extent to which AAV1 vectors containing
either AAV1-CBΔ27-264 or ΔR-CFTR will be effective in rescuing the CF phenotype and how long the rescue
will last following a single dose of AAV. Aim 3: To determine whether dosing with an AAV1 vector con-
taining a truncated CFTR will lead to transduction in the ferret GI tract and human enteroids. Given that
gene therapy for CF will have to target multiple organs, the goal here is to show that AAV1-derived vectors will
transduce the GI tract. For this Aim, we will take a two-pronged approach: First, from the ferrets transduced in
Aims 1 and 2, we will isolate sections of GI tract (ileum and colon) and measure the transport characteristics of
the transduced, excised tissue. Second, given that the ultimate goal of our studies is to treat patients with CF,
we will study to what extent AAV1 virus containing truncated CFTR will rescue human enteroids from patients
with mutations that are hard to treat with current therapies.
Significance: CF is an autosomal disease that l...

## Key facts

- **NIH application ID:** 10293917
- **Project number:** 1R01DK126778-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Liudmila Cebotaru
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,375
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293917

## Citation

> US National Institutes of Health, RePORTER application 10293917, Rescue of multiorgan pathophysiology by adeno-associated virus 1 gene therapy (1R01DK126778-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10293917. Licensed CC0.

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