# Endothelial-targeted adenovirus for organ-selective gene editing in vivo

> **NIH NIH UG3** · WASHINGTON UNIVERSITY · 2021 · $741,071

## Abstract

PROJECT SUMMARY
A wide range of biological applications have derived from the CRISPR/Cas9 site-specific nuclease system in
recent years. Of note, the capacity to accomplish gene editing in a targeted manner has also impacted the design
of gene therapy strategies for an expanding repertoire of disorders. Critical to realizing the gene editing functions
of the CRISPR/Cas9 system in a gene therapeutic context is the requirement to accomplish effective co-delivery
in vivo of the constituent components. This delivery issue has been approached applying both non-viral and viral
vector systems. In selected instances, successful gene-editing facilitated gene therapies have been
accomplished in model systems of inherited genetic disease.
Despite these elegant proof-of-principle studies, limits in available vector technology have greatly restricted the
application of CRISPR/Cas9-facilitated gene therapy. In this regard, effective in vivo co-delivery of CRISPR/Cas9
to target somatic cells is required for many of these applications. Such delivery should be restricted exclusively
to the key cellular targets in vivo to minimize off-target effects. In addition, the mandated co-delivery must be
accomplished in the potential presence of pre-formed anti-vector immunity. Finally, methods to limit Cas9
expression must be endeavored to limit the potential of off-target editing. Of note, these functionalities should
ideally be configured into the context of a single vector particle context to facilitate practical upscaling and human
clinical translation.
To this end, we have exploited the molecular promiscuities of adenovirus (Ad) to address the requirements of
CRISPR/Cas9-facilitated gene therapy. In this regard, we have endeavored capsid engineering of adenovirus to
achieve targeted modifications of vector tropism. In addition to allowing for re-directed tropism, capsid
engineering provides the means to allow Ad to circumvent pre-formed vector immunity. We have also applied a
strategy of capsid engineering to accomplish transient expression of heterologous proteins. On this basis, during
the UG3 Phase (3 years) we will establish proof-of-principle with respect to delivery of genome editing machinery
into disease relevant cells and tissues in vivo. The follow-on UH3 Phase (1 year) will address scale up and
testing of our novel approach in a large animal model. This will be accomplished in collaboration with the SCGE
Large Animal Testing Centers.

## Key facts

- **NIH application ID:** 10228031
- **Project number:** 5UG3TR002851-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David Terry Curiel
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $741,071
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228031

## Citation

> US National Institutes of Health, RePORTER application 10228031, Endothelial-targeted adenovirus for organ-selective gene editing in vivo (5UG3TR002851-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10228031. Licensed CC0.

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