# Human microtissues for in situ detection and functional measurement of adverse consequences caused by genome editing

> **NIH NIH U01** · J. DAVID GLADSTONE INSTITUTES · 2020 · $720,836

## Abstract

PROJECT SUMMARY
Genome editing technologies are advancing rapidly toward clinical therapies, but robust methods for accurately
assessing the potential adverse effects of genome editing activity and delivery vehicles on physiological tissue
function have yet to be developed and broadly disseminated. Since animal models are often poor predictors of
human biological responses, it is imperative to establish well-defined tissue systems composed of human cells
as an intermediate testbed to assess the safety as well as the efficacy of genome editing and its effect(s) on
tissue function. Human pluripotent and post-natal tissue-derived stem cells provide valuable sources of human
differentiated cells, such as cardiomyocytes, neurons and hepatobiliary cells, that can be used to create 3D
tissues to model diseases and test therapies ex vivo. Traditionally, the toxicity of novel therapies in the heart,
nervous system and liver manifest with severe consequences that can often lead to organ failure and mortality.
For this reason, a thorough preclinical characterization of potential toxicities and adverse events caused by
genome editing in human microtissues that recapitulate critical physiologic functions will be essential for these
therapies to be ultimately translated for clinical use. The primary objective of this proposal is to develop and
validate human tissue platforms capable of sensitively and accurately detecting adverse effects of genome
editing on physiologic tissue function. To achieve this objective, we have established a multi-disciplinary team of
leading investigators with complementary expertise in tissue engineering, genome editing, stem cell biology,
single cell genomics and technology development. We will pursue this overall goal through three projects in
parallel that focus initially on the development of individual microtissue platforms in concert with a specific
genome editing strategy before proceeding to testing each of the editing scenarios on all three of the tissue
systems. In the first project, we will examine the effects of single-site editing on defined off-target sites and
endogenous loci on cardiac microtissue electrical and mechanical function. In the second project, we will
examine large scale genomic alterations following deletion of variable size fragments in neurons and the effects
on physiologic parameters. In the third project, we will assess biomarker expression and secretion by
hepatobiliary microtissues following the genomic insertion of exogenous genes. These human tissue models
tested with various clinical genome editing strategies will be integrated within the Somatic Gene Editing
Consortium, to test novel delivery vehicles and help inform the development of future genome editing therapies.
Altogether, the outcomes of this work should significantly benefit the safety and predictability of curative genome
therapies of the future.

## Key facts

- **NIH application ID:** 9985110
- **Project number:** 8U01ES032673-03
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Todd C McDevitt
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $720,836
- **Award type:** 8
- **Project period:** 2018-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985110

## Citation

> US National Institutes of Health, RePORTER application 9985110, Human microtissues for in situ detection and functional measurement of adverse consequences caused by genome editing (8U01ES032673-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9985110. Licensed CC0.

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