# Therapeutic potential of CRISPR/Cas9 genome engineering in humanized mouse

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $549,652

## Abstract

PROJECT SUMMARY
 Liver-directed gene editing has the potential to correct numerous severe monogenic
disorders. The two major hurdles of translating this therapy to the clinic are efficacy and safety.
We will address both concerns using an innovative therapeutic genome editing approach in a
novel humanized mouse model.
 CRISPR/Cas9 genome editing technology has proven extremely efficient in introducing
double strand brakes (DSB) in many cellular systems. In mammals, DSB are preferentially
repaired by the error prone non-homologous end joining (NHEJ) and to a lesser extent by
homology-directed repair (HDR). Here, we propose to treat refractory lipid disorders with
compensatory deletion of a whole exon (exon-excision) from lipid genes that increase the
cholesterol levels in blood or contribute to slower clearance of blood cholesterol. Deletion will be
mediated by NHEJ after introduction of two CRISPR/Cas9 induced DSBs in the two flanking
introns. This repair mechanism is very efficient in non-proliferating hepatocytes and avoids the
introduction of potentially harmful mutations in the coding sequence.
 We recently developed a mouse strain that can be repopulated with cadaveric human
hepatocytes. Since genome editing is sequence dependent, it must be tested within the context
of human cells of the desired target tissue. Using mice repopulated with normal human
hepatocytes, we will be able to determine the safety and efficacy of liver-directed human
genome editing by CRISPR/Cas9. We will then test his approach in mice repopulated with
human hepatocytes from a patient with familial hypercholesterolemia (FH). This first xenograft
model for FH can be used to evaluate the therapeutic efficacy and potential compensatory
adaptation for this experimental therapy.

## Key facts

- **NIH application ID:** 10291691
- **Project number:** 7R01HL134510-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Karl-Dimiter Bissig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,652
- **Award type:** 7
- **Project period:** 2020-01-20 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291691

## Citation

> US National Institutes of Health, RePORTER application 10291691, Therapeutic potential of CRISPR/Cas9 genome engineering in humanized mouse (7R01HL134510-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10291691. Licensed CC0.

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