# Therapeutic pathway reprogramming for metabolic liver disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $355,195

## Abstract

PROJECT SUMMARY
 Metabolic liver disease is an emerging public health problem. In the United States,
diabetes- and obesity-related metabolic liver disease is the most common cause for orthotopic
liver transplantation (OLT), which requires life-long immunosuppression and is associated with
substantial morbidity and mortality (10-year survival 60-80%). More than twice as many patients
are listed for OLT relative to organs available, illustrating a compelling need to explore
alternative treatment strategies for metabolic liver disease.
 We have recently developed a novel therapeutic strategy called metabolic pathway
reprogramming. The concept rests on deletion of a critical metabolic gene in a disease-
associated pathway, causing the metabolic pathway to be rerouted resulting in a benign disease
phenotype. As a proof-of-principle, we focus on hereditary tyrosinemia type I (HT-1), which is
caused by mutations of the fumarylacetoacetate gene (FAH). For many years, HT-1 patients
have been treated with nitisinone, a drug that inhibits hydroxyphenylpyruvate dioxigenase
(HPD), a gene upstream of FAH, and leads to accumulation of less toxic, excretable catabolites
similar to the comparatively benign tyrosinemia type III (HT-III). We hypothesize that metabolic
pathway reprogramming via somatic HPD gene deletion is an alternative to OLT for HT-1
patients and superior to the current pharmacological approach. We tested the concept of
metabolic pathway reprogramming for HT-1 in a short-term (3 months) experiment using
CRISPR/Cas9 genome editing and hydrodynamic tail vein injections (Pankowicz et al. Nat
Commun.). While our approach was successful in mice, there are three major roadblocks for
clinical translation; the long-term consequences of this therapy, the gene delivery method and
the translation of this sequence specific therapy into the human setting.
 We propose to investigate these major roadblocks in the murine model of HT-1 and
human liver chimeric mice utilizing a gene therapy approach with Adeno-Associated Virus (AAV)
(Aim 1a). We will determine long-term benefit and risk of Hpd deletion by AAV in tyrosinemic
mice over the state of the art therapy with nitisinone (Aim 1b), as well as determine efficiency
and risk of such a therapy in humanized mice (Aim 2).
 Successful execution of this proposal will validate therapeutic applications of metabolic
pathway reprogramming in primary human cells and has the potential to establish a new
therapeutic paradigm for metabolic liver disease.

## Key facts

- **NIH application ID:** 10004031
- **Project number:** 5R01DK115461-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Karl-Dimiter Bissig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,195
- **Award type:** 5
- **Project period:** 2018-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004031

## Citation

> US National Institutes of Health, RePORTER application 10004031, Therapeutic pathway reprogramming for metabolic liver disease (5R01DK115461-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004031. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*