# Targeting POGLUT1 to promote biliary development in Alagille syndrome

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $374,542

## Abstract

PROJECT SUMMARY/ABSTRACT
Alagille syndrome (ALGS) is a genetic, multisystem developmental disorder affecting the liver biliary system,
cardiovascular system, kidney and other organs. The most common phenotype observed in ALGS patients is a
severe decrease in the number of bile ducts in the liver (called bile duct paucity). Similar to other diseases
involving intrahepatic biliary system, bile duct paucity and its consequences often lead to cholestatic
phenotypes (like severe itching) and end-stage liver disease in ALGS patients. Dominant mutations in a gene
called JAG1, which encodes a ligand in the Notch signaling pathway, were identified as the cause of ALGS in
1997, and were later shown to be responsible for about 95% of ALGS cases. However, despite the wealth of
knowledge on the function and regulation of Notch pathway and despite the passage of more than 2 decades
from the discovery of JAG1 in ALGS patients, there is still no mechanism-based therapy for this disease. The
only cure for ALGS liver disease and diseases of bile duct paucity is liver transplantation. However, the
shortage in liver donor poses a significant challenge to this patient population. Moreover, involvement of other
organ systems—including the cardiovascular and renal systems—in many ALGS patients makes them poor
candidates for liver transplantation. Moreover, for those who do receive a liver transplant, a higher frequency of
cardiovascular and kidney complications are observed, and the long-term effects of immunosuppressive
therapy can be problematic. Therefore, development of therapies that can correct or decrease the degree of
bile duct paucity and help avoid or delay transplant is a major unmet clinical/medical need of patients with
ALGS and other diseases with bile duct paucity. Building on our recently published and preliminary data, the
current application proposes preclinical studies to directly address this need. We have established a mouse
model for ALGS by removing one copy of Jag1 on a C57BL/6 genetic background. This model allowed us to
identify two dosage-sensitive genetic modifiers of the Jag1 heterozygosity in the liver, which can rescue the
bile duct paucity and liver phenotypes without causing side effects. Moreover, our preliminary data generated
in collaboration with an industry partner indicate that postnatal reduction in the expression of one of these
modifiers by a novel approach can significantly improve the liver phenotypes in our ALGS mouse model. In the
two Aims of this proposal, we will determine the optimal dosage, long-term benefits, and the potential side
effects of our treatment strategy in Jag1 heterozygous and other genetic models of ALGS with more severe
liver involvement and/or multiple organ involvement. If successful, our research will establish a strategy for
augmentation of the biliary tree in bile duct paucity models and will pave the way for clinical studies which
might one day help ALGS patients avoid liver transplantation.

## Key facts

- **NIH application ID:** 10887491
- **Project number:** 5R01DK132751-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Stacey S Huppert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,542
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887491

## Citation

> US National Institutes of Health, RePORTER application 10887491, Targeting POGLUT1 to promote biliary development in Alagille syndrome (5R01DK132751-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887491. Licensed CC0.

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