# A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $258,500

## Abstract

Project Summary:
We aim to develop a new mouse model for studying diseases caused by GBA1 mutations in multiple organ
systems. GBA1 encodes a lysosomal glucocerebrosidase (GCase) responsible for degradation of its
glycosphingolipid substrates. Mutations in GBA1 gene disrupt GCase function and cause Gaucher disease (GD)
that presents heterogeneous disease phenotypes in visceral or central nervous system (CNS) organs. Typical
manifestations of visceral form GD1 include hepatosplenomegaly, anemia, thrombocytopenia and osteopenia.
Neuronopathic GD (nGD, GD2 and GD3) are rapidly progressive CNS diseases leading to mortality and
accompanied with visceral symptoms. GD affects multiple organs that align with the research mission of NIDDK
(liver), NHLBI (lung), NINDS (CNS) and NIAMS (bone). GBA1 gene mutations are also genetic risks in
developing Parkinson disease (PD). The approved therapies, Substrate Reduction Therapy (SRT) and Enzyme
Replacement Therapy, are only effective in GD with visceral symptoms and do not treat CNS diseases. The
effective disease modifying therapy is not available to treat PD. GBA1 mutation-caused diseases are complex
affecting multiple organs. Faithful modeling of GD and GBA1-associated PD in an animal model is crucial to
study the associated disease processes and to establish a clinically-relevant model for testing therapeutic
approaches. A barrier in studying GBA1 mutation-associated diseases is the absence of animal models that
recapitulate all aspect of human disease in multiple organs. Previously developed Gba1 mutant mouse models
either show no detectable phenotype or affect restricted organs. Their nGD and PD phenotypes are very mild to
absent. Our recent study has identified progranulin as a modifier of GCase. Deletion of progranulin in Gba1
mutant mice resulted in rapid progression of substrates accumulation, Gaucher-like macrophages and
inflammation in liver, lung and brain organs, the typical GD phenotypes. This new model (termed PG9V) also
developed neuronal phenotypes recapitulating nGD and PD. Our new PG9V model overcomes the limitations in
the existing models. We hypothesize that genetic modification of Gba1 mutant mice by progranulin deletion
impacts inflammation and glycosphingolipid metabolism in visceral and CNS organs, establishing a novel
clinically-relevant animal model for GD and PD. We will characterize visceral GD phenotypes (Aim 1) and
evaluate CNS phenotypes (Aim 2) in PG9V mouse model to establish criteria for testing therapies. Furthermore,
we will test if SRT compound alleviate the disease in PG9V mice to determine preclinical value of PG9V model.
This new GBA1 mutation-associated mouse model represents a major advance forward from existing mouse
models. Comprehensive characterization of PG9V mice will facilitate pathophysiological studies and enables
therapy evaluation and toxicity testing in a single model with multiple organs involvement.

## Key facts

- **NIH application ID:** 10508985
- **Project number:** 1R21OD033660-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Chuanju Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $258,500
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508985

## Citation

> US National Institutes of Health, RePORTER application 10508985, A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement (1R21OD033660-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10508985. Licensed CC0.

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