Animal Models for Gaucher's Disease
Appropriate animal models may be of great value as tools for the preclinical development of new therapies for Gaucher's disease. Our company focuses on the development of molecular genetics and bioengineering technologies to help our clients generate animal models that effectively mimic the many visceral and neurological aspects of Gaucher's disease. Our continued efforts to develop more relevant and feasible animal models support the study of various aspects of Gaucher's disease such as its progression, the effectiveness of different therapies, and the underlying molecular mechanisms.
Gaucher's disease is an autosomal recessive disorder caused by a genetic defect in β-glucocerebrosidase (GBA). It is characterized by the accumulation of glucocerebroside in the lysosomes of reticuloendothelial cells, leading to bone abnormalities (pain and osteonecrosis), organ enlargement (spleen and liver), and cytopenia in type 1 Gaucher's disease. To study Gaucher's disease, researchers have established a number of mouse models, but the short survival of these models in young mice and the dramatic decline in mouse function after birth have limited the study of the mechanisms and treatment of Gaucher's disease.
Despite the challenges of generating suitable animal models for Gaucher's disease research, the mouse models that have been generated have made some progress in understanding the mechanisms underlying the pathology of Gaucher's disease and in testing putative novel therapeutic approaches. In recent years, generated models of Gaucher's disease have accelerated the development of multiple therapies, such as ERTs, bone marrow transplantation, and miglustat.
Fig. 1 Quantification of astrocytosis and activated microglia in 4L/PS-NA mice over age. (Schiffer V, et al., 2020)
Disease Modeling Services
We help clients generate custom animal models for Gaucher's disease research, using techniques such as CRISPR/Cas9 gene editing or transgenic technology. These models can be customized for specific research issues, allowing research into different aspects of the disease. Our disease modeling services include, but are not limited to:
- Chemically induced models of Gaucher's disease
We administered the GlcCerase inhibitor conduritol-β-epoxide (CBE) to mice to create a relatively rapid and inexpensive model that can be widely used to examine neurological deficits and test the efficacy of new therapies.
- Chimeric mouse models of Gaucher's disease
We created chimeric mice by infusing hematopoietic stem cells from fetuses homozygous for glucocerebrosidase knockout into irradiated mice. These models exhibit increased glycolipid stores in the reticuloendothelial system, which is characteristic of Gaucher's disease.
- L444P/L444P mice
We generated mice homozygous for the L444P mutation (L444P/L444P mice) using a single insertion mutagenesis procedure. And, we improved the lifespan of L444P/L444P mice by crossing L444P+/- mice with a mouse bearing a knockout in the gene encoding GlcCer synthase (Ugcg) to generate Gba+/L444P; Ugcg+/- mice. These mouse models we generated can be used to study the efficacy of some chemical chaperones as therapeutic approaches to Gaucher's disease as well as used as a source of cultured neurons.
- N370S, V394L, D409H and D409V point mutations
We generated mouse models of Gaucher's disease by introducing point mutations (N370S, V394L, D409H, and D409V) into the GBA locus. We tested the appearance and clearance of glucocerebrosides stores in cells in these models to provide efficacy parameters for the development of glucosylceramide synthase inhibitors.
- 4L/PS-NA mice
We help our clients develop 4L/PS-NA mice that live longer than Gaucher's other mouse models, providing a better window of time for therapeutic studies. These models effectively reflect human symptoms, including nerve cell characteristics.
Animal Model Testing Services
We provide our clients with testing services for animal models of Gaucher's disease, including imaging, histology, and biochemical analysis. These services can help researchers characterize their models and assess their suitability for particular experiments.
- Behavioral tests (such as Rota Rod and Wire suspension test, Pasta gnawing test, and Beam Walk test)
- Biochemical and histological analyses
- Glucocerebrosidase measurement
- Glucosylceramide and glucosylsphingosine measurements
Preclinical Research Services
We provide a range of services to support the use of animal models for preclinical studies of Gaucher's disease to evaluate the safety and efficacy of potential therapies. These studies can help to identify promising treatments and inform the design of clinical trials.
Our expertise in animal model generation and testing, combined with state-of-the-art facilities and experienced staff, make us an ideal partner for Gaucher's disease research. Furthermore, We are committed to ethical and responsible animal research practices to ensure the welfare of the animals in our care. If you are interested in our services, please contact us for more details.
- Schiffer, V.; et al. Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease. Plos one, 2020, 15(1): e0227077.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.