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An immune deficient mouse model for mucopolysaccharidosis IIIA (Sanfilippo syndrome)
Kari Pollock1, Sabrina Noritake2, Denise M Imai3
1Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, CA, USA. kmpollock@ucdavis.edu.
Abstract:
Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA. A mouse model for MPSIIIA was characterized in 1999 and later backcrossed onto the C57BL/6 background. In the present study, a novel immune deficient MPSIIIA mouse model (MPSIIIA-TKO) was created by backcrossing the immune competent, C57BL/6 MPSIIIA mouse to an immune deficient mouse model lacking Rag2, CD47 and Il2rg genes. The resulting mouse model has undetectable SGSH activity, exhibits histological changes consistent with MPSIIIA and lacks T cells, B cells and NK cells. This new mouse model has the potential to be extremely useful in testing human cellular therapies in an animal model as it retains the MPSIIIA disease phenotype while tolerating xenotransplantation.
Insights
A new immune-deficient mouse model for Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) was developed. This model enables testing of human cellular therapies for MPSIIIA by tolerating xenotransplantation.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a severe neurodegenerative lysosomal storage disease.
- MPSIIIA results from sulfamidase (SGSH) deficiency, leading to heparin sulfate accumulation and neuronal damage.
- Current treatments for MPSIIIA are limited, with no cure available.
Purpose of the Study:
- To develop a novel, immune-deficient mouse model for MPSIIIA.
- To facilitate the testing of human cellular therapies in a relevant animal model.
- To overcome limitations of existing immunocompetent MPSIIIA models for xenotransplantation studies.
Main Methods:
- Created a triple knockout (TKO) immune-deficient MPSIIIA mouse model by backcrossing.
- Utilized mice lacking Rag2, CD47, and Il2rg genes to achieve immune deficiency.
- Characterized the MPSIIIA-TKO model for SGSH activity and histological MPSIIIA hallmarks.
Main Results:
- The MPSIIIA-TKO model exhibits undetectable SGSH activity.
- Histological changes consistent with MPSIIIA pathology were observed.
- The model is devoid of T cells, B cells, and NK cells, confirming immune deficiency.
Conclusions:
- The novel MPSIIIA-TKO mouse model accurately recapitulates the disease phenotype.
- This immune-deficient model is suitable for xenotransplantation of human cells.
- The MPSIIIA-TKO model offers a promising platform for developing novel cellular therapies.
