A new mouse model of Gaucher disease type 3 may be more useful for studies of disease biology and preliminary tests of possible treatments than those now in use.
The study, “Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease,” was published in the journal Neurobiology of Disease.
Of the three types of Gaucher disease, only type 2 and type 3 involve neurological symptoms; because of the involvement of the brain, these types are currently the most difficult to treat. Type 2 is the most severe form of the disease, often resulting in death in early childhood, whereas in type 3 disease progression is much slower.
This has posed something of a problem when it comes to mouse models of Gaucher disease, which are usually created by engineering mice to have mutant or defective versions of the GBA gene, whose defects are disease-causing.
Most available models either have very mild phenotypes, similar to type 1 Gaucher, or experience rapid disease progression and death, similar to what is seen in type 2. It has been difficult to generate a model that reflects the slower progression and neural involvement of type 3.
The researchers hypothesized that they might be able to generate such a model by reducing the amount of glucocerebrosidase (GCase, the protein encoded by the GBA gene) in the brains of mice with type 1 Gaucher disease. Essentially, they wanted to make the disease more severe, but not so severe that it modeled type 2.
To this end, they developed a viral vector to carry a small molecule called a microRNA (miRNA) that would specifically interfere with the production of GCase from the GBA gene. They injected this vector into the nervous systems of mice with type 1 Gaucher disease on the day the mice were born.
Researchers confirmed that this injection reduced levels of GCase in the brain and increased those of molecules like glucocerebroside that accumulate in Gaucher disease. The mice also showed neurological involvement (e.g. motor abnormalities, hyperactivity, and inflammation in the brain) that progressed slowly, mimicking what has been observed in type 3 disease.
Wild-type mice (mice with no GBA mutation) that were injected with the same viral vector did not demonstrate these characteristics.
The slower advance of the disease in this model may allow researchers to do tests at various stages of progression; that is, before symptoms develop and early or late after symptoms are evident.
“Importantly,” the researchers concluded, “this model has a delayed onset of neurological dysfunction and an extended lifespan (up to 36 weeks of age) allowing for greater flexibility for testing therapeutics. As potential therapies for types 2 and 3 GD are developed, this model may represent an important preclinical tool for proof of efficacy studies.”