Mouse model for pompe disease and methods of use thereof
View Patent ↗The present invention provides mouse models for Pompe disease and methods of using the same to test agents that may be effective in the treatment of Pompe disease.
1. A mouse model for Pompe disease comprising a knockout transgenic mouse wherein the endogenous alpha-glucosidase gene is disrupted such that the knockout transgenic mouse lacks the capacity to express the gene for mouse alpha-glucosidase and whose genome comprises at least a P545L mutation in a gene encoding human alpha-glucosidase, wherein the amount of human alpha-glucosidase protein expressed and the level of human alpha-glucosidase activity in at least one disease-relevant tissue of the knockout transgenic mouse is in a range of about 3% to about 10% relative to that of a wild-type mouse, where the at least one disease-relevant tissue is selected from the group consisting of: heart, diaphragm, skeletal muscle, skin, and brain.
2. A mouse model for Pompe disease comprising a knockout transgenic mouse wherein the endogenous alpha-glucosidase gene is disrupted such that the knockout transgenic mouse lacks the capacity to express the gene for mouse alpha-glucosidase and whose genome comprises at least a P545L mutation in a gene encoding human alpha-glucosidase, wherein the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse is at least 2-fold higher than a wild-type mouse, where the at least one disease-relevant tissue is selected from the group consisting of: heart, diaphragm, skeletal muscle, skin, and brain.
3. A method of screening for a therapeutic agent for Pompe disease, comprising administering a test agent to the knockout transgenic mouse of claim 1 and evaluating the effect of the test agent on at least one of: the amount of alpha-glucosidase protein, the level of alpha-glucosidase activity or the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse, wherein at least one of: an increase in the amount of alpha-glucosidase protein, an increase in the level of alpha-glucosidase activity or a reduction in the level of glycogen in at least one disease-relevant tissue relative to a similar knockout transgenic mouse that does not receive the test agent indicates the test agent is therapeutic for Pompe disease.
4. A method for assessing one or more agents for the treatment of Pompe disease, comprising administering one or more agents to the knockout transgenic mouse of claim 1 and evaluating the effect of the agents on at least one of: the amount of alpha-glucosidase protein, the level of alpha-glucosidase activity or the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse, wherein at least one of: an increase in the amount of alpha-glucosidase protein, an increase in the level of alpha-glucosidase activity or a reduction in the level of glycogen in at least one disease-relevant tissue as compared to a similar knockout transgenic mouse that does not receive one or more agents is therapeutic for Pompe disease.
5. The method of claim 4 wherein one or more agents is a pharmacological chaperone, a recombinant alpha glucosidase, an antineoplastic agent, an antirheumatic agent, a reproductive control agent, or any combination of two or more thereof.
6. The method of claim 4 wherein one or more agents is DNJ, recombinant alpha glucosidase, Cyclophosphamide, Methotrexate, Rituximab, or any combination of two or more thereof.
7. The method of claim 6 wherein one or more agents includes DNJ and recombinant alpha glucosidase.
8. The method of claim 6 wherein one or more agents includes DNJ.
9. The knockout transgenic mouse of claim 1 wherein the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse is at least 2-fold higher than that of a wild-type mouse.
10. A method of screening for a therapeutic agent for Pompe disease, comprising administering a test agent to the knockout transgenic mouse of claim 2 and evaluating the effect of the test agent on at least one of: the amount of alpha-glucosidase protein, the level of alpha-glucosidase activity or the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse, wherein at least one of: an increase in the amount of alpha-glucosidase protein, an increase in the level of alpha-glucosidase activity or a reduction in the level of glycogen in at least one disease relevant tissue relative to a similar knockout transgenic mouse that does not receive the test agent indicates the test agent is therapeutic for Pompe disease.
11. A method for assessing one or more agents for the treatment of Pompe disease, comprising administering one or more agents to the knockout transgenic mouse of claim 2 and evaluating the effect of the agents on at least one of: the amount of alpha-glucosidase protein, the level of alpha-glucosidase activity or the level of glycogen in at least one disease-relevant tissue of the knockout transgenic mouse, wherein at least one of: an increase in the amount of alphaglucosidase protein, an increase in the level of alpha-glucosidase activity or a reduction in the level of glycogen in at least one disease-relevant tissue as compared to a similar knockout transgenic mouse that does not receive one or more agents is therapeutic for Pompe disease.