Compositions and methods for treating an Aβ-modulated disease or disorder or improving cognition in a subject
The present invention provides compositions and methods for treating and preventing an Aβ-modulated disease. In certain embodiments, the invention provides an inhibitor of Fyn tyrosine kinase, and methods of using the same. In certain embodiments, the inhibitor of the invention inhibits Aβ oligomer induced signaling and reduces or halts the progression of Alzheimer's Disease.
1. A method of treating an Aβ-modulated disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of saracatinib, or a pharmaceutically acceptable salt thereof, wherein the free concentration of saracatinib in the plasma of the mammal ranges from about 2.6 to about 41.2 nM, wherein the Aβ-modulated disease or disorder is selected from the group consisting of Alzheimer's Disease (AD), prodromal Alzheimer's Disease, amnestic mild cognitive impairment (MCI), Down syndrome dementia, Lewy body dementia, Parkinson's Disease with dementia, and any combinations thereof.
2. The method of claim 1 , wherein Aβ oligomer-induced signaling is inhibited in the mammal.
3. The method of claim 1 , wherein the saracatinib, or pharmaceutically acceptable salt thereof is selected from the group consisting of saracatinib free base, saracatinib difumarate, and any combinations thereof.
4. The method of claim 1 , wherein administration of the saracatinib, or pharmaceutically acceptable salt thereof, to the mammal affords a trough CSF concentration of saracatinib in the mammal ranging from about 0.9 to about 14.0 nM.
5. The method of claim 4 , wherein the trough CSF concentration range of saracatinib is selected from the group consisting of: from about 0.9 to about 2.2 nM; from about 2.1 to about 8.3 nM; and from about 2.5 to about 14.0 nM.
6. The method of claim 1 , wherein the average brain concentration of saracatinib in the mammal ranges from about 3 to about 46 nM.
7. The method of claim 1 , wherein the mammal is human.
8. The method of claim 1 , wherein the free concentration of saracatinib in the plasma of the human is selected from the group consisting of: from about 2.6 to about 6.5 nM, from about 6.2 to about 24.4 nM, and from about 7.4 to about 41.2 nM.
9. The method of claim 1 , wherein the saracatinib, or pharmaceutically acceptable salt thereof, is administered to the mammal by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous routes.
10. The method of claim 1 , further comprising administering to the mammal at least one additional agent that treats the Aβ-modulated disease or disorder in the mammal.
11. The method of claim 10 , wherein the saracatinib, or pharmaceutically acceptable salt thereof, and at least one additional agent are coformulated.
12. The method of claim 7 , wherein the human is administered a daily dose of saracatinib, or a pharmaceutically acceptable salt thereof, that comprises an amount of saracatinib free base selected from the group consisting of about 50 mg, about 100 mg, and about 125 mg.
13. The method of claim 7 , wherein the human is administered a daily dose of saracatinib free base selected from the group consisting of about 50 mg, about 100 mg, and about 125 mg.
14. The method of claim 7 , wherein the human is administered a daily dose of saracatinib difumarate selected from the group consisting of about 71.4 mg, about 142.9 mg, and about 178.6 mg.
15. A method of minimizing or reversing further loss of cognition in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of saracatinib, or pharmaceutically acceptable salt thereof, wherein the free concentration of saracatinib in the plasma of the mammal ranges from about 2.6 to about 41.2 nM, wherein mammal suffers from an Aβ-modulated disease or disorder selected from the group consisting of Alzheimer's Disease (AD), prodromal Alzheimer's Disease, amnestic mild cognitive impairment (MCI), Down syndrome dementia, Lewy body dementia, Parkinson's Disease with dementia, and any combinations thereof.
16. The method of claim 15 , wherein synapse density is restored or further loss of synapse density is minimized or reversed in the mammal.
17. The method of claim 15 , wherein the saracatinib, or pharmaceutically acceptable salt thereof, is selected from the group consisting of saracatinib free base, saracatinib difumarate, and any combinations thereof.
18. The method of claim 15 , wherein administration of the saracatinib, or pharmaceutically acceptable salt thereof, to the mammal affords a trough CSF concentration of saracatinib in the mammal ranging from about 0.9 to about 14.0 nM.
19. The method of claim 18 , wherein the trough CSF concentration range of saracatinib is selected from the group consisting of: from about 0.9 to about 2.2 nM; from about 2.1 to about 8.3 nM; and from about 2.5 to about 14.0 nM.
20. The method of claim 15 , wherein the average brain concentration of saracatinib in the mammal ranges from about 3 to about 46 nM.
21. The method of claim 15 , wherein the mammal is human.
22. The method of claim 21 , wherein the free concentration of saracatinib in the plasma of the human is selected from the group consisting of: from about 2.6 to about 6.5 nM, from about 6.2 to about 24.4 nM, and from about 7.4 to about 41.2 nM.
23. The method of claim 15 , wherein the saracatinib, or pharmaceutically acceptable salt thereof, is administered to the mammal by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous routes.
24. The method of claim 15 , further comprising administering to the mammal at least one additional agent that restores further loss of synapse density in the mammal.
25. The method of claim 24 , wherein the saracatinib, or pharmaceutically acceptable salt thereof, and at least one additional agent are coformulated.
26. The method of claim 21 , wherein the human is administered a daily dose of saracatinib, or a pharmaceutically acceptable salt thereof, that comprises an amount of saracatinib free base selected from the group consisting of about 50 mg, about 100 mg, and about 125 mg.
27. The method of claim 21 , wherein the human is administered a daily dose of saracatinib free base selected from the group consisting of about 50 mg, about 100 mg, and about 125 mg.
28. The method of claim 21 , wherein the human is administered a daily dose of saracatinib difumarate selected from the group consisting of about 71.4 mg, about 142.9 mg, and about 178.6 mg.