Chaperone-based therapy for Niemann-Pick disease
View Patent ↗The present invention provides a method for treating individuals affected with the acid sphingomyelinase-deficient forms of Niemann-Pick disease (i.e., Type A or Type B Niemann-Pick) by administering small molecules as specific molecular “chaperones” for the deficient acid sphingomyelinase (ASM) enzyme associated with the disease. The molecules are ceramide, sphingomyelin, or phosphonucleotide analogues.
1. A method of treating an individual having Niemann-Pick disease, or being genetically pre-disposed to developing Niemann-Pick disease, comprising administering to the individual a composition comprising a mutant acid sphingomyelinase (ASM) activity-enhancing amount of a compound wherein the compound is an inhibitor of wild-type ASM and is a ceramide analogue of Formula III:
wherein R n is an independently optionally substituted C 1-10 alkyl, n=0-5, R 7 is H or OH, R 8 is H or C 1-10 alkyl, and R 9 is C 10-20 alkyl.
2. The method of claim 1 , wherein the compound is D-MAPP, represented by the following structure:
3. The method of claim 1 , wherein the ASM mutant is L302 (SEQ ID NO: 3).
4. The method of claim 1 , wherein the ASM mutant is R496L (SEQ ID NO: 2).
5. The method of claim 1 , wherein the ASM mutant is delta R608 (SEQ ID NO: 4).
6. A method of enhancing the activity of a mutant acid sphingomyelinase (ASM) comprising administering a mutant ASM activity-enhancing amount of a compound to a diseased individual with Niemann-Pick disease or an individual who is genetically pre-disposed to Niemann-Pick disease, wherein the compound is a ceramide analog of Formula III:
wherein R n is an independently optionally substituted C 1-10 alkyl, n=0-5, R 7 is H or OH, R 8 is H or C 1-10 alkyl, and R 9 is C 10-20 alkyl or a sphingomyelin analogue.
7. The method of claim 6 , wherein the compound is D-MAPP, represented by the following structure:
8. The method of claim 6 , wherein the ASM mutant is L302 (SEQ ID NO: 3).
9. The method of claim 6 , wherein the ASM mutant is R496L (SEQ ID NO: 2).
10. The method of claim 6 , wherein the ASM mutant is delta R608 (SEQ ID NO: 4).