BIOTIN COMPLEXES FOR TREATMENT AND DIAGNOSIS OF ALZHEIMER'S DISEASE

• US 20170326244A1
• Filed: 05/22/2017
• Published: 11/16/2017
• Est. Priority Date: 08/31/2012
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Elmaleh, David R.
• Granted Patent: US 10,532,104 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/3517 Marker; Tag
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin

Abstract

Described herein are compositions and methods for treating or imaging Alzheimer'"'"'s disease (AD). The compositions comprise a biotin moiety and a siRNA moiety, without the need for a targeting agent such as an antibody, avidin, or streptavidin. In certain embodiments, the compositions further comprise a diagnostic agent.

Claims

1. A composition comprising a biotin moiety and a siRNA moiety, wherein the siRNA moiety comprises a nucleotide selected from the group consisting of:

any of SEQ ID NOS;

2-15, or a nucleic acid that has at least 85% sequence homology with any one of SEQ ID NOS;

2-15.

2. The composition of claim 1, wherein the composition further comprises a linker between the siRNA and the biotin.

3. The composition of claim 1, wherein the composition does not comprise an antibody, an antigen, avidin, or streptavidin.

4. The composition of claim 1, wherein the composition further comprises a diagnostic agent.

5. The composition of claim 4, wherein the diagnostic agent is selected from the group consisting of a fluorophore, a chromophore, a chemoluminescing agent, a radionuclide, an unpair spin atom, a free radical, and a contrast agent.

6. The composition of claim 1, wherein the siRNA moiety comprises a nucleotide selected from the group consisting of:

any of SEQ ID NOS;

2-8, or a nucleic acid that has at least 85% sequence homology with any one of SEQ ID NOS;

2-8.

8. The composition of claim 1, wherein the composition is able to transfect cells in vivo.

9. The composition of claim 1, wherein the composition partially, substantially, or completely deletes, silences, inactivates, interferes with, or down-regulates a gene that encodes a protein involved in AD pathogenesis.

10. The composition of claim 9, wherein the protein involved in AD pathogenesis is selected from the group consisting of amyloid precursor protein, beta amyloid cleaving enzyme-1, Tau, presenilin, selenoprotein P, apolipoprotein E, insulin-degrading protein, neprilysin, and alpha-synuclidin.

11. The composition of claim 9, wherein the gene is selected from the group consisting of MARK2, PAK3, PAK2, ADCK5, AKAP13, LOC55971, PLK2, DYRK1A, MAK, ITK, PIM1, RAGE, ITPK1, CKB, PFKM, DGKB, and SPHK2.

12. The composition of claim 9, wherein the gene is selected from the group consisting of EIF2AK2, CDKL1, DCK, DGKQ, PFKFB3, ERK8, STK19, PRKG2, and PAM2K1IP1.

13. The composition of claim 1, wherein the siRNA moiety comprises a guanosine at the 5′

-end.

14. The composition of claim 1, wherein the sense or the antisense strand of the siRNA moiety is equal to or less than 30, 25, 24, 23, 22, 21, 20, 19, 18 or 17 nucleotides in length.

15. A pharmaceutically acceptable formulation, wherein the pharmaceutically acceptable formulation comprises a therapeutically-effective amount of a composition of claim 1 and a pharmaceutically acceptable carrier or diluent.

16. A method of treating Alzheimer'"'"'s disease in a mammal, comprising the step of:

administering to said mammal a therapeutically effective amount of a composition of claim 1.

17. The method of claim 16, wherein said mammal is a human.

18. A method generating an image of a subject, comprising the steps of:

administering to a subject in need of imaging a detectable amount of a composition of claim 4, and

generating an image.

19. The method of claim 18, wherein said subject is a human.

7. A composition consisting of a biotin moiety and a siRNA moiety, wherein the composition partially, substantially, or completely deletes, silences, inactivates, interferes with, or down-regulates a gene that encodes a protein involved in AD pathogenesis.

20. A method of treating Alzheimer'"'"'s disease in a mammal, comprising the step of:

administering to said mammal a therapeutically effective amount of a composition comprising a biotin moiety and a siRNA moiety, wherein the siRNA moiety comprises a nucleotide of SEQ ID NO;

1 or a nucleic acid that has at least 95% sequence homology with SEQ ID NO;

1.

21. The method of claim 20, wherein said mammal is a human.

22. A method generating an image of a subject, comprising the steps of:

administering to a subject in need of imaging a detectable amount of a composition comprising a diagnostic agent, a biotin moiety, and a siRNA moiety, wherein the siRNA moiety comprises a nucleotide of SEQ ID NO;

1 or a nucleic acid that has at least 95% sequence homology with SEQ ID NO;

1, and

generating an image.

23. The method of claim 22, wherein said subject is a human.