التفاصيل البيبلوغرافية
| العنوان: |
COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF Nav1.8 GENE |
| Document Number: |
20110124711 |
| تاريخ النشر: |
May 26, 2011 |
| Appl. No: |
13/016896 |
| Application Filed: |
January 28, 2011 |
| مستخلص: |
The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the Nav1.8 gene (Nav1.8 gene), comprising an antisense strand having a nucleotide sequence which is less that 25 nucleotides in length and which is substantially complementary to at least a part of the Nav1.8 gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression of the Nav1.8 gene using the pharmaceutical composition; and methods for inhibiting the expression of the Nav1.8 gene in a cell. |
| Inventors: |
Sah, Dinah (Boston, MA, US); Frank-Kamenetsky, Maria (Brookline, MA, US); Geick, Anke (Bayreuth, DE); Hadwiger, Philipp (Alenkunstadt, DE); Roehl, Ingo (Memmelsdorf, DE); Tan, Pamela (Kulmbach, DE); Vornlocher, Hans-Peter (Bayreuth, DE) |
| Assignees: |
ALNYLAM PHARMACEUTICALS, INC. (Cambridge, MA, US) |
| Claim: |
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human Nav1.8 gene in a cell, wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. |
| Claim: |
2. The dsRNA of claim 1, wherein said first sequence is selected from the group consisting of Tables 1, 4 and 6 and said second sequence is selected from the group consisting of Tables 1, 4 and 6. |
| Claim: |
3. The dsRNA of claim 1, wherein said dsRNA comprises at least one modified nucleotide. |
| Claim: |
4. The dsRNA of claim 2, wherein said dsRNA comprises at least one modified nucleotide. |
| Claim: |
5. The dsRNA of claim 3, wherein said modified nucleotide is chosen from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. |
| Claim: |
6. The dsRNA of claim 3, wherein said modified nucleotide is chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-O-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. |
| Claim: |
7. A cell comprising the dsRNA of claim 1. |
| Claim: |
8. A pharmaceutical composition for inhibiting the expression of the Nav1.8 gene in an organism, comprising a dsRNA and a pharmaceutically acceptable carrier, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. |
| Claim: |
9. The pharmaceutical composition of claim 8, wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. |
| Claim: |
10. The pharmaceutical composition of claim 9, wherein said composition is formulated for administration selected from the group consisting of intrathecal infusion or injection, or intravenous infusion or injection. |
| Claim: |
11. A method for inhibiting the expression of the Nav1.8 gene in a cell, the method comprising: (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the Nav1.8 gene, thereby inhibiting expression of the Nav1.8 gene in the cell. |
| Claim: |
12. The method of claim 11, wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. |
| Claim: |
13. A method of treating, preventing or managing pain comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a dsRNA, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. |
| Claim: |
14. The method of claim 13, wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. |
| Claim: |
15. The method of claim 14, wherein said pain is selected from the group consisting of neuropathic pain and inflammatory pain. |
| Claim: |
16. A vector for inhibiting the expression of the Nav1.8 gene in a cell, said vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a dsRNA, wherein one of the strands of said dsRNA is substantially complementary to at least a part of a mRNA encoding Nav1.8 and wherein said dsRNA is less than 30 base pairs in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits the expression of said Nav1.8 gene by at least 20%. |
| Claim: |
17. The vector of claim 16, wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. |
| Claim: |
18. A cell comprising the vector of claim 16. |
| Claim: |
19. A cell comprising the vector of claim 17. |
| Current U.S. Class: |
514/44/A |
| Current International Class: |
61; 07; 61; 12; 12; 12; 12 |
| رقم الانضمام: |
edspap.20110124711 |
| قاعدة البيانات: |
USPTO Patent Applications |