Claims for Patent: 9,717,750

Summary for Patent: 9,717,750

Title:	Compositions and methods for modulation of SMN2 splicing in a subject
Abstract:	Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.
Inventor(s):	Bennett; C. Frank (Carlsbad, CA), Hung; Gene (San Diego, CA), Rigo; Frank (Carlsbad, CA), Krainer; Adrian R. (Huntington Square, NY), Hua; Yimin (Jericho, NY), Passini; Marco A. (Shrewsbury, MA), Shihabuddin; Lamya (Brighton, MA), Cheng; Seng H. (Natick, MA), Klinger; Katherine W. (Sudbury, MA)
Assignee:	Biogen MA Inc. (Cambridge, MA) Cold Spring Harbor Laboratory (Cold Spring Harbor, NY)
Application Number:	14/617,388
Patent Claims:	1. A method comprising administering by a bolus injection into the intrathecal space of a human subject having type II spinal muscular atrophy (SMA) an antisense compound comprising an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO: 1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2'-MOE nucleoside, and wherein the administering of the antisense compound ameliorates at least one symptom of SMA in the human subject. 2. The method of claim 1, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subject. 3. The method of claim 1, wherein inclusion of exon 7 of SMN2 mRNA in a motoneuron in the subject is increased. 4. The method of claim 1, wherein a 5 mg to 20 mg dose of the antisense compound is administered. 5. The method of claim 1, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 6. The method of claim 1, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age. 7. The method of claim 4, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 8. The method of claim 4, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age. 9. The method of claim 1, wherein inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject is increased. 10. The method of claim 4, wherein inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject is increased. 11. A method comprising administering by a bolus injection into the intrathecal space of a human subject having type III spinal muscular atrophy (SMA) an antisense compound comprising an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO: 1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2'-MOE nucleoside, and wherein the administering of the antisense compound ameliorates at least one symptom of SMA in the human subject. 12. The method of claim 11, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subject. 13. The method of claim 11, wherein inclusion of exon 7 of SMN2 mRNA in a motoneuron in the subject is increased. 14. The method of claim 11, wherein a 5 mg to 20 mg dose of the antisense compound is administered. 15. The method of claim 11, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 16. The method of claim 11, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age. 17. The method of claim 14, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 18. The method of claim 14, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age. 19. The method of claim 11, wherein inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject is increased. 20. The method of claim 14, wherein inclusion of exon 7 amino acids in SMN2 polypeptide in a motoneuron in the subject is increased. 21. A method of increasing inclusion of exon 7 in SMN2 messenger ribonucleic acid (mRNA) transcripts in a human subject having loss of both functional copies of the SMN1 gene, the method comprising administering by a bolus injection into the intrathecal space of the human subject an antisense compound comprising an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO: 1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2'-MOE nucleoside, and wherein the administering of the antisense compound increases inclusion of exon 7 in SMN2 mRNA transcripts in the human subject. 22. The method of claim 21, wherein the human subject is identified by a genetic test as having a mutation in the SMN1 gene. 23. The method of claim 21, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subject. 24. The method of claim 21, wherein a 5 mg to 20 mg dose of the antisense compound is administered. 25. A method of increasing exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts in a human subject having mutations in the SMN1 gene that lead to functional SMN protein deficiency, the method comprising administering by a bolus injection into the intrathecal space of the human subject an antisense compound comprising an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO: 1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2'-MOE nucleoside, and wherein the administering of the antisense compound increases exon 7 inclusion in SMN2 mRNA transcripts in the human subject. 26. The method of claim 25, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subj ect. 27. The method of claim 25, wherein a 5 mg to 20 mg dose of the antisense compound is administered. 28. The method of claim 25, wherein a first dose of the antisense compound is administered within one week of birth of the subject. 29. The method of claim 25, wherein a first dose of the antisense compound is administered within one month of birth of the subject. 30. The method of claim 25, wherein a first dose of the antisense compound is administered within three months of birth of the subject. 31. The method of claim 25, wherein a first dose of the antisense compound is administered within six months of birth of the subject. 32. The method of claim 25, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 33. The method of claim 25, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age. 34. A method of treating spinal muscular atrophy (SMA) in a human subject having SMA, the method comprising administering by a bolus injection into the intrathecal space of the human subject an antisense compound comprising an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO: 1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2'-MOE nucleoside, and wherein the administering of the antisense compound increases inclusion of exon 7 in SMN2 messenger ribonucleic acid (mRNA) transcripts in the human subject. 35. The method of claim 34, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subj ect. 36. The method of claim 34, wherein a 5 mg to 20 mg dose of the antisense compound is administered. 37. The method of claim 34, wherein a first dose of the antisense compound is administered within one week of birth of the subject. 38. The method of claim 34, wherein a first dose of the antisense compound is administered within one month of birth of the subject. 39. The method of claim 34, wherein a first dose of the antisense compound is administered within three months of birth of the subject. 40. The method of claim 34, wherein a first dose of the antisense compound is administered within six months of birth of the subject. 41. The method of claim 34, wherein a first dose of the antisense compound is administered when the subject is from 1 to 2 years of age. 42. The method of claim 34, wherein a first dose of the antisense compound is administered when the subject is from 1 to 15 years of age.