COMPOSITIONS AND METHODS OF MODULATION OF SMN2 SPLICING IN A SUBJECT

Claims

1. Use of an antisense oligonucleotide for treating spinal muscular atrophy (SMA) in a human subject, wherein the antisense oligonucleotide is administered intrathecally to the human subject, wherein the antisense oligonucleotide consists of 18 linked nucleosides, wherein the antisense oligonucleotide has a nucleic acid sequence consisting of the nucleic acid sequence of 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, wherein each cytosine base of the antisense oligonucleotide is 5-methyl substituted.

2. The use of claim 1, wherein said treatment comprises widely distributing the antisense oligonucleotide throughout the spinal cord of a human subject.

3. The use according to claim 2, wherein the spinal cord includes the thoracic, lumbar and cervical regions of the spinal cord.

4. The use according to any one of claims 1 to 3, wherein the antisense oligonucleotide comprises a pharmaceutically acceptable salt.

5. The use according to claim 4, wherein the pharmaceutically acceptable salt is sodium.

6. The use according to any one of claims 1 to 5, wherein the antisense oligonucleotide is administered in the form of a pharmaceutical composition comprising the antisense oligonucleotide and a pharmaceutically acceptable diluent or carrier.

7. The use according to any one of paragraphs 1-6, wherein the subject is a human being and has type I SMA.

8. The use according to any one of paragraphs 1-6, wherein the subject is a human being and has type II SMA.

9. The use according to any one of paragraphs 1-6, wherein the subject is a human being and has type III SMA.

10. The use according to any one of claims 1 to 9, wherein the antisense oligonucleotide is formulated for bolus administration.

11. The use according to any one of claims 1-10, wherein said antisense oligonucleotide is administered intrathecally in a dose of 5 mg to 20 mg.

12. The use according to any one of claims 1-11, wherein the treatment delays or reduces the loss of motor function in a human subject.

13. The use according to any one of claims 1-11, wherein the treatment improves survival in a human subject.

14. The use according to any one of paragraphs 1-11, wherein the first dose of the antisense oligonucleotide is administered: (i) within 1 week from the date of birth of a subject who is a human being; (ii) within 1 month from the date of birth of a subject who is a human being; (iii) within 3 months from the date of birth of a subject who is a human being; (iv) within 6 months from the date of birth of a subject who is a human being; (v) when the subject is between 1 and 2 years of age; or (vi) when the subject is between 1 and 15 years of age.

15. A method for treating spinal muscular atrophy (SMA) in a human subject, comprising intrathecally administering to the human subject an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the antisense oligonucleotide has a nucleic acid sequence consisting of the nucleic acid sequence of 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, wherein each cytosine base of the antisense oligonucleotide is 5-methyl substituted, and wherein administering the antisense compound enhances inclusion of exon 7 in SMN2 messenger ribonucleic acid (mRNA) transcripts in the human subject.

16. Use of an antisense oligonucleotide for enhancing inclusion of exon 7 in mRNA (messenger ribonucleic acid) transcripts of the human survival motor neuron 2 (SMN2) gene in a human subject having a loss of both functional copies of the survival motor neuron 1 (SMN1) gene, wherein the antisense oligonucleotide is administered intrathecally to the human subject, wherein the antisense oligonucleotide is comprised of 18 linked nucleosides, wherein the antisense oligonucleotide has a nucleic acid sequence consisting of the nucleic acid sequence of 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, wherein each cytosine base of the antisense oligonucleotide is 5-methyl substituted.