Loading patent…
AssigneeUniversity of Massachusetts
InventorsRavindra N. Singh, Natalia N. Singh, Nirmal K. Singh, Elliot J. Androphy
Estimating the term…
The present invention is directed to methods and compositions capable of blocking the inhibitory effect of a newly-identified intronic inhibitory sequence element, named ISS-N1 (for “intronic splicing silencer”), located in the SMN2 gene. The compositions and methods of the instant invention include oligonucleotide reagents (e.g., oligoribonucleotides) that effectively target the SMN2 ISS-N1 site in the SMN2 pre-mRNA, thereby modulating the splicing of SMN2 pre-mRNA to include exon 7 in the processed transcript. The ISS-N1 blocking agents of the invention cause elevated expression of SMN protein, thus compensating for the loss of SMN protein expression commonly observed in subjects with spinal muscular atrophy (SMA).
A method of enhancing the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in a cell or cell extract, comprising contacting the cell or cell extract with an oligonucleotide or oligoribonucleotide that is substantially complementary to at least 8 nucleotides of intron 7 of the SMN2 gene, such that the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in the cell or cell extract is enhanced.
(canceled)
(canceled)
9-19. (canceled)
A method of enhancing the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in an organism, comprising administering to the organism an oligonucleotide or oligoribonucleotide that is substantially complementary to at least 8 nucleotides of intron 7 of the SMN2 gene, such that the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in the organism extract is enhanced.
A method of treating spinal muscular atrophy (SMA) in a patient, comprising administering to the patient an oligonucleotide or oligoribonucleotide that is substantially complementary to at least 8 nucleotides of intron 7 of the SMN2 gene in a dose effective to enhance the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in cells of the patient, such that SMA in the patient is treated.
A method for inhibiting an SMN2 pre-mRNA intronic splicing silencer site in a cell or cell extract or organism comprising contacting the cell with an oligonucleotide complementary to the ISSN-N1 sequence set forth in SEQ ID NO:1, or administering to the organism an oligonucleotide complementary to the ISSN-N1 sequence set forth in SEQ ID NO:1, such that the SMN2 intronic splicing silencer site is inhibited.
(canceled)
(canceled)
A method of treating a subject that would benefit from enhanced levels of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in neuronal cells, comprising administering to the patient an oligonucleotide or oligoribonucleotide that is substantially complementary to at least 8 nucleotides of intron 7 of the SMN2 gene in a dose effective to enhance the level of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in cells of the patient, such that levels of exon 7-containing SMN2 mRNA relative to exon-deleted SMN2 mRNA in neuronal cells.
Dependencies are inferred from the claim text.