Methods for treating spinal muscular atrophy
AssigneePTC Therapeutics, Inc.
InventorsSergey V. Paushkin, Nikolai Naryshkin, Charles Romfo, Ellen Welch
Life of this patent
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Abstract
The present invention provides nucleic acid constructs, methods for identifying and validating compounds that increase the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, compounds and pharmaceutical compositions that increase levels of SMN protein produced from the SMN2 gene, and methods for use thereof in treating of SMA.
Claims23
A nucleic acid construct comprising a minigene which comprises, in 5′ to 3′ order:
- the nucleic acid residues of exon 6 of survival motor neuron (SMN), the nucleic acid residues of intron 6 of SMN, the nucleic acid residues of exon 7 of SMN2, the nucleic acid residues of intron 7 of SMN, a fragment of exon 8 of SMN, and the nucleic acid residues of the coding sequence of a reporter gene lacking a start codon, wherein either a single adenine, thymine or cytosine residue is inserted after nucleic acid residue 48 of the nucleic acid residues of exon 7 of SMN2, or a single nucleotide is inserted after nucleic acid residue 45, 46 or 47 of exon 7 of SMN2.
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A nucleic acid construct comprising a minigene which comprises, in 5′ to 3′ order:
- a start codon, the nucleic acid residues of exon 6 of SMN or a fragment thereof, the nucleic acid residues of intron 6 of SMN or a fragment thereof, the nucleic acid residues of exon 7 of SMN2, the nucleic acid residues of intron 7 of SAM or a fragment thereof, a fragment of exon 8 of SMN, and the nucleic acid residues of the coding sequence of a reporter gene lacking a start codon, wherein either a single adenine, thymine or cytosine residue is inserted after nucleic acid residue 48 of the nucleic acid residues of exon 7 of SMN2, or a single nucleotide is inserted after nucleic acid residue 45, 46 or 47 of exon 7 of SMN2, and wherein the first codon of the coding sequence of the reporter gene and the start codon of the minigene are in the same open reading frame.
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A nucleic acid construct comprising a minigene which comprises, in 5′ to 3′ order:
- a start codon, nucleic acid residues encoding a first amino acid sequence, the nucleic acid residues of intron 6 of SMN or a fragment thereof, the nucleic acid residues of exon 7 of SMN2, the nucleic acid residues of intron 7 of SMN or a fragment thereof, nucleic acid residues encoding a second amino acid sequence, and the nucleic acid residues of the coding sequence of a reporter gene lacking a start codon, wherein (i) either a single adenine, thymine or cytosine residue is inserted after nucleic acid residue 48 of the nucleic acid residues of exon 7 of SMN2, or a single nucleotide is inserted after nucleic acid residue 45, 46 or 47 of exon 7 of SMN2;
- (ii) the nucleic acid residues encoding the first and second amino acid sequences permit removal of an intron via mRNA splicing, and (iii) the first codon of the coding sequence of the reporter gene and the start codon of the minigene are in the same open reading frame.
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A method for increasing the expression of SMN in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound that increases the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.
A method for treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound that increases the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.
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Dependencies are inferred from the claim text.