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• W2026419243 abstract "Duchenne Muscular Dystrophy (DMD) is a lethal X-linked disorder caused by truncating mutations in the DMD gene which result in an absence of the dystrophin protein. However, deletion mutations that preserve an open reading frame, lead to an internally truncated functional dystrophin which is associated with the milder Becker Muscular Dystrophy (BMD). This observation as led to exon-skipping therapies in DMD patients to restore the reading frame and generate a BMD phenotype. Our group has recently shown that mutations in the 5′ exons of the DMD gene that disrupt the open reading frame (ORF) induce expression of a functional N-truncated dystrophin via IRES-driven translation initiation within exon 6. We have previously shown that the exon 5 IRES can be activated by disruption of the ORF by AAV9. U7snRNA-mediated skipping of exon 2 by intramuscular (IM) or intravascular (IV) injection. We have now extended those studies to address the minimal efficacious dose (MED), a prerequisite for clinical development. To assess dose ranging with IM delivery, TA (tibialis anterior) injections were performed at 5 different doses, ranging from 1.1 × 1010 to 1.1 × 1012 total vector genomes (vg) in half-log steps (N = 6 TAs per dose). A gradient of exon 2 exclusion was seen by RT-PCR at all doses, but high levels of properly localized dystrophin expression were seen at 3.5 × 1011 vg and above. Experiments to determine the correction of TA physiology at this dose are underway. Similarly, dose ranging experiments using IV tail vein injections with 5 doses (N = 3 per dose) ranging from 1 × 1012 to 1 × 1014 vg/kg are underway, and results of both protein expression and physiology studies will be presented. Our results show that U7snRNA-mediated exon skipping in Dup2 is both titratable and highly efficient. The establishment of a IV MED for this vector will allow planning of IND-enabling GLP toxicology studies. Duchenne Muscular Dystrophy (DMD) is a lethal X-linked disorder caused by truncating mutations in the DMD gene which result in an absence of the dystrophin protein. However, deletion mutations that preserve an open reading frame, lead to an internally truncated functional dystrophin which is associated with the milder Becker Muscular Dystrophy (BMD). This observation as led to exon-skipping therapies in DMD patients to restore the reading frame and generate a BMD phenotype. Our group has recently shown that mutations in the 5′ exons of the DMD gene that disrupt the open reading frame (ORF) induce expression of a functional N-truncated dystrophin via IRES-driven translation initiation within exon 6. We have previously shown that the exon 5 IRES can be activated by disruption of the ORF by AAV9. U7snRNA-mediated skipping of exon 2 by intramuscular (IM) or intravascular (IV) injection. We have now extended those studies to address the minimal efficacious dose (MED), a prerequisite for clinical development. To assess dose ranging with IM delivery, TA (tibialis anterior) injections were performed at 5 different doses, ranging from 1.1 × 1010 to 1.1 × 1012 total vector genomes (vg) in half-log steps (N = 6 TAs per dose). A gradient of exon 2 exclusion was seen by RT-PCR at all doses, but high levels of properly localized dystrophin expression were seen at 3.5 × 1011 vg and above. Experiments to determine the correction of TA physiology at this dose are underway. Similarly, dose ranging experiments using IV tail vein injections with 5 doses (N = 3 per dose) ranging from 1 × 1012 to 1 × 1014 vg/kg are underway, and results of both protein expression and physiology studies will be presented. Our results show that U7snRNA-mediated exon skipping in Dup2 is both titratable and highly efficient. The establishment of a IV MED for this vector will allow planning of IND-enabling GLP toxicology studies." @default.
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• W2026419243 date "2014-10-01" @default.
• W2026419243 modified "2023-09-26" @default.
• W2026419243 title "G.P.96" @default.
• W2026419243 doi "https://doi.org/10.1016/j.nmd.2014.06.110" @default.
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