Ian R. Graham

TL;DR: A single-blind, placebo-controlled, dose-escalation study in patients with Duchenne muscular dystrophy to assess the safety and biochemical efficacy of an intramuscular morpholino splice-switching oligonucleotide (AVI-4658) that skips exon 51 in dystrophin mRNA.

TL;DR: A series of systematic experiments are described to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom, preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 50 into the mature mRNA by the splicing machinery.

TL;DR: Results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.

TL;DR: For the first time, a chronic long-term administration of LDs of unmodified PMO, equivalent to doses in use in DMD boys, is safe, significantly ameliorates the muscular dystrophic phenotype and improves the activity of dystrophin-deficient mice, thus encouraging the further clinical translation of this approach in humans.

TL;DR: In this article, the authors designed phosphorodiamidate morpholino oligomer (PMO) AOs to skip additional exons that border the deletions such that the reading frame is restored and internally truncated, but functional, dystrophin expressed.