AAN Annual Meeting
Initial Efficacy and Safety Evaluation in Cynomolgus Monkeys of AVI-5038, a Peptide Conjugated Phosphorodiamidate Morpholino Oligomer (PPMO) Being Developed To Skip Exon 50 in Duchenne Muscular Dystrophy
Peter Sazani, Stephen Shrewsbury, Bothell, WA
OBJECTIVE: To evaluate the efficacy of AVI-5038 at inducing skipping of dystrophin exon 50, as determined by RT-PCR, and also perform an initial toxicology assessment. BACKGROUND: AVI-5038 is a PPMO that induces dystrophin exon 50, and is designed to restore the reading frame and enable dystrophin expression in DMD patients. DESIGN/METHODS: Cynomolgus monkeys were dosed IV with 0, 3, or 9 mg/kg with AVI-5038, once weekly for 4 weeks. Following a 21 day recovery period, animals were sacrificed and a toxicological evaluation was performed. Selected muscle tissues were also evaluated by RT-PCR for evidence of skipping of dystrophin exon 50. RESULTS: AVI-5038 was well tolerated, with no adverse effects detected at doses up to 9 mg/kg. Toxicological findings were generally limited to the kidney, and included basophilic granules and instances of tubular degeneration / regeneration that was dose dependant. No clear evidence of kidney function change was detected, as shown by clinical chemistry and urinalysis evaluations. Significant levels of exon skipping were detected by RT-PCR in all major muscle groups evaluated, including diaphragm, heart, and quadriceps, at 9 mg/kg. CONCLUSIONS/RELEVANCE: AVI-5038, the first PPMO for DMD, was extremely well tolerated at all tested doses in primates. In addition, the safety data indicate that higher doses could be used to produce greater efficacy. Exon skipping was induced by the PPMO in healthy primate's muscles following systemic administration.
Category - Muscle Disease/Neuromuscular Junction - Therapeutics
Wednesday, April 14, 2010 3:15 PM
Poster Session: Integrated Neuroscience: Emerging Treatments in Neuromuscular Disease (3:15 PM-4:30 PM)
Is the latest finding applicable to PPMO only or PMO also?