Tratamento de longo prazo com nova formulação de oligonucleotídeos em camundongos com distrofia muscular
USA – nesta pesquisa os oligonucleotídeos foram acoplados a uma pequena proteína para aumentar a sua penetração nas células musculares. Os resultados de um ano de tratamento demonstraram que os animais apresentaram um significante aumento da distrofina muscular e cardíaca, superior ao observado com o uso dos oligonucleotídeos convencionais.
O resumo em inglês pode ser lido abaixo:
(American Journal of Pathology, 2012) Long-Term Rescue of Dystrophin Expression and Improvement in Muscle Pathology and Function in Dystrophic mdx Mice by Peptide-Conjugated Morpholino
Bo Wu, Peijuan Lu, Caryn Cloer, Mona Shaban, Snimar Grewal, Stephanie Milazi, Sapana N. Shah, Hong M. Moulton,Qi L. Lu – USA
Exon skipping is capable of correcting frameshift and nonsense mutations in Duchenne musculardystrophy (DMD). Phase 2 clinical trials in the United Kingdom and the Netherlands have reported induction of dystrophin expression in muscle of DMD patients by systemic administration of both phosphorodiamidate morpholino oligomers (PMO) and 2′-O-methyl phosphorothioate. Peptide-conjugated PMO (PPMO) offers significantly higher efficiency than PMO, with the ability to induce near-normal levels of dystrophin, and restores function in both skeletal and cardiac muscle. We examined 1-year systemic efficacy of PPMO targeting exon 23 in dystrophic mdx mice. The LD50 of PPMO was determined to be approximately 85 mg/kg. The half-life of dystrophin expression was approximately 2 months in skeletal muscle, but shorter in cardiac muscle. Biweekly injection of 6 mg/kg PPMO produced >20% dystrophin expression in all skeletal muscles and ≤5% in cardiac muscle, with improvement in muscle function and pathology and reduction in levels of serum creatine kinase. Monthly injections of 30 mg/kg PPMO restored dystrophin to >50% normal levels in skeletal muscle (but 15% in cardiac muscle), which was associated with greatly reduced serum creatine kinase levels, near-normal histology, and functional improvement of skeletal muscle. Our results demonstrate for the first time that regular 1-year administration of PPMO can be safely applied to achieve significant therapeutic effects in an animal model.
