O uso de oligonucleotídeos para salto de vários exons em cães
Canada, Japão, USA – oligonucleotideos para salto de exon tem sido testado inclusive em pacientes com distrofia muscular de Duchenne; normalmente este tratamento é específico para um determinado exon. Nesta pesquisa em cães os autores descrevem um cocktail de oligonucleotídeos capaz de saltar vários exons que poderia beneficiar uma quantidade maior de pacientes. O resultado observado em cães foi promissor com expressão da distrofina e melhora das alterações histológicas dos músculos.
O resumo em inglês que será apresentado em dezembro pode ser lido abaixo:
(ASCB 2011, Denver – Colorado) Therapeutic Multiple Exon-skipping Using Cell-penetrating Morpholinos for Dystrophic Dogs
T. Yokota, T. Nagata, A. Nakamura, N. Urasawa, T. Saito, R. Kole, P. Sazani, T. Partridge, E. Hoffman, S. Takeda – Canada, Japan, USA
Duchenne muscular dystrophy (DMD), the most common and fatal X-linked myopathy, and its milder form, Becker muscular dystrophy (BMD), are caused by mutations in the dystrophin (DMD) gene. Antisense-mediated exon skipping therapy is currently one of the most promising molecular therapies for DMD. The exon skipping leads to the production of internally deleted in-frame mRNA transcripts but the truncated quasi-dystrophin retains some functions like BMD. Previously we demonstrated the first successful exon-skipping treatment in body-wide skeletal muscles in Canine X-linked muscular dystrophy (CXMD) using a cocktail of phosphorodiamidate morpholino oligomers (PMOs, morpholinos) targeting exon 6 and exon 8 of dystrophin mRNA. However, unmodified (bare) morpholino injections led to inefficient delivery to the heart, and dystrophin induction was barely detectable in the cardiac muscle. Here, we sought to recover the dystrophin expression in cardiac muscles in dystrophic dogs using morpholinos conjugated with negatively charged arginine-rich cell-penetrating peptides (PPMOs). We demonstrated that the delivery moieties significantly improved dystrophin production in both skeletal and cardiac muscles. Intravenous injections with PPMOs restored dystrophin expression in cardiac muscles accompanied by ameliorated histology. No obvious toxicity was detected by blood tests and histology. Our results show the potential of PMO conjugates as therapeutic agents for DMD.
