Duchenne muscular dystrophy (DMD) is a severe hereditary neurodegenerative disorder due to mutations in the dystrophin gene. Effectiveness of antisense−mediated targeted exon skipping for inducing dystrophin rescue has been demonstrated in a pilot trial in vivo by using a naked 2'OMePs antisense oligoribonucleotide. Other DMD PhaseI/II trials using backboned PMO antisense are ongoing. We demonstrated as proof of principle that a novel biocompatible type of nanoparticle (T1, with a core of polymethilmethacrylate) was able to bind and convey 2'OMePS antisense and to induce dystrophin restoration in body wide mdx animal model. In order to get insights onto nanoparticles as AONs vehicles we will explore systemically in mdx mice: 1) other nanoparticles for identifying the best nanoparticle−AON compound as well as the optimal AON concentration able to have a sustained therapeutic effect; 2) different routes of administration; 3) clearance modes and possible side effects of nanoparticle−AON complexes. Studying other nanoparticles with higher AON loading capacity for their ability to induce dystrophin rescue in the mdx animal model will also allow us to optimise the dose regimen since we have evidences that NP have a depot effect, with long lasting release of AONs. For the most effective nanoparticle we will perform pharmacokinetic studies of the nanoparticle−AON complex in order to assess the clearance mode and timing and the half−life of these nanomaterials in the mdx animal model. We will also test different administration routes, including oral, since the known protective effect that nanoparticles exert on AON molecules. Furthermore we will evaluate the safety aspects of these novel compounds in regard to the sarcolemma components. This work will be performed in order to establish if nanoparticle−antisense complex might represent suitable, safe and efficacious compounds to be possibly transferred into DMD therapies.

Pre−clinical evaluation of biocompatible nanoparticles as delivery system of 2O−methyl−phosphorothioate (2OMePS) antisense oligoribonucleotides for exon skipping−mediated dystrophin restoration (Telethon GGPO9093)

FERLINI, Alessandra
2010

Abstract

Duchenne muscular dystrophy (DMD) is a severe hereditary neurodegenerative disorder due to mutations in the dystrophin gene. Effectiveness of antisense−mediated targeted exon skipping for inducing dystrophin rescue has been demonstrated in a pilot trial in vivo by using a naked 2'OMePs antisense oligoribonucleotide. Other DMD PhaseI/II trials using backboned PMO antisense are ongoing. We demonstrated as proof of principle that a novel biocompatible type of nanoparticle (T1, with a core of polymethilmethacrylate) was able to bind and convey 2'OMePS antisense and to induce dystrophin restoration in body wide mdx animal model. In order to get insights onto nanoparticles as AONs vehicles we will explore systemically in mdx mice: 1) other nanoparticles for identifying the best nanoparticle−AON compound as well as the optimal AON concentration able to have a sustained therapeutic effect; 2) different routes of administration; 3) clearance modes and possible side effects of nanoparticle−AON complexes. Studying other nanoparticles with higher AON loading capacity for their ability to induce dystrophin rescue in the mdx animal model will also allow us to optimise the dose regimen since we have evidences that NP have a depot effect, with long lasting release of AONs. For the most effective nanoparticle we will perform pharmacokinetic studies of the nanoparticle−AON complex in order to assess the clearance mode and timing and the half−life of these nanomaterials in the mdx animal model. We will also test different administration routes, including oral, since the known protective effect that nanoparticles exert on AON molecules. Furthermore we will evaluate the safety aspects of these novel compounds in regard to the sarcolemma components. This work will be performed in order to establish if nanoparticle−antisense complex might represent suitable, safe and efficacious compounds to be possibly transferred into DMD therapies.
2010
Ferlini, Alessandra
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1401449
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