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Proc Natl Acad Sci U S A ; 107(5): 1864-9, 2010 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-20080679

RESUMO

Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.


Assuntos
Materiais Biocompatíveis/química , Inativação Gênica , Lipídeos/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Animais , Materiais Biocompatíveis/síntese química , Sistemas de Liberação de Medicamentos , Fator VII/antagonistas & inibidores , Fator VII/genética , Células HeLa , Hepatócitos/metabolismo , Humanos , Lipídeos/síntese química , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Interferência de RNA
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