Novas pesquisas para tratamento da mutação sem sentido (mutação de ponto) em distrofias musculares
Israel e Japão - após o insucesso do ataluren para tratamento da distrofia muscular de Duchenne as atenções voltam-se novamente para os aminoglicosídeos, antibióticos que podem atuar na mutação sem sentido (mutação de ponto) da distrofia muscular. Nesta semana foram publicados duas pesquisas sobre o tema: na primeira os autores identificaram dois novos aminoglicosídeos com potencial de uso, mais efetivos e menos tóxicos; o segundo explora a possibilidade de uso da gentamincina por via transdérmica (através da pele).
O resumo destas pesquisas pode ser lido abaixo:
(J. Biochem., Apr 2010; 147: 463 - 470) Transdermal delivery of a readthrough-inducing drug: a new approach of gentamicin administration for the treatment of nonsense mutation-mediated disorders
Masataka Shiozuka, Akira Wagatsuma, Tadafumi Kawamoto, Hiroyuki Sasaki, Kenichi Shimada, Yoshikazu Takahashi, Yoshiaki Nonomura, and Ryoichi Matsuda - Japan
To induce the readthrough of premature termination codons, aminoglycoside antibiotics such as gentamicin have attracted interest as potential therapeutic agents for diseases caused by nonsense mutations. The transdermal delivery of gentamicin is considered unfeasible because of its low permeability through the dermis. However, if the skin permeability of gentamicin could be improved, it would allow topical application without the need for systemic delivery. In this report, we demonstrated that the skin permeability of gentamicin increased with the use of a thioglycolate-based depilatory agent. After transdermal administration, the readthrough activity in skeletal muscle, as determined using a lacZ/luc reporter system, was found to be equivalent to systemic administration when measured in transgenic mice. Transdermally applied gentamicin was detected by liquid chromatography-tandem mass spectrometry in the muscles and sera of mice only after depilatory agent-treatment. In addition, expansion of the intercellular gaps in the basal and prickle-cell layers was observed by electron microscopy only in the depilatory agent-treated mice. Depilatory agent-treatment may be useful for the topical delivery of readthough-inducing drugs for the rescue of nonsense mutation-mediated genetic disorders. This finding may also be applicable for the transdermal delivery of other pharmacologically active molecules.
(Bioorganic & Medicinal Chemistry,2010) Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations
Igor Nudelamn, Dana Glikin, Boris Smolkin, Mariana Hainrichson, Valery Belakhov and Timor Baasov - Israel
New pseudo-di- and pseudo-trisaccharide derivatives of the aminoglycoside drug G418 were designed, synthesized and their ability to readthrough nonsense mutations was examined in both in vitro and ex vivo systems, along with the toxicity tests. Two novel lead structures, NB74 and NB84, exhibiting significantly reduced cell toxicity and superior readthrough efficiency than those of gentamicin, were discovered. The superiority of new leads was demonstrated in six different nonsense DNA-constructs underling the genetic diseases cystic fibrosis, Duchenne muscular dystrophy, Usher syndrome and Hurler syndrome.
Fonte: http://distrofiamuscular.net/noticias.htm |
