Post by David Feder on Dec 21, 2008 13:41:40 GMT -5
Readthrough-inducing ointment : the new approach for the treatment of nonsense mutation-mediated disorders
M. SHIOZUKA1; T. Kawamoto2; H. Sasaki3; K. SHIMADA1; A. Wagatsuma1; Y. Nonomura4; R. Matsuda1
1. Dept. of Life Sci., The Univ. of Tokyo, Tokyo, Japan.
2. RI Research, Tsurumi Univ., Yokohama, Japan.
3. DNA Medicine, The Jikei Univ., Tokyo, Japan.
4. Microbial Chemistry Research Foundation, Tokyo, Japan.
The ability of aminoglycoside antibiotics, such as gentamicin, to promote readthrough of premature termination codons has attracted interest in these drugs as potential therapeutic agents in nonsense mutations. In order to measure readthrough efficiency with quantitative accuracy, we have established transgenic mouse strain containing dual-reporter gene composed of beta-galactosidase and luciferase connected with premature termination codon region. The objective of this study was to evaluate the transdermal drug delivery (TDD) potential for treatment of genetic diseases caused by nonsense mutations. TDD is an appealing alternative that offers good patient compliance and the possibility of controlled release over time while avoiding possible degradation due to the gastrointestinal tract or first-pass liver effects. Despite these advantages, TDD is severely limited by the low permeability of skin caused mainly by stratum corneum. Here, we show that skin permeability can be increased through the use of chemical enhancer. It was found that the readthrough activity by transdermal administration of gentamicin resulted similar to those by subcutaneous injection. To evaluate in vivo permeation of gentamicin in serum or muscle tissue from hairless mice, as measured with liquid chromatography-tandem mass spectrometry. Application of chemical enhancer to the skin increased its permeability and enabled the delivery of gentamicin through the skin. Further, the expansion of the intercellular gaps in the prickle cell layer was observed by electron microscopic analysis of the skin. These readthrough therapy on TDD may provide significant value in treating or preventing genetic diseases associated with nonsense mutations. This work was supported by a Research Grant for Nervous & Mental Disorders and by a Grant for Research in Brain Science from the Ministry of Health, Labor and Welfare, Japan.
M. SHIOZUKA1; T. Kawamoto2; H. Sasaki3; K. SHIMADA1; A. Wagatsuma1; Y. Nonomura4; R. Matsuda1
1. Dept. of Life Sci., The Univ. of Tokyo, Tokyo, Japan.
2. RI Research, Tsurumi Univ., Yokohama, Japan.
3. DNA Medicine, The Jikei Univ., Tokyo, Japan.
4. Microbial Chemistry Research Foundation, Tokyo, Japan.
The ability of aminoglycoside antibiotics, such as gentamicin, to promote readthrough of premature termination codons has attracted interest in these drugs as potential therapeutic agents in nonsense mutations. In order to measure readthrough efficiency with quantitative accuracy, we have established transgenic mouse strain containing dual-reporter gene composed of beta-galactosidase and luciferase connected with premature termination codon region. The objective of this study was to evaluate the transdermal drug delivery (TDD) potential for treatment of genetic diseases caused by nonsense mutations. TDD is an appealing alternative that offers good patient compliance and the possibility of controlled release over time while avoiding possible degradation due to the gastrointestinal tract or first-pass liver effects. Despite these advantages, TDD is severely limited by the low permeability of skin caused mainly by stratum corneum. Here, we show that skin permeability can be increased through the use of chemical enhancer. It was found that the readthrough activity by transdermal administration of gentamicin resulted similar to those by subcutaneous injection. To evaluate in vivo permeation of gentamicin in serum or muscle tissue from hairless mice, as measured with liquid chromatography-tandem mass spectrometry. Application of chemical enhancer to the skin increased its permeability and enabled the delivery of gentamicin through the skin. Further, the expansion of the intercellular gaps in the prickle cell layer was observed by electron microscopic analysis of the skin. These readthrough therapy on TDD may provide significant value in treating or preventing genetic diseases associated with nonsense mutations. This work was supported by a Research Grant for Nervous & Mental Disorders and by a Grant for Research in Brain Science from the Ministry of Health, Labor and Welfare, Japan.
