AI Article Synopsis
- The challenge of intragenic heterogeneity in dominant disease-causing genes complicates the development of effective and affordable treatments, as seen in autosomal dominant retinitis pigmentosa caused by numerous rhodopsin mutations.
- An RNA interference (RNAi)-based method is proposed that can target the problematic native transcripts without affecting engineered replacement genes, suggesting a mutation-independent therapeutic strategy.
- Experiments show that this RNAi approach can reduce murine rhodopsin levels by up to 90% while still allowing the expression of the replacement genes, validating its effectiveness in cell cultures and live mouse models.
Article Abstract
The intragenic heterogeneity encountered in many dominant disease-causing genes represents a significant challenge with respect to development of economically viable therapeutics. For example, 25% of autosomal dominant retinitis pigmentosa is caused by over 100 different mutations within the gene encoding rhodopsin, each of which could require a unique gene therapy. We describe here an RNA interference (RNAi)-based mutation-independent approach, targeting as an example murine rhodopsin. Native transcripts are suppressed by a single RNAi molecular species, whereas transcripts from replacement genes engineered at degenerate third-codon wobble positions are resistant to suppression. We demonstrate suppression of murine rhodopsin transcript by up to 90% with full concomitant expression of replacement transcript and establish the validity of this approach in cell culture, retinal explants, and mouse liver in vivo.
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| http://dx.doi.org/10.1016/j.ymthe.2005.03.028 | DOI Listing |
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