Gearóid Tuohy

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A major difficulty associated with the design of gene therapies for autosomal dominant diseases is the immense intragenic heterogeneity often encountered in such conditions. In order to overcome such difficulties we have designed, and evaluated in vitro, three strategies which avoid a requirement to target individual mutations for genetic suppression. In(More)
Mutational heterogeneity represents one of the greatest barriers impeding the progress toward the clinic of gene therapies for many dominantly inherited disorders. A general strategy of gene suppression in conjunction with replacement has been proposed to overcome this mutational heterogeneity. In the current study, various aspects of this strategy are(More)
Over 100 dominant-negative mutations within the COL1A1 gene have been identified in osteogenesis imperfecta (OI). In terms of human therapeutics, targeting each of these mutations independently is unlikely to be feasible. Here we show that the hammerhead ribozyme Rzpol1a1, targeting a common polymorphism within transcripts from the COL1A1 gene,(More)
PURPOSE To design, generate, and compare in vitro a range of hammerhead ribozymes targeting retinal transcripts implicated in autosomal dominant retinitis pigmentosa (adRP) and thereby identify ribozymes that may be valuable as therapeutic agents for adRP. To address mutational heterogeneity in rhodopsin and peripherin-linked adRP using mutation-independent(More)
A combined total of approximately 100 mutations have been encountered within the rhodopsin gene in retinitis pigmentosa (RP) and congenital night blindness. Mice carrying a targeted disruption of the rhodopsin gene phenotypically mimic RP, losing their photoreceptors over a period of 3 months and having no recordable rod electroretinogram. These animals(More)
Given that mutant COL1A1 is known to cause Osteogenesis Imperfecta (OI), tools to modulate COL1A1 expression are likely to be of significant therapeutic value. In this context, we have evaluated RNA interference (RNAi) as a means to downregulate COL1A1 expression in Cos-7 cells and in human mesenchymal progenitor stem cells (MPCs), the latter cells giving(More)