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<p>Osteogenesis imperfecta (OI) is generally caused by a dominant mutation in Collagen I, encoded by the genes <i>COL1A1</i> and<i> COL1A2</i>. To date there is no satisfactory therapy for OI, but inactivation of the mutant allele through small interfering RNAs (siRNA) is a promising approach, as siRNAs targeting each allele of a polymorphism could be used for allele-specific silencing irrespective of the location of the actual mutations. In this study we examined the allele dependent effects of several tiled siRNAs targeting a region surrounding an exonic <i>COL1A2 </i>T/C polymorphism (rs1800222) in heterozygous primary human bone cells. Relative abundances of <i>COL1A2</i> alleles were determined by cDNA sequencing and overall <i>COL1A2</i> abundance was analyzed by quantitative PCR. One of the siRNAs decreased overall <i>COL1A2</i> abundance by 71% of which 75% was due to silencing of the targeted T-allele. In conclusion, allele-preferential silencing of Collagen type I genes may be a future therapeutic approach for OI.</p>