Targeting Several CAG Expansion Diseases by a Single Antisense Oligonucleotide

To date there are 9 known diseases caused by an expanded polyglutamine repeat, with the most prevalent being Huntington's disease. Huntington's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available. It is caused by a CAG repeat expansion in the HTT gene, which results in an expansion of a glutamine stretch at the N-terminal end of the huntingtin protein. This polyglutamine expansion plays a central role in the disease and results in the accumulation of cytoplasmic and nuclear aggregates. Here, we make use of modified 2′-O-methyl phosphorothioate (CUG)n triplet-repeat antisense oligonucleotides to effectively reduce mutant huntingtin transcript and protein levels in patient-derived Huntington's disease fibroblasts and lymphoblasts. The most effective antisense oligonucleotide, (CUG)7, also reduced mutant ataxin-1 and ataxin-3 mRNA levels in spinocerebellar ataxia 1 and 3, respectively, and atrophin-1 in dentatorubral-pallidoluysian atrophy patient derived fibroblasts. This antisense oligonucleotide is not only a promising therapeutic tool to reduce mutant huntingtin levels in Huntington's disease but our results in spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy cells suggest that this could also be applicable to other polyglutamine expansion disorders as well

Ongoing foreign body reaction to subcutaneous implanted (heparin) modified Dacron in rats

Dacron-containing heart valve repair devices trigger chronic inflammation characterized by the presence of activated macrophages, foreign body giant cells, and capsule formation. Upon blood contact, proinflammatory proteins adsorb to the material and provide a substrate for monocyte binding and differentiation. Various heparin-coated polymers have been shown to reduce adsorption of proinflammatory proteins in vitro and in vivo. In this study, the effect of knitted, heparin-coated Dacron on the foreign body reaction was tested subcutaneously in rats. We hypothesized that the anti-inflammatory effect of heparin would reduce monocyte recruitment and differentiation and therefore limit the inflammatory reaction. An ongoing foreign body reaction, characterized by the presence of foreign body giant cells and high vascularization, was observed in uncoated as well as (heparin-)coated Dacron at up to 180 days of implantation. Also, a thin capsule was formed around each material up to this time. In conclusion, although heparin coatings might have an effect on the acute inflammatory response, we were not able to show a difference between heparin-coated and uncoated Dacron after 180 days' implantation in rats. Further research needs to be conducted to assess the difference in proinflammatory protein adsorption between the tested materials and the effect this has on the long-term foreign body reaction. (C) 2004 Wiley Periodicals, Inc