1035. Short G-Rich Oligonucleotides as a Therapeutic for Huntingtonss Disease
Authors: Michael Skogen, Jennifer Roth, Hetal Parekh-Olmedo, Eric Kmiec
Journal: Molecular Therapy (2006)

Huntington's Disease (HD) is an inherited autosomal dominant genetic disorder in which neuronal tissue degenerates. The pathogenesis of the disease appears to center on the development of protein aggregates that arise initially from the misfolding of the mutant HD protein. Mutant huntingtin (Htt) is produced by HD genes that contain an increased number of glutamine codons and this expansion leads to the production of a protein that misfolds. Recentstudies suggest that mutant Htt can nucleate protein aggregation and interfere with a multitude of normal cellular functions. As such, efforts to find a therapy for HD have focused on agents that disrupt or block the Htt aggregation pathway. Here, we show that short guanosine monomeric oligonucleotides capable of adopting a G- quartet structure, are effective inhibitors of Htt aggregation. Using a structure/function approach, we have identified a potentially active structure for GROs that block Htt aggregation. By utilizing a biochemical/immunoblotting assay as an initial screen, we identified a 20-mer, all G-oligonucleotide (HDG) as an active molecule. Subsequent testing in a cell-based assay revealed that HDG was an effective inhibitor of aggregation of a fusion protein, comprised of a mutant Htt fragment and green fluorescent protein (eGFP). Taken together, our results suggest that monomeric G-oligonucleotides, capable of adopting a G-quartet conformation are effective inhibitors of Htt aggregation. These results reveal a brand new class of molecular medicine agents for development as therapeutics for Huntington's Disease. Huntington's Disease (HD) is an inherited autosomal dominant genetic disorder in which neuronal tissue degenerates. The pathogenesis of the disease appears to center on the development of protein aggregates that arise initially from the misfolding of the mutant HD protein. Mutant huntingtin (Htt) is produced by HD genes that contain an increased number of glutamine codons and this expansion leads to the production of a protein that misfolds. Recentstudies suggest that mutant Htt can nucleate protein aggregation and interfere with a multitude of normal cellular functions. As such, efforts to find a therapy for HD have focused on agents that disrupt or block the Htt aggregation pathway. Here, we show that short guanosine monomeric oligonucleotides capable of adopting a G- quartet structure, are effective inhibitors of Htt aggregation. Using a structure/function approach, we have identified a potentially active structure for GROs that block Htt aggregation. By utilizing a biochemical/immunoblotting assay as an initial screen, we identified a 20-mer, all G-oligonucleotide (HDG) as an active molecule. Subsequent testing in a cell-based assay revealed that HDG was an effective inhibitor of aggregation of a fusion protein, comprised of a mutant Htt fragment and green fluorescent protein (eGFP). Taken together, our results suggest that monomeric G-oligonucleotides, capable of adopting a G-quartet conformation are effective inhibitors of Htt aggregation. These results reveal a brand new class of molecular medicine agents for development as therapeutics for Huntington's Disease.