Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat
| Autor: | Zhongtian Liu, Daniel O'Reilly, Frank Rigo, Thazha P. Prakash, David R. Corey, Xiulong Shen, Michaela Norrbom, Liande Li, Vivek Sharma, Jonathan K. Watts, Masad J. Damha |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Adolescent Mutant Primary Cell Culture Oligonucleotides Biochemistry Cell Line 03 medical and health sciences 0302 clinical medicine Iron-Binding Proteins Drug Discovery Genetics Humans RNA Messenger Child Molecular Biology Gene RNA Double-Stranded Regulation of gene expression biology Chemistry Intron Original Articles Genetic Therapy Fibroblasts Oligonucleotides Antisense Triazoles Introns Cell biology 030104 developmental biology Gene Expression Regulation Duplex (building) Cell culture Friedreich Ataxia Nucleic acid Frataxin biology.protein Molecular Medicine Female Trinucleotide Repeat Expansion 030217 neurology & neurosurgery |
| Popis: | Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA. |
| Databáze: | OpenAIRE |
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