Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat

Li Liande, Shen Xiulong, Liu Zhongtian, Norrbom Michaela, Prakash Thazha P., O'Reilly Daniel, Sharma Vivek K., Damha Masad J., Watts Jonathan K., Rigo Frank, and Corey David R.. January 2018, ahead of print.doi:10.1089/nat.2017.0703

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.

Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich’s ataxia fibroblasts

De Samber B, Meul E, Laforce B, De Paepe B, Smet J, De Bruyne M, et al. (2018). PLoS ONE 13(1): e0190495. doi:10.1371/journal.pone.0190495

Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.