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 Patrick; Sharma, Vivek; Damha, Masad J.; Watts, Jonathan K.; Rigo, Frank; Corey, David R.

doi:10.1089/nat.2017.0703

Cited by 38 publications

(31 citation statements)

References 29 publications

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“…Antisense Oligonucleotides (ASOs). ASOs have also been used to increase gene expression in cell lines derived from patients with Friedreich's ataxia and spinal muscular dystrophy [53,54]. The proposed mechanism by which ASOs increase gene expression involves the binding of these compounds to the expanded repeat and blockade of the expanded RNA, which inhibits recognition of DNA, prevents R-loop formation and allows more gene expression.…”

Section: Dna Targeting Strategiesmentioning

confidence: 99%

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Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Cardoso¹

2018

obm genet

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Some repeats of three or more nucleotides in tandem, which are present in a gene or in its vicinity, tend to increase in number and for this reason are called dynamic mutations. These triplet repeats are unstable and can expand from one generation to the next. According to the expansion size, an unaffected individual can carry a pre-mutation that will expand through generations leading to the development of triplet repeat expansion diseases. The increase in the number of repeats over time leads to earlier development and increased severity of symptoms in affected individuals in successive generations. Although there is still no treatment for this type of disease, several strategies are under investigation. Here, we describe treatment approaches for triplet repeat expansion diseases that have been developed over recent years, using DNA or RNA molecules as targets. Some of these strategies have the potential for future use in gene therapy for trinucleotide repeat disorders.

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Section: Dna Targeting Strategiesmentioning

confidence: 99%

“…A study by Li et al [53] demonstrated that ASOs and dsRNAs can activate frataxin protein expression in Friedreich's ataxia patient-derived cell lines that possess varied numbers of GAA repeats. Increased frataxin protein expression was achieved by ASOs incorporating diverse chemical modifications [53].…”

Section: Dna Targeting Strategiesmentioning

confidence: 99%

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Cardoso¹

2018

obm genet

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“…We demonstrated previously that duplex RNAs, singlestranded silencing RNAs (ss-siRNAs), and ASOs can target the expanded GAA repeat, reverse R-loop formation, and cause threefold restoration of FXN protein expression (Li et al 2016(Li et al , 2018. These experiments were performed in patient-derived fibroblast cells.…”

Section: Introductionmentioning

confidence: 99%

Efficient electroporation of neuronal cells using synthetic oligonucleotides: identifying duplex RNA and antisense oligonucleotide activators of human frataxin expression

Shen

Beasley

Putman

et al. 2019

RNA

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Oligonucleotide drugs are experiencing greater success in the clinic, encouraging the initiation of new projects. Resources are insufficient to develop every potentially important project, and persuasive experimental data using cell lines close to disease target tissue is needed to prioritize candidates. Friedreich's ataxia (FRDA) is a devastating and currently incurable disease caused by insufficient expression of the enzyme frataxin (FXN). We have previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived fibroblast cells. We chose to further test these compounds in induced pluripotent stem cell-derived neuronal progenitor cells (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPCs using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using patient-derived fibroblast cells. A duplex RNA and several antisense oligonucleotides (ASOs) with different combinations of 2 ′ ′ ′ ′ ′-methoxyethyl (2 ′ ′ ′ ′ ′-MOE), 2 ′ ′ ′ ′ ′-fluoro (2 ′ ′ ′ ′ ′-F), and constrained ethyl (cEt) were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. Our data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FRDA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.

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“…Given that reduced amount of frataxin is the principal cause of the disease, the main goal of a specific therapy for FRDA is to restore physiological frataxin levels. Several therapeutic approaches under development aim at increasing frataxin levels, using both drug repositioning or drug discovery approaches …”

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confidence: 99%

Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

et al. 2019

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Background Friedreich's ataxia is an autosomal‐recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. Objectives With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market‐available drugs able to increase frataxin levels. Methods Using a cell‐based reporter assay to monitor variation in frataxin amount, we performed a high‐throughput screening of a library containing 853 U.S. Food and Drug Administration–approved drugs. Results Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti–human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron‐sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Conclusions Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease‐related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia. © 2019 International Parkinson and Movement Disorder Society

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

Cited by 38 publications

References 29 publications

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Experimental DNA- or RNA-Directed Therapies for Trinucleotide Repeat Disease

Efficient electroporation of neuronal cells using synthetic oligonucleotides: identifying duplex RNA and antisense oligonucleotide activators of human frataxin expression

Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

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