Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat.
Nucleic Acid Ther
; 28(1): 23-33, 2018 02.
Article
em En
| MEDLINE
| ID: mdl-29341839
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
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RNA de Cadeia Dupla
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RNA Mensageiro
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Oligonucleotídeos Antissenso
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Expansão das Repetições de Trinucleotídeos
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Proteínas de Ligação ao Ferro
Limite:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Nucleic Acid Ther
Ano de publicação:
2018
Tipo de documento:
Article