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Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7.

Publication ,  Journal Article
Niu, C; Prakash, TP; Kim, A; Quach, JL; Huryn, LA; Yang, Y; Lopez, E; Jazayeri, A; Hung, G; Sopher, BL; Brooks, BP; Swayze, EE; Bennett, CF ...
Published in: Sci Transl Med
October 31, 2018

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

October 31, 2018

Volume

10

Issue

465

Location

United States

Related Subject Headings

  • Vision, Ocular
  • Spinocerebellar Ataxias
  • Retinal Degeneration
  • Retina
  • Protein Aggregates
  • Photoreceptor Cells, Vertebrate
  • Phenotype
  • Peptides
  • Oligonucleotides, Antisense
  • Mutant Proteins
 

Citation

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Niu, C., Prakash, T. P., Kim, A., Quach, J. L., Huryn, L. A., Yang, Y., … La Spada, A. R. (2018). Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med, 10(465). https://doi.org/10.1126/scitranslmed.aap8677
Niu, Chenchen, Thazah P. Prakash, Aneeza Kim, John L. Quach, Laryssa A. Huryn, Yuechen Yang, Edith Lopez, et al. “Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7.Sci Transl Med 10, no. 465 (October 31, 2018). https://doi.org/10.1126/scitranslmed.aap8677.
Niu C, Prakash TP, Kim A, Quach JL, Huryn LA, Yang Y, et al. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med. 2018 Oct 31;10(465).
Niu, Chenchen, et al. “Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7.Sci Transl Med, vol. 10, no. 465, Oct. 2018. Pubmed, doi:10.1126/scitranslmed.aap8677.
Niu C, Prakash TP, Kim A, Quach JL, Huryn LA, Yang Y, Lopez E, Jazayeri A, Hung G, Sopher BL, Brooks BP, Swayze EE, Bennett CF, La Spada AR. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med. 2018 Oct 31;10(465).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

October 31, 2018

Volume

10

Issue

465

Location

United States

Related Subject Headings

  • Vision, Ocular
  • Spinocerebellar Ataxias
  • Retinal Degeneration
  • Retina
  • Protein Aggregates
  • Photoreceptor Cells, Vertebrate
  • Phenotype
  • Peptides
  • Oligonucleotides, Antisense
  • Mutant Proteins