June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Antisense oligonucleotide mediated increase of OPA1 expression using TANGO technology for the treatment of autosomal dominant optic atrophy
Author Affiliations & Notes
  • ADITYA VENKATESH
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Zhiyu Li
    Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Anne Christiansen
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Kian Huat Lim
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Jacob Kach
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Robert Hufnagel
    Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Isabel Aznarez
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Gene Liau
    Stoke Therapeutics, Bedford, Massachusetts, United States
  • Footnotes
    Commercial Relationships   ADITYA VENKATESH, Stoke Therapeutics (E), Stoke Therapeutics (I), Stoke Therapeutics (P); Zhiyu Li, Stoke Therapeutics (F); Anne Christiansen, Stoke Therapeutics (E), Stoke Therapeutics (I); Kian Huat Lim, Stoke Therapeutics (E), Stoke Therapeutics (I), Stoke Therapeutics (P); Jacob Kach, Stoke Therapeutics (E), Stoke Therapeutics (I), Stoke Therapeutics (P); Robert Hufnagel, Stoke Therapeutics (F); Isabel Aznarez, Stoke Therapeutics (E), Stoke Therapeutics (I), Stoke Therapeutics (P); Gene Liau, Stoke Therapeutics (E), Stoke Therapeutics (I), Stoke Therapeutics (P)
  • Footnotes
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Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2755. doi:
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      ADITYA VENKATESH, Zhiyu Li, Anne Christiansen, Kian Huat Lim, Jacob Kach, Robert Hufnagel, Isabel Aznarez, Gene Liau; Antisense oligonucleotide mediated increase of OPA1 expression using TANGO technology for the treatment of autosomal dominant optic atrophy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2755.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Autosomal dominant optic atrophy (ADOA) is one of the most commonly diagnosed optic neuropathies. This optic nerve disease is associated with structural and functional mitochondrial deficits that lead to degeneration of the retinal ganglion cells and progressive, irreversible loss of vision. 65-90% of ADOA patients carry mutations in OPA1 and most mutations lead to haploinsufficiency. OPA1 encodes a mitochondrial GTPase with a critical role in mitochondrial fusion, ATP synthesis and apoptosis. Currently, there is no approved disease-modifying treatment for ADOA patients. Here, we employ TANGO (Targeted Augmentation of Nuclear Gene Output), a novel therapeutic approach, that uses antisense oligonucleotides (ASOs), to increase the endogenous expression of OPA1. TANGO targets a naturally-occurring, alternatively spliced exon that has an in-frame stop codon whose inclusion results in a non-productive OPA1 transcript that is degraded by nonsense-mediated mRNA decay. This alternatively spliced exon is conserved in human, non-human primates and rabbit.

Methods : We designed and tested ASOs to prevent the inclusion of the alternatively-spliced exon with the goal of increasing productive OPA1 mRNA and protein. ASOs were administered either by lipid-based transfection or gymnotic delivery to HEK293 or human fibroblast cells and RNA/protein was extracted to assess the impact on OPA1 mRNA splicing, and changes in mRNA and protein expression. ASOs were also administered to wild-type rabbits by intravitreal injection and retinae were collected to evaluate the impact of ASOs on OPA1 mRNA splicing.

Results : In vitro screens identified ASOs that decreased the non-productive, alternatively spliced OPA1 transcript and increased expression of OPA1 mRNA and protein. Intravitreal injection of lead ASOs in wild-type rabbits were well tolerated and led to a dose-dependent reduction in non-productive OPA1 mRNA levels after 15 days. Ongoing studies are evaluating the effect of ASOs on mitochondrial function in ADOA patient fibroblasts.

Conclusions : These results indicate that TANGO can be used to potentially address ADOA caused by OPA1 haploinsufficiency by using ASOs to increase endogenous OPA1 mRNA and protein expression levels. This approach leverages the OPA1 wild-type allele and can be applied in a mutation-independent manner to treat ADOA.

This is a 2020 ARVO Annual Meeting abstract.

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