June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Intravitreal administration of small molecule read-through agents demonstrate functional activity in a nonsense mutation mouse model
Author Affiliations & Notes
  • Susan Schneider
    Eloxx Pharmaceuticals, Massachusetts, United States
  • Dan Crawford
    Eloxx Pharmaceuticals, Massachusetts, United States
  • Al Pierce
    Eloxx Pharmaceuticals, Massachusetts, United States
  • Phillip Vanland
    EyeCRO, Oklahoma, United States
  • Matt Goddeeris
    Eloxx Pharmaceuticals, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Susan Schneider, Eloxx Pharmaceuticals (E); Dan Crawford, Eloxx Pharmaceuticals (E); Al Pierce, Eloxx Pharmaceuticals (E); Phillip Vanland, EyeCRO (E); Matt Goddeeris, Eloxx Pharmaceuticals (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4940. doi:
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    • Get Citation

      Susan Schneider, Dan Crawford, Al Pierce, Phillip Vanland, Matt Goddeeris; Intravitreal administration of small molecule read-through agents demonstrate functional activity in a nonsense mutation mouse model. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4940.

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

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Abstract

Purpose : Mutations across many essential genes can lead to progressive photoreceptor loss. This presents challenges to the development of common therapeutic strategies. However, the prevalence of nonsense mutations as a class presents an opportunity to apply a singular therapeutic agent across a variety of inherited retinal disorders (IRDs). We propose a novel approach to addressing IRDs, including Usher Syndrome, utilizing Eukaryotic Ribosome Selective Glycosides (ERSGs) delivered to the eye by intravitreal (IVT) injection.

Methods : We investigated our library of ERSG small molecules for read-through activity when administered by IVT injection in a mouse model of oculocutaneous albinism type 2. This model contains a naturally occurring R262X nonsense mutation in the Oca2 gene that results in a lack of Oca2 channel protein responsible for establishing pH in the melanocyte. Multiple ERSGs were evaluated in this model and compared with in vitro reporter results for the same nonsense mutation.

Results : After a single IVT injection, we observed dose-dependent melanin production, which is consistent with read-through activity by our compounds and functional restoration of the Oca2 channel.

Conclusions : These data help establish a target exposure range for development of a sustained release IVT formulation and demonstrate the potential for these molecules to show activity in applications targeting photoreceptors, retinal pigment epithelial cells or choroid. These results, in combination with other data such as rabbit tolerability, also support selection of a lead compound for IVT administration for the potential treatment of a spectrum of nonsense mutation-related IRDs.

This is a 2020 ARVO Annual Meeting abstract.

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