June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
ABCA4 RNA exon editing in vitro and in vivo
Author Affiliations & Notes
  • Shimyn Slomovic
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Akiko Doi
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Jesse M Gray
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Kirk B Burkhart
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Rebekka Krumbach
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • John Bachmann
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Adam Clemens
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Tayla Cormier
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Lai Mung Fong
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Xiaojin Liu
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Savita Matapurkar
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Akiko Noma
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Anika Pavis
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Lingtao Peng
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Dennis Wu
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Robert D Bell
    Ascidian Therapeutics, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Shimyn Slomovic None; Akiko Doi None; Jesse Gray None; Kirk Burkhart None; Rebekka Krumbach None; John Bachmann None; Adam Clemens None; Tayla Cormier None; Lai Mung Fong None; Xiaojin Liu None; Savita Matapurkar None; Akiko Noma None; Anika Pavis None; Lingtao Peng None; Dennis Wu None; Robert Bell None
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3869. doi:
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      Shimyn Slomovic, Akiko Doi, Jesse M Gray, Kirk B Burkhart, Rebekka Krumbach, John Bachmann, Adam Clemens, Tayla Cormier, Lai Mung Fong, Xiaojin Liu, Savita Matapurkar, Akiko Noma, Anika Pavis, Lingtao Peng, Dennis Wu, Robert D Bell; ABCA4 RNA exon editing in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3869.

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

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Abstract

Purpose : Gene therapies have begun to show their promise with the development and advancement of evolving approaches and delivery methods. However, a range of indications, such as Stargardt disease, remain out of reach for treatment due to limited AAV packaging capacity and high mutational variance within gene targets and/or narrow therapeutic indices. To address this unmet need, we have developed Exon Editor technology, by which an Exon Editor RNA molecule is designed to replace a substantial portion of a targeted disease gene’s pre-mRNA with the correct sequence via RNA trans-splicing using the host cell’s spliceosome and without the aid of exogenous protein expression, resulting in a full-length, correct mRNA molecule and protein rescue.

Methods : To unlock the full potential of this approach, we generated a high throughput, multiplexed screening platform to design, evaluate, and optimize the RNA editing efficiency of thousands of Exon Editor candidates at a time.

Results : Here, we report on Exon Editors that can efficiently replace the 5’ half of the 7 kb ABCA4 coding sequence, which covers ~60% of known patient mutations, resulting in protein rescue in vitro in an engineered mutant cell line, as well as in Non-Human Primate (NHP) retina following subretinal injection of an AAV-encoded Exon Editor construct.

Conclusions : As we continue to work toward realizing the full potential of RNA exon editing while extending it to a number of additional indications, this report demonstrates the translational viability of this therapeutic strategy.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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