June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Pharmacological and molecular features of DT-168, a topical GeneTACTM small molecule being developed as potential treatment for Fuchs Endothelial Corneal Dystrophy caused by CTG repeat expansions in the TCF4 gene
Author Affiliations & Notes
  • Andrew Powers
    Design Therapeutics, Carlsbad, California, United States
  • Katie Cheung
    Design Therapeutics, Carlsbad, California, United States
  • Nicola Osgood
    Design Therapeutics, Carlsbad, California, United States
  • Andrea Kudwa
    Design Therapeutics, Carlsbad, California, United States
  • Peter Shepard
    Design Therapeutics, Carlsbad, California, United States
  • Sumon Datta
    Design Therapeutics, Carlsbad, California, United States
  • Muhammad Safadi
    Design Therapeutics, Carlsbad, California, United States
  • Santosh Sinha
    Design Therapeutics, Carlsbad, California, United States
  • Jim Kerr
    Design Therapeutics, Carlsbad, California, United States
  • Chengzhi Zhang
    Design Therapeutics, Carlsbad, California, United States
  • Nancy Levin
    Design Therapeutics, Carlsbad, California, United States
  • Doane Chilcoat
    Design Therapeutics, Carlsbad, California, United States
  • Sean Jeffries
    Design Therapeutics, Carlsbad, California, United States
  • Jae Kim
    Design Therapeutics, Carlsbad, California, United States
  • Joao Siffert
    Design Therapeutics, Carlsbad, California, United States
  • Footnotes
    Commercial Relationships   Andrew Powers Design Therapeutics, Code E (Employment); Katie Cheung Design Therapeutics, Code E (Employment); Nicola Osgood Design Therapeutics, Code E (Employment); Andrea Kudwa Design Therapeutics, Code E (Employment); Peter Shepard Design Therapeutics, Code E (Employment); Sumon Datta Design Therapeutics, Code E (Employment); Muhammad Safadi Design Therapeutics, Code E (Employment); Santosh Sinha Design Therapeutics, Code E (Employment); Jim Kerr Design Therapeutics, Code E (Employment); Chengzhi Zhang Design Therapeutics, Code E (Employment); Nancy Levin Design Therapeutics, Code E (Employment); Doane Chilcoat Design Therapeutics, Code E (Employment); Sean Jeffries Design Therapeutics, Code E (Employment); Jae Kim Design Therapeutics, Code E (Employment); Joao Siffert Design Therapeutics, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1333. doi:
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      Andrew Powers, Katie Cheung, Nicola Osgood, Andrea Kudwa, Peter Shepard, Sumon Datta, Muhammad Safadi, Santosh Sinha, Jim Kerr, Chengzhi Zhang, Nancy Levin, Doane Chilcoat, Sean Jeffries, Jae Kim, Joao Siffert; Pharmacological and molecular features of DT-168, a topical GeneTACTM small molecule being developed as potential treatment for Fuchs Endothelial Corneal Dystrophy caused by CTG repeat expansions in the TCF4 gene. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1333.

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

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Abstract

Purpose : Over 70% of Fuchs endothelial corneal dystrophy (FECD) cases are caused by cytosine-thymine-guanine (CTG) nucleotide repeat expansions in the TCF4 gene (CTG18.1) transcribed into toxic TCF4 RNA. This pathogenic RNA sequesters splicing proteins and forms nuclear foci, elicits transcript mis-splicing (spliceopathy), and drives corneal endothelial cell (CEC) death. We evaluated the tolerability, corneal biodistribution, and pharmacologic activity of topical ophthalmic DT-168 – a novel small molecule inhibitor of CTG18.1 transcription under development as a potential treatment for FECD.

Methods : CECs were cultured from donors with a clinical diagnosis of FECD who underwent endothelial keratoplasty and from unaffected cadavers (control CECs). Repeat expansions in the TCF4 gene were measured using optical genome mapping. FECD and control CECs were treated in vitro with DMSO or DT-168 and evaluated for i) nuclear foci labeling via fluorescent in situ hybridization and ii) splicing analysis via RNA sequencing. Frequency of exon inclusion and splice junction use, termed percent spliced-in (PSI), was used to establish a panel of splicing events that differed significantly between DMSO treated control and FECD CECs. In addition, rabbits were treated twice-daily for 14 days with DT-168 eye drops to assess safety based on standard ophthalmologic assessments and biodistribution.

Results : FECD CECs had CTG repeat expansions of ~9 to 21 kilobases in the TCF4 gene; expansions were not detected in control CECs. Untreated FECD CECs averaged 2.9 ± 0.2 foci per nucleus, while levels in control CECs were negligible. DT-168 reduced foci in FECD CECs to control levels, with IC50 values of 24 to 102 nM. DT-168 significantly improved splicing in FECD CECs for all panel genes, with correction that exceeded 50% of control values. DT-168 eye drops were well-tolerated and distributed throughout the cornea, including CECs. Plasma levels of DT-168 were negligible.

Conclusions : DT-168 markedly reduced nuclear foci and improved spliceopathy in FECD CEC cultures, was well-tolerated in rabbits, and had good biodistribution throughout the cornea. These findings show that DT-168 could address the most common genetic cause of FECD and support development of DT-168 as a potential disease-modifying therapy.

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

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