June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Pharmacological chaperones improve rhodopsin homeostasis and protects photoreceptors in the RHO P23H mouse model of retinitis pigmentosa
Author Affiliations & Notes
  • Abhishek Vats
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Yibo Xi
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Bing Feng
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Owen Clinger
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Xujie Liu
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Archisha Ghosh
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Anthony St. Leger
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Kira L Lathrop
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Gregory Tochtrop
    Chemistry, Case Western Reserve University, Cleveland, Ohio, United States
  • Serge Picaud
    Institut de la vision, Paris, Île-de-France, France
  • Yuanyuan Chen
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Abhishek Vats None; Yibo Xi None; Bing Feng None; Owen Clinger None; Xujie Liu None; Archisha Ghosh None; Anthony St. Leger None; Kira Lathrop None; Gregory Tochtrop None; Serge Picaud None; Yuanyuan Chen None
  • Footnotes
    Support  NIHR01 EY030991, NIH CORE Grant P30 EY08098
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 681 – F0135. doi:
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      Abhishek Vats, Yibo Xi, Bing Feng, Owen Clinger, Xujie Liu, Archisha Ghosh, Anthony St. Leger, Kira L Lathrop, Gregory Tochtrop, Serge Picaud, Yuanyuan Chen; Pharmacological chaperones improve rhodopsin homeostasis and protects photoreceptors in the RHO P23H mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2022;63(7):681 – F0135.

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

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Abstract

Purpose : Mutations in RHODOPSIN (RHO) accounts for ~25-30% of autosomal dominant retinitis pigmentosa (adRP). No pharmacological treatments are available for RP. Many RHO mutants are structurally unstable and trigger dominant negative effects including disrupted proteostasis and rod cell death, which cause vision loss. We hypothesize that small molecule chaperones can stabilize the native folding and homeostasis RHO, which in turn will rescue rods in RHO-associated adRP. We previously discovered non-retinoid chaperones of RHO (such as YC-001). The purpose of this study is to test this hypothesis using in vitro, ex vivo and in vivo models and to develop new drug candidates for RP treatment.

Methods : We used high content imaging to profile the chaperone activities of two non-retinal chaperones towards 27 RP-causing human RHO mutants by quantifying cell-surface level of these RHO mutants in NIH3T3 cells. AutodockVina was used for docking calculation of chaperones. Two chaperone molecules were treated to the RhoP23H/+ knock-in mouse retinal explants to evaluate their chaperon activities to RHO. Intravitreal injections of two compounds were performed to RhoP23H/+ knock-in mice and efficacies were evaluated by OCT, ERG, and retinal histology.

Results : The in vitro high-content imaging assay showed that YC-001 and the other chaperone molecule rescued the transport of 9 and 11 mutants, respectively, in NIH3T3 cells. Docking calculations indicate that YC-001 binds in the β-ionone ring pocket with ΔG=-7.9 kCal/mol while the other chaperone molecule fills in a larger space of chromophore pocket with ΔG=-5.5 kCal/mol. Further, YC-001 treatment led to improved RHO homeostasis in the RhoP23H/+ retinal explants. Interestingly, YC-001 also reduces the number of residential macrophages (microglia) in the retinal explants. Finally, single, or double intravitreal injections of chaperones microparticles increased photoreceptor function and ONL thickness in RhoP23H/+ mice.

Conclusions : We showed that the YC-001 and the other non retinal chaperones increased RHO transport, improved RHO homeostasis and protected photoreceptors in RhoP23H/+ adRP mouse model. Collectively, here we provide a strong proof-of-principle that non-retinoid chaperones are promising drug candidates in treating RHO-associated RP.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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