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The Chen Laboratory

Protein misfolding is commonly seen in inherited retinal degeneration such as Leber congenital amaurosis, Stargardt disease or retinitis pigmentosa. Genetic mutation of one nucleotide often leads to the change of one amino acid in the encoded protein that may disrupt the amino acid interactions essential for stabilizing the native folding of the protein. Unfortunately, most inherited retinal degenerations currently lack effective treatments.

Even though gene therapy has brought new hope to the treatment of inherited retinal degenerations, pharmacological treatment is still favored because small molecule drugs are easy for manufacture and storage, easy to be taken orally or topically, and are easy to withdraw in case of adverse effects. Specifically, we are focusing on understanding the disease mechanism and drug discovery of retinitis pigmentosa associated with mutations in the gene encoding the visual pigment, rhodopsin. Targeting the early events that cumulatively lead to retinal degeneration, we have identified novel small molecules that restore the homeostasis of rhodopsin mutants. We are studying the mechanism of actions of the most effective and potent compounds, characterizing their metabolism and effects in a mouse model expressing a rhodopsin mutant, to develop an efficacious and safe treatment regimen that can be further tested in large animals and clinical trials. Additionally, we are trying to test the retinal protective agents discovered from the rhodopsin misfolding model to other retinal degeneration models, such as light-damage.

News

Improved Drugs for Eye Care Featuring the Chen and Dileo Labs (Oct 2023):

https://www.upmcphysicianresources.com/physician-journal/10042023-improved-drugs-for-eye-care

Welcome Dr. Li Sheng and Gillian Williams to the Chen Lab family! Aug 2023

Our preclinical studies in rodents led to a phase II clinical trial by Aldeyra, which showed visual functional improvement RP patients carrying RHO mutations!

https://www.businesswire.com/news/home/20230629018435/en/Aldeyra-Therapeutics-Announces-Improvement-from-Baseline-in-Retinal-Function-in-Phase-2-Clinical-Trial-of-ADX%E2%80%912191-in-Patients-with-Retinitis-Pigmentosa

Jun 29, 2023

Congrats to Owen D. Clinger for his prestigious RPB Med Student Fellowship! Jan 2023

Welcome, Riley Arbuckle and congrats for enrolling to the Ph.D program! Aug 2022

Congrats to Dr. Vats for our JCI Insight research article! Apr 2022. Well done!

Farewell to Yibo and good luck! Dec, 2021

Dr. Chen received the Allen Humphrey, PhD Excellence in Mentoring Award.

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We got the Wiegand Entrepreneurial Research Award!

"Discovery of a novel, first-in-class endogenous, small molecule, potent and efficacious protective agent with restorative actions on retinal degenerative diseases" 2020

We published a new research paper in FASEB J!

Liu X, Feng B, Vats A, Tang H, Seibel W, Swaroop M, Tawa G, Zheng W, Byrne L, Schurdak M, Chen Y. Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa. FASEB J. 2020 Jun 14;. doi: 10.1096/fj.202000282R. [Epub ahead of print] PubMed PMID: 32536017.

We got our R01 funding! R01EY030991

"Pharmacological studies of rhodopsin metabolism" 2020-2025

We nailed it with a 9 percentile!

RECENT Publications

Chen Y, Chen Y, Jastrzebska B, Golczak M, Gulati S, Tang H, Seibel W, Li X, Jin H, Han Y, Gao S, Zhang J, Liu X, Heidari-Torkabadi H, Stewart PL, Harte WE, Tochtrop GP, Palczewski K. A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration. Nat Commun. 2018 May 17;9(1):1976. PubMed PMID: 29773803; PubMed Central PMCID: PMC5958115. Corresponding Authors.

Feng, B., Liu, X., Chen, Y. A Rhodopsin Transport Assay by High-Content Imaging Analysis. J. Vis. Exp. 2019 Jan 143, e58703, doi:10.3791/58703.

Getter T, Suh S, Hoang T, Handa JT, Dong Z, Ma X, Chen Y, Blackshaw S, Palczewski K. The selective estrogen receptor modulator raloxifene mitigates the effect of all-trans-retinal toxicity in photoreceptor degeneration. J Biol Chem. 2019 Jun 14;294(24):9461-9475. doi: 10.1074/jbc.RA119.008697. Epub 2019 May 9. PubMed PMID: 31073029; PubMed Central PMCID: PMC6579480.

Getter T, Gulati S, Zimmerman R, Chen Y, Vinberg F, Palczewski K. Stereospecific modulation of dimeric rhodopsin. FASEB J. 2019 Aug;33(8):9526-9539. doi: 10.1096/fj.201900443RR. Epub 2019 May 23. PubMed PMID: 31121099; PubMed Central PMCID: PMC6662988.

Liu X, Feng B, Vats A, Tang H, Seibel W, Swaroop M, Tawa G, Zheng W, Byrne L, Schurdak M, and Chen Y. Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa. The FASEB Journal. 2020; https://doi.org/10.1096/fj.202000282R. Equal contributions.

Xi Y, Chen Y. Pharmacological strategies for treating misfolded rhodopsin-associated autosomal dominant retinitis pigmentosa. Neural Regen Res. 2022 Jan;17(1):110-112. doi: 10.4103/1673-5374.314306. PubMed PMID: 34100444; PubMed Central PMCID: PMC8451548.

Vats A, Xi Y, Feng B, Clinger OD, St Leger AJ, Liu X, Ghosh A, Dermond CD, Lathrop KL, Tochtrop GP, Picaud S, Chen Y. Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa. JCI Insight. 2022 May 23;7(10). doi: 10.1172/jci.insight.153717. PubMed PMID: 35472194; PubMed Central PMCID: PMC9220944.