An interdisciplinary consortium of investigators from the Departments of Pharmacology and Ophthalmology at Case Western Reserve University, the Cleveland Louis Stokes VA Medical Center, the Cole Eye Institute at Cleveland Clinic Foundation, Washington University, Michigan State University, Johns Hopkins University and ingenious Targeting Laboratory, Inc., proposes to increase the pace at which basic science discoveries of disease mechanisms can be translated into therapies for complex visual system disorders and disease, a goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse expertise to evaluate potential therapies for retinal diseases in animal models by using a cutting-edge systems pharmacology paradigm. By screening a combination of G protein-coupled receptor (GPCR) agonist/antagonist drugs (modulators) for their ability to prevent retinal pathology in animal models of various rod and cone photoreceptor cell retinopathies, we will identify suitable candidates for future testing in humans. High resolution imaging methods and transcriptional analysis among other approaches will be used to monitor the efficacy and safety of these combination therapies. The goals of this project are:
Aim 1. Test in mice the efficacy of a combination of GPCR agonists/antagonists in protecting against light-induced retinal damage and with either spontaneous rapid or slowly-progressing cone degeneration.
Aim 2. Pharmacologically and genetically validate the involvement and specificity of identified GPCRs and their precise subcellular localization using knockin mice with T4 lysosome (T4L) fused into their signaling domains and an antibody we developed against T4L. We also will use the FAST system that allows various genetic outcomes (from inactivation to overexpression) to be engineered in a single mouse model.
Aim 3. Assess the effectiveness of GPCR therapy in a canine rod-cone retinopathy model.
Aim 4. Expand the range of receptor modulators to include therapeutic antibodies. Fulfilling these interrelated aims will direct our development of more successful therapies for people with incurable blinding diseases.

Public Health Relevance

Degeneration of photoreceptor cells and the retinal pigment epithelium is the underlying cause of a large number of progressive retinal diseases, of which many have only minimally effective or no treatment options. Thus, additional therapeutic approaches are urgently needed to reduce vision loss associated with these disorders. The long-term objective of this proposal is to provide mechanism-based therapeutic interventions that successfully combat degenerative retinal diseases. Systems pharmacology holds promise as a safe and highly efficacious therapeutic approach for such disorders. Using this novel approach, we aim to identify therapeutic agents that slow or halt the development and progression of retinopathies in animal models as a prelude to their clinical evaluation in humans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
3R24EY027283-01S1
Application #
9554184
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
2017-07-01
Project End
2018-03-31
Budget Start
2017-09-30
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Chen, Yuanyuan; Chen, Yu; Jastrzebska, Beata et al. (2018) A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration. Nat Commun 9:1976
Schur, Rebecca M; Gao, Songqi; Yu, Guanping et al. (2018) New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models. FASEB J 32:3289-3300
Gulati, Sahil; Jin, Hui; Masuho, Ikuo et al. (2018) Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor. Nat Commun 9:1996
Owen, Timothy S; Salom, David; Sun, Wenyu et al. (2018) Increasing the Stability of Recombinant Human Green Cone Pigment. Biochemistry 57:1022-1030
Palczewska, Grazyna; Stremplewski, Patrycjusz; Suh, Susie et al. (2018) Two-photon imaging of the mammalian retina with ultrafast pulsing laser. JCI Insight 3:
Choi, Elliot H; Suh, Susie; Sander, Christopher L et al. (2018) Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65. Hum Mol Genet 27:2225-2243
Orban, Tivadar; Leinonen, Henri; Getter, Tamar et al. (2018) A Combination of G Protein-Coupled Receptor Modulators Protects Photoreceptors from Degeneration. J Pharmacol Exp Ther 364:207-220
Daruwalla, Anahita; Choi, Elliot H; Palczewski, Krzysztof et al. (2018) Structural biology of 11-cis-retinaldehyde production in the classical visual cycle. Biochem J 475:3171-3188
Gao, Songqi; Kahremany, Shirin; Zhang, Jianye et al. (2018) Retinal-chitosan Conjugates Effectively Deliver Active Chromophores to Retinal Photoreceptor Cells in Blind Mice and Dogs. Mol Pharmacol 93:438-452
Kiser, Philip D; Zhang, Jianye; Sharma, Aditya et al. (2018) Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function. J Gen Physiol 150:571-590

Showing the most recent 10 out of 20 publications