Several important retinal disease are caused by excess proliferation of cells in the eye;major ones which we plan to target with a novel pharmacologic approach include retinal detachment due to trauma and proliferative vitreoretinopathy as well as choroidal neovascularization in age related macular degeneration. One of the major problems in using local therapy for retinal diseases is the short half-life of most intraocular drugs that must be administered frequently. There is an important unmet need to develop a way to prolong the intraocular duration of intravitreally or similarly administered antiproliferative drugs. We have developed a novel chemical method of modifying nucleosides which provides for low solubility and long-acting antiproliferative or antiviral activity. Following a single intravitreal injection, we have already demonstrated persistent biological activity of prototype compounds for up to 20 weeks or longer. Our overarching goal is to develop long acting crystalline drugs that can be injected into the vitreous cavity in the eye in small volumes. Because these crystalline compounds are chemically designed to have low water solubility, they will act as extremely long acting anti-proliferative compounds which will help reduce retinal damage and vision loss from the above diseases and other retinal diseases. This grant focuses on diseases of proliferation but we stress that should this crystalline drug delivery system be successful in animal and in the future, in human studies, it will be able to be extended for treatment of many other intraocular diseases. This grant is a collaboration of two research groups, the Retina Research Laboratory at the Jacobs Retina Center (Drs. Freeman and Cheng) and Dr. Karl Hostetler in the Dept. of Medicine, both at UCSD. Dr. Hostetler's group is well known for synthesis and evaluation of lipid nucleoside analogs while Dr. Freeman's group is highly skilled in development and characterization of intraocular drugs and animal models of retinal disease. Together, we will synthesize and evaluate key lipid analogs of crystalline minimally soluble anti-proliferative compounds. Various in vitro and in vivo evaluations will determine the optimal structural and formulation variables to provide for a high therapeutic index and long intraocular half life. The best compounds and formulations will be tested in accepted animal models of the important retinal diseases mentioned above. This project may provide drugs with a prolonged duration of action which will be safe and have a high therapeutic index and may lead to new agents and treatment methods for important retinal diseases. Public Health Relevance: This research grant will allow the development of a long-acting intraocular injection that will prevent retina detachment and reduce the damage due to scarring from age-related macular degeneration. Our research group has discovered ways to modify small antiproliferative molecules so that they last for over 5 months in the eye and are thus optimal to help prevent these severe causes of blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018589-03
Application #
7898784
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Mariani, Andrew P
Project Start
2008-09-30
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$510,230
Indirect Cost
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Bartsch, Dirk-Uwe; Muftuoglu, Ilkay K; Freeman, William R (2016) Laser Pointers Revisited. Retina 36:1611-3
Espina, Mark; Arcinue, Cheryl A; Ma, Feiyan et al. (2016) Outer retinal tubulations response to anti-VEGF treatment. Br J Ophthalmol 100:819-23
Arcinue, Cheryl A; Ma, Feiyan; Barteselli, Giulio et al. (2015) One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 159:426-36.e2
Espina, Mark P; Arcinue, Cheryl A; Ma, Feiyan et al. (2015) ANALYSIS OF A CONFOCAL SCANNING LASER OPHTHALMOSCOPE NONCONTACT ULTRA-WIDE FIELD LENS SYSTEM IN RETINAL AND CHOROIDAL DISEASE. Retina 35:2664-8
Barteselli, Giulio; Amini, Payam; Ezon, Isaac C et al. (2015) Impact on intraocular pressure after 20-mg decanted triamcinolone acetonide (kenalog) injection when using prophylactic antiglaucoma therapy. Retina 35:75-81
Arcinue, Cheryl A; Bartsch, Dirk-Uwe; El-Emam, Sharif Y et al. (2015) Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis. PLoS One 10:e0132996
Ma, Feiyan; Nan, Kaihui; Lee, SuNa et al. (2015) Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system. Eur J Pharm Biopharm 89:271-9
Barteselli, Giulio; Kozak, Igor; El-Emam, Sharif et al. (2014) 12-month results of the standardised combination therapy for diabetic macular oedema: intravitreal bevacizumab and navigated retinal photocoagulation. Br J Ophthalmol 98:1036-41
Ma, Feiyan; Arcinue, Cheryl A; Barteselli, Giulio et al. (2014) Optical coherence tomography findings of the vitreoretinal interface in asymptomatic fellow eyes of patients with acute posterior vitreous detachment. Retina 34:447-54
Barteselli, G; Gomez, M L; Doede, A L et al. (2014) Visual function assessment in simulated real-life situations in patients with age-related macular degeneration compared to normal subjects. Eye (Lond) 28:1231-8

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