We are attempting to establish a nonhuman primate model of inherited retinal degeneration. In two female rhesus monkeys from the same father, retinal degeneration was detected with the electroretinogram (ERG) within the first year of life. In the first case, postmortem examination confirmed the loss of virtually all rod photoreceptors. In the second animal, widespread peripheral retinal degeneration is now visible ophthalmoscopically. The current project is beginning the development of this animal model by producing multiple offspring of the living affected female, using the expertise of the ORPRC Assisted Reproductive Technologies Core Laboratory. This goal is being accomplished by hormonal stimulation of the affected female to produce multiple eggs, retrieval of the eggs and their in vitro fertilization by intracytoplasmic sperm injection, and transfer of the embryos to surrogate mothers. Two such cycles have been completed. The affected female responded we ll to ho rmonal stimulation, which resulted in the collection of 16-23 oocytes and 8-10 successfully fertilized embryos, all of which were transferred to surrogate mothers on the optimum day of her menstrual cycle as determined by daily hormone assays. Two healthy infants were born in September 1998 and a third pregnancy is due May 1999. A third cycle will be attempted in the next year. Our initial goal is to confirm the hereditary nature of this retinal degeneration by producing 8-12 offspring. The offspring will be monitored for signs of retinal degeneration by ERG, ophthalmic exams, retinal photographs and fluorescein angiograms. Based on the course of the disease in the mother, this form of retinal degeneration should be detectable by ERG within the first year. Meanwhile, we have developed an improved ERG system and new ERG methods for measuring the processes of phototransduction and recovery which will be used to test the offspring. Candidate gene screening is proceeding in the laboratory of Dr. Edwin M. Stone at the University of Iowa, beginning with the sequencing of all exons of rhodopsin and rds/peripherin for the affected female and unaffected rhesus monkeys. Several points of divergence from the human sequence were found for each of these genes, which required the selection of new PCR primers for areas resistant to amplification. One base pair difference in the rhodopsin gene was detected but was silent with respect to amino acid sequence (Thr4Thr, ACG->ACA). If we are successful at producing affected offspring, the potential for further production of affected monkeys would expand geometrically. The availability of such a nonhuman primate model of retinitis pigmentosa would make possible the relatively rapid testing of a variety of potential therapeutic treatments including gene therapy, retinal transplantation, growth factors and nutritional variables (e.g., vitamin A, vitamin E and omega-3 fatty acids), all of which could be initiated from birth or prenatally. In addition, the macula, which underlies acute central vision, is present only in higher primates including humans and monkeys, so that a nonhuman primate model would be uniquely valuable for understanding the factors involved in the preservation of central vision in people with retinitis pigmentosa and other retinal diseases. FUNDING The Foundation Fighting Blindness PUBLICATIONS Neuringer M, Weleber RG, Feeney-Burns L, Klein ML, Kittelson C. Retinal degeneration in two half-sibling rhesus monkeys Potential model of inherited retinal disease. Invest Ophthalmol Vis Sci 39:S725, 1998 (abstract 3334).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
2P51RR000163-40
Application #
6116107
Study Section
Project Start
1999-05-15
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
40
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Oregon Regional Primate Research Center
Department
Type
DUNS #
City
Beaverton
State
OR
Country
United States
Zip Code
97006
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