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Paul S Bernstein, Aruna Gorusupudi, Ramesh Rallabandi, Jon Rainier; Absorption and Delivery of Synthetic VLC-PUFAs to Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3086. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Stargardt Type 3 (STGD3) is a dominant, early-onset blinding disease caused by defects in the ELOVL4 gene which has many symptoms that mirror dry AMD. Mutations in ELOVL4 impair the synthesis of non-dietary very long chain-polyunsaturated fatty acids (VLC-PUFAs, C≥24) in the retina, and similar deficiencies of VLC-PUFAs are found in AMD donor eyes. VLC-PUFAs are a special class of fatty acids identified only in the retina which cannot be synthesized de novo in vertebrates and are rarely consumed in normal diets. We hypothesize that exogenous VLC-PUFAs could serve as an effective treatment strategy for STGD3 and other retinal degenerative diseases, but until now there has been no known method for producing them in sufficient quantities required for supplementation studies. We therefore synthesized VLC-PUFA compounds chemically to study their absorption and delivery to the retina.
In the present study, we confirmed the synthesis of 32:6 (n-3) from DHA ethyl ester using NMR, LC-MS and GC-MS. To measure uptake and metabolism of orally administered VLC-PUFAs in 8 weeks old WT (C57B6L) mice, synthetic 32:6 (n-3) (250mg/kg/day) was mixed in safflower oil and gavage fed. At 0, 2, 4, 8 and 24 hour time points after feeding, 4 mice were sacrificed to collect serum, red blood cells (RBCs), brain, liver, and retina. All tissues were analyzed for LC- and VLC-PUFAs using standardized methods.
At baseline, no VLC-PUFAs were detectable in serum, but we observed 32:6 (n-3) in serum 2h after gavage feeding (~2% of total fatty acids). Retinal 32:6 (n-3) levels increased significantly to 50% above baseline within 8h. We did not detect any VLC-PUFAs in liver, brain or RBCs at any time points.
This study shows that a chemically synthesized VLC-PUFA is present in the serum soon after oral administration and can be specifically delivered to the retina. Further supplementation studies in mouse models for STGD3 and AMD will provide insight into the potential value of exogenously administered VLC-PUFAs for the treatment of retinal degenerative diseases associated with abnormally low VLC-PUFA levels.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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