A Scripps Research-led team has identified erucamide as a lipid signal linked to retinal degeneration, finding that its levels fall as photoreceptors deteriorate and that restoring it improves neurovascular outcomes in preclinical models.
To identify candidate signals, the researchers used an unbiased high-resolution metabolomics screen in rodent models of retinal degeneration. Among the most strongly dysregulated metabolites were primary fatty acid amides, with erucamide standing out as the most abundant member in healthy retina and one that was markedly depleted in both RCS rats and rd10 mice. Liquid chromatography-mass spectrometry also detected erucamide in postmortem human retinal tissue, suggesting that the molecule is present across species.
“The retina doesn’t simply deteriorate; in fact, it actively responds to injury,” senior author Martin Friedlander said in the team’s recent press release. “Our work identifies erucamide as a signaling molecule that helps coordinate that response.”
Because erucamide is highly hydrophobic and disperses poorly after direct injection, the team packaged it into organosilane-modified porous silicon nanoparticles. They then used those particles to deliver erucamide into the eye, where treatment preserved retinal layer thickness, improved scotopic ERG responses, and reduced degeneration of the deep vascular plexus in rd10 mice. Similar rescue effects were also seen in the RhoP23H model, extending the findings beyond a single genetic background.
Mechanistically, the study points away from photoreceptors themselves and toward retinal myeloid cells. Confocal imaging with fluorescently labeled erucamide showed that the molecule was taken up by CD11b+ cells, while gene-expression analysis indicated increased production of factors linked to vascular and neuronal support. The team then used photoaffinity labeling and multiplexed proteomics to identify TMEM19 as a candidate erucamide-binding protein. Follow-up RNA-seq and knockdown experiments showed that reducing TMEM19 weakened both the signaling response and the retinal benefits of treatment.
“Instead of targeting the photoreceptors themselves, erucamide appears to work by engaging the surrounding environment,” said first author Guoqin Wei. “That shift in perspective could be important for treating degenerative retinal diseases going forward.”
The authors say the pathway now warrants testing in additional retinal disease models, alongside efforts to optimize erucamide analogs and ocular delivery. “The goal is to reinforce a signal that’s already present,” said Friedlander.
“If we can learn how to modulate that response carefully, it could offer a new path for slowing the progression of retinal diseases where treatment options remain limited.”
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