A lipid better known to materials scientists than ophthalmologists may have a role in protecting the degenerating retina. In a new Nature Neuroscience study, researchers report that erucamide – a 22:1 monounsaturated omega-9 primary fatty acid amide – is markedly depleted during photoreceptor degeneration and can, when delivered appropriately, improve both neuronal and vascular outcomes in mouse models of inherited retinal disease.
The work began with an untargeted high-resolution metabolomics screen in degenerating retinas. Primary fatty acid amides emerged as one of the most dysregulated metabolite classes, with erucamide standing out as the most abundant member in healthy rat eyes. Its levels were sharply reduced in the Royal College of Surgeons rat models, as well as in rd10 mice, a model of retinitis pigmentosa. The team also detected erucamide in postmortem human retinal tissue, suggesting that the molecule is conserved across species and may be relevant beyond rodent biology.
Delivering erucamide to the eye posed a practical problem: the molecule is highly hydrophobic and does not disperse well after direct intravitreal injection. To overcome this, the researchers loaded erucamide into organosilane-modified porous silicon nanoparticles. These particles allowed intravitreal delivery in rd10 mice at timepoints spanning the onset of photoreceptor degeneration.
Erucamide-treated rd10 mice showed preservation of retinal architecture, including increased outer nuclear layer and inner nuclear layer thickness compared with vehicle-treated controls. Electroretinography revealed improved scotopic B-wave amplitudes, particularly at higher flash intensities, indicating partial functional rescue in a rod-dominated degenerating retina. The treatment also protected the deep retinal vascular plexus from vaso-obliteration.
Mechanistically, erucamide did not appear to act directly on photoreceptors. Instead, the study points to CD11b-positive myeloid cells – including retinal microglia-like cells – as its principal target. Erucamide treatment activated and recruited these cells across retinal layers, particularly into the outer nuclear layer in degenerating eyes. Fluorescently labelled erucamide was taken up by CD11b-positive cells, and isolated myeloid cells from treated retinas showed increased expression of angiogenic and neurotrophic factors, including PDGF, CTGF, CX3CL1, angiopoietin-1 and BDNF. Similar effects were observed in human iPSC-derived macrophage precursor cells, where erucamide increased factors such as VEGF, FGF-2, IGF-1 and BDNF.
The investigators then used photoaffinity labelling and quantitative proteomics to identify TMEM19, a poorly characterized transmembrane protein, as a selective erucamide-binding protein. Knocking down TMEM19 in human iPSC-derived myeloid cells blunted the erucamide-induced cytokine and growth factor response. In vivo, AAV-mediated TMEM19 knockdown in rd10 mice prevented erucamide’s protective effects on retinal structure, vascular density, and ERG responses. Blocking downstream factors with neutralizing antibodies similarly reduced the rescue effect.
The study positions erucamide–TMEM19 signalling as a previously unrecognized pathway for neurovascular support in the retina. Rather than replacing lost cells, the approach appears to coax endogenous myeloid cells into a trophic, tissue-supportive role. The study authors suggest that erucamide analogues could be explored as candidate therapeutics for retinal degenerations such as retinitis pigmentosa and age-related macular degeneration, reinforcing a signal that’s already present in the body to slow the progression of these types of retinal diseases.
