Therapeutics For Dry AMD and Other Aging related DIsorders

At Lucina Biotherapeutics, we are developing therapeutics to treat aging related disorders. Aging is the leading risk factor for numerous disorders that impair quality of life. Research has shown that the age-related decline in Very Long Chain Poly-Unsaturated Fatty Acids (VLCPUFA) tissue levels, driven by epigenetic down-regulation of  a gene  known as ELOVL2 (a key regulator of VLCPUFA biosynthesis), accelerates aging processes and contributes to dysfunction across multiple organ systems. Our PUFActive Platform is based on restoring VLC-PUFA concentrations in tissues to rejuvenate cells and reverse aging-related dysfunction. Our initial focus is on Dry Age-Related Macular Degeneration (Dry AMD).

The evidence supporting the causal role of VLCPUFA deficiency in AMD has been evolving for decades. It is now widely accepted that VLCPUFA are essential components of cell / organelle membranes, where they maintain the biophysical properties which govern membrane function. In the retina, which is remarkable for its high VLCPUFA content, they are crucial for initiating and propagating the visual signal and maintaining  healthy bioenergetics.  

Studies in both human and mouse retinas have demonstrated a decline in VLC-PUFAs is strongly associated several retinal pathologies including Stargardt 3 Macular Dystrophy and Dry AMD.  The ELOVL2 gene encodes an  enzyme necessary for the biosynthesis of VLC PUFA.   Mice engineered with a point mutation that reduces ELOVL2-activity exhibit low levels of VLC-PUFA with decreased visual acuity, slower dark adaptation, infiltration of complement and accumulation of drusen like deposits.  

ELOVL2 is known to undergo aging related methylation of its gene promoter and down regulation of expression.  In aging mice ELOVL2 methylation coincides with decreased levels of retinal VLCPUFA and development of an AMD phenotype. An aging related decline in retinal VLCPUFA levels has also been observed in human donor retinas.  Of note, significantly lower levels of VLCPUFA were observed in retinas from patients with AMD compared to age matched donors without AMD.

The immediate  product of ELOVL2 is known as C 24:5  which is the fatty acid precursor for all VLCPUFA.  We hypothesize decline in retinal C 24:5  underlies AMD and that C 24:5 replacement therapy will treat AMD.  Consistent with this hypothesis, treatment with intravitreal  C24:5 significantly improved visual function (as measured by ERG and Dark Adaptation response), reduce accumulation of lipid and complement deposits, and lowered expression of aging-related markers in aged mice (exhibiting an AMD phenotype at baseline). Importantly, the treatment effect was sustained for 4 weeks with only a modest decline in effect suggesting a durable treatment response.   Notably, visual rescue was not observed when other PUFAs were used.