Retina-Targeted Estrogen Prodrug: A New Concept for Retinal Protection

Retinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, we developed a bioprecursor prodrug, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor from light-induced damage, male C57BL/6J mice were injected with or without 200 µg/kg DHED (n=9) and 200 µg/kg E2 (n=9) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) and retinal detachment. Additionally, DHED significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. The photoreceptor protective effects upon DHED treatment are stronger than that of E2, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. Our liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based bioassay indicated that DHED delivers the biologically active estrogen to the neuronal cells including the retinal cells without affecting other tissues - unlike the systemic exposure that is seen with estrogen. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection.