Wai-Ching Lam

Background: Retinopathy of prematurity (ROP) is a predominant contributor to preventable childhood blindness driven by oxidative stress and inflammation, but with limited treatment options. Safe, non-invasive adjunctive strategies become attractive. Lutein displays antioxidant and anti-inflammatory properties, but its clinical efficacy remains controversial. We proposed that formulating lutein in extra-virgin olive oil (EVOO) might enhance its absorption and efficacy in ROP. Here, we evaluated the effects of lutein-in-EVOO (LEVOO) in oxygen-induced retinopathy (OIR), a mouse model of ROP. Methods: C57BL/6J mouse neonates received daily gavage of LEVOO (0.4 μg/g, 1.8 μg/g and 3.6 μg/g of lutein in EVOO) after OIR challenge from postnatal day (P) 12 to P16. Assessments were conducted at P17, including retinal vasculature, function, cytoarchitecture, inflammation, and oxidative damage; serum biochemical and antioxidant profiles; and proteomic analysis and targeted retinal metabolomic analysis. Results: Oral supplementation of LEVOO was well-tolerated and safe in mouse neonates. It reduced retinal avascular and neovascular areas, increased electroretinographic b-wave amplitudes, and restored amacrine cells and rod bipolar cells. LEVOO administration reduced oxidative damage and activated microglia. LEVOO administration inhibited the hypoxia-inducible factor-1α (HIF-1α)/macrophage migration inhibitory factor (MIF) signaling and low-density lipoprotein receptor-related protein-1 (LRP1)-dependent cyclophilin A (CypA)/matrix metalloproteinase-9 (MMP9) signaling. It also helped to partially restore retinal docosahexaenoic acid and dopamine in OIR mice. Conclusions: LEVOO demonstrated multifaceted efficacy in OIR. It reconstructed retinal vasculature, restored retinal function, and rescued neuronal cell loss with strong antioxidative and anti-inflammatory effects. Collectively, these findings establish LEVOO as a promising non-invasive complementary strategy for ROP.

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen–alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen-alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial cell line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases (RDDs). This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium iodate (SI)-induced retinal degeneration. The findings indicated that CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.