Zhongshan Ophthalmic Center

Sight loss in certain inherited eye diseases may be caused by gut bacteria, and is potentially treatable by antimicrobials, finds a new study in mice. Sight loss in certain inherited eye diseases may be caused by gut bacteria, and is potentially treatable by antimicrobials, finds a new study in mice co-led by a UCL and Moorfields researcher. The international study observed that in eyes with sight loss caused by a particular genetic mutation, known to cause eye diseases that lead to blindness, gut bacteria were found within the damaged areas of the eye. The authors of the new paper, published in Cell and jointly led by researchers in China, say their findings suggest that the genetic mutation may relax the body's defences, thus allowing harmful bacteria to reach the eye and cause blindness. The gut contains trillions of bacteria, many of which are key to healthy digestion. However, they can also be potentially harmful. The researchers were investigating the impact of the Crumbs homolog 1 (CBR1) gene, which is known to be expressed in the retina (the thin layer of cells at the back of the eye) and is crucial to building the blood-retina barrier to regulate what flows in and out of the eye. The CRB1 gene is associated with inherited eye disease, most commonly forms of Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP); the gene is the cause of 10% of LCA cases and 7% of RP cases worldwide. Using mouse models, the research team discovered the CRB1 gene is key to controlling the integrity of the lower gastrointestinal tract, the first ever such observation. There, it combats pathogens and harmful bacteria by regulating what passes between the contents of the gut and the rest of the body. The team found that when the gene has a particular mutation, dampening its expression (reducing its effect), these barriers in both the retina and the gut can be breached, enabling bacteria in the gut to move through the body and into the eye, leading to lesions in the retina that cause sight loss. Crucially, treating these bacteria with antimicrobials, such as antibiotics, was able to prevent sight loss in the mice even though it did not rebuild the affected cell barriers in the eye. Inherited eye diseases are the UK's leading cause of blindness in working-age people. Onset of disease may vary from very early childhood to adulthood, but deterioration is irreversible and has lifelong implications. To date, the development of treatments has largely focused on gene therapies. The findings of this study suggest that simply using antimicrobials might help prevent deterioration in CRB1-associated inherited eye diseases. Future work will investigate whether this applies in humans. Co-lead author Professor Richard Lee (UCL Institute of Ophthalmology and Moorfields Eye Hospital NHS Foundation Trust) said: "We found an unexpected link between the gut and the eye, which might be the cause of blindness in some patients. "Our findings could have huge implications for transforming treatment for CRB1-associated eye diseases. We hope to continue this research in clinical studies to confirm if this mechanism is indeed the cause of blindness in people, and whether treatments targeting bacteria could prevent blindness. "Additionally, as we have revealed an entirely novel mechanism linking retinal degeneration to the gut, our findings may have implications for a broader spectrum of eye conditions, which we hope to continue to explore with further studies." The study was an international collaboration led by researchers from Zhongshan Ophthalmic Center, Sun Yat-sen University, China, working with UCL Institute of Ophthalmology and Moorfields Eye Hospital NHS Foundation Trust.

Researchers have developed a light-activatable prodrug nanomedicine for age-related macular degeneration (AMD) therapy. Through the intravenous injection of the nanomedicine and application of light irradiation to diseased eyes, anti-angiogenic and photodynamic combination therapy can be activated, offering a minimally invasive alternative for the treatment of AMD and other ocular disorders characterized by abnormal blood vessel growth. Researchers at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed), and collaborators from the Zhongshan Ophthalmic Centre of Sun Yat-sen University, Guangzhou, have developed a light-activatable prodrug nanomedicine for age-related macular degeneration (AMD) therapy. Through the intravenous injection of the nanomedicine and application of light irradiation to diseased eyes, anti-angiogenic and photodynamic combination therapy can be activated, offering a minimally invasive alternative for the treatment of AMD and other ocular disorders characterised by abnormal blood vessel growth. The research has been published in Advanced Science and a Patent Cooperation Treaty application was filed based on the research. According to the Hong Kong Eye Survey data published in 2019, the prevalence of early AMD among individuals aged 70 and older has reached 7.5% in Hong Kong1, making AMD the second most common cause of visual impairment and blindness in the adult population of Hong Kong. Currently, intravitreal injections of antibodies against vascular endothelial growth factor are the first-line treatment for wet AMD. However, this invasive procedure is uncomfortable for patients, and carries the risk of serious ocular complications, such as endophthalmitis and retinal detachment. Therefore, there is an urgent need for novel formulations that enable the delivery of anti-angiogenic agents into the eye without an intravitreal injection, such as intravenous injection. Additionally, anti-angiogenic agents have limited efficacy in regressing existing neovascularisation. Photodynamic therapy (PDT) offers a clinical solution by utilising non-toxic photosensitisers activated by specific wavelengths of light to generate reactive oxygen species (ROS), which can damage and obliterate neovascularisation. PDT is widely used for the treatment of polypoidal choroidal vasculopathy, a common subtype of wet AMD in Asia. Therefore, combining anti-angiogenesis therapy with PDT may offer a more effective approach to treating wet AMD, thus helping slow down the progression of the disease and improve the vision outcome for patients. Research methods and findings The research team designed a novel photoactivatable prodrug nanosystem. After a single intravenous injection of the nanoparticles into a choroidal neovascularisation mouse model, red-light irradiation of the mouse's eye activated the nanoparticles to generate ROS, which not only causes the regression of abnormal neovascularisation, but also triggers the release of anti-angiogenic drugs from the nanoparticles to inhibit the growth of new blood vessels. This combinational therapy demonstrated excellent therapeutic efficacy without any noticeable systemic or ocular side effects. Research significance The study represents the first attempt at integrating a photoactivatable anti-angiogenic agent with a photosensitiser into a single nanoformulation for AMD treatment. The treatment procedure is simple and safe, as the therapeutic effect of the anti-angiogenic agent and photosensitiser in ocular lesions can be achieved through the intravenous administration of nanoparticles and light irradiation to the eye. This pioneering research may open up new avenues for the development of minimally-invasive therapeutics for AMD and other neovascular ocular disorders. The formulation uses US FDA-approved therapeutic agents and excipients, making it promising for future clinical translation. The study was led by Dr Wang Weiping, Associate Professor of Dr Li Dak-Sum Research Centre and Department of Pharmacology and Pharmacy, HKUMed, and Principal Investigator of the State Key Laboratory of Pharmaceutical Biotechnology, HKU. The other corresponding author was Professor Liang Xiaoling, Department of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, and Zhongshan Ophthalmic Centre, Sun Yat-sen University; the co-first authors were Xu Shuting, PhD candidate, Department of Pharmacology and Pharmacy, HKUMed, and Dr Cui Kaixuan, Postdoctoral fellow, Department of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University. Other researchers included Long Kaiqi, PhD candidate, Department of Pharmacology and Pharmacy, HKUMed; Dr Li Jia and Dr Fan Ni, Postdoctoral fellows, Department of Pharmacology and Pharmacy; and Professor Lam Wai-ching, Head and Clinical Professor of the Department of Ophthalmology, Vancouver General Hospital and University of British Columbia, Canada, and Honorary Clinical Professor, Department of Ophthalmology, School of Clinical Medicine, HKUMed. This work was supported by the National Natural Science Foundation of China Excellent Young Scientists Fund (No. 82222903) and the National Natural Science Foundation of China (No. 82271099).