The microbiome in neovascular age-related macular degeneration
Presenter: Sebastian Wolf, Switzerland
There are around 100 trillion bacteria in the human gut,1 with >10,000 species identified, which play a major role in digestion but can also influence the immune/complement system. Changes in the intestinal microbiome have been identified in patients with metabolic disorders, including atherosclerosis, as well as those with autoimmune conditions and have been investigated in neovascular age-related macular degeneration (nvAMD).
nvAMD is a multifactorial disease that represents the most frequent cause of blindness in the elderly. Its development has been linked to nutrition, in addition to recognised environmental and genetic factors.2,3
In a mouse model, the link between changes in the microbiota in the gut and development of nvAMD has been investigated.4 It was found that high-fat diets exacerbated choroidal neovascularization (CNV) by altering gut microbiota.
Recently, clear compositional and functional diversities in the intestinal microbiome in patients with nvAMD versus controls was noted, suggesting a role for changes in the microbiota in the development of nvAMD.3 nvAMD patients were found to have fewer bacteria relating to fatty acid digestion but increased levels of bacteria related to high fat diets.
These results suggest that the intestinal microbiome may play an important role in the development of nvAMD and may constitute a link between nutrition and development of this common disease. Research is ongoing to further establish this relationship.
Are we ready for gene therapy in chronic eye diseases?
Presenter: Robert MacLaren, UK
Gene therapy has arrived for inherited retina diseases, with the approval of LUXTURNATM (voretigene neparvovec-rzyl) to treat mutations in the RPE65 gene.5 This is a very active area of research, with several other treatments under investigation, including a soon to be published study on a subretinal injection of Rab escort protein 1 (REP1) using an adeno-associated viral (AAV) vector in patients with a confirmed diagnosis of choroideremia (NCT02407678).6 Choroideremia is an X-linked recessive inherited disease associated with mutation of the choroideremia gene (CHM), which encodes REP1, and is characterised by outer retinal degeneration.7 In this study, visual acuity was significantly improved over a period of 2 years in treated eyes versus untreated eyes and versus baseline. This improvement was maintained for 5 years.6 The advent and further advancement of gene therapy provides hope for the future of these devastating diseases.
Fluid location in neovascular age-related macular degeneration – does it really matter?
Presenter: Ursula Schmidt-Erfurth, Austria
Digital images providing millions of morphological datasets can provide a fast, comprehensive and noninvasive analysis using artificial intelligence (AI).8 An analysis of the HARBOR study data set was used to validate a fully automated method to detect and quantify macular fluid in conventional optical coherence tomography (OCT) images.9 Intraretinal cystoid fluid (IRC) and subretinal fluid (SRF) volumes were analysed in 1,200 OCT eyes with neovascular age-related macular degeneration (nvAMD, n=400), diabetic macular oedema (DMO, n=400) or retinal vein occlusion (RVO, n=400). The newly designed, fully automated diagnostic method based on deep learning achieved optimal accuracy for the detection and quantification of IRC for all three conditions with a high level of accuracy, precision and recall. IRF was associated with poorer anatomical and functional outcome when compared to SRF. In additional when IRF and SRF were analysed in patients receiving anti-vascular endothelial growth factor (VEGF) therapy, a strong relationship between fluid location and function was demonstrated. The impact on BCVA was highest for IRF, and it was found that individual BCVA outcomes after 1 year could be predicted from initial BCVA and fluid measurements.
The identification of these new biomarkers of disease will enable personalised medicine for patients with retinal disease ensure the efficient delivery of healthcare.
Looking to the next generation of anti-VEGFs
Presenter: Frank Holz, Germany
Anti-VEGF therapy is frequently the first-choice therapy for patients with neovascular age-related macular degeneration (nvAMD). However, frequency of injections can be an issue for many patients. A humanised single-chain antibody fragment anti-VEGF, brolucizumab, has been developed and investigated in two large international Phase III trials (>1,800 patients), HAWK and HARRIER (NCT02307682).10 This single-chain antibody fragment is smaller in size than current anti-VEGF molecules, which enables enhanced tissue penetration, rapid clearance from systemic circulation and improved drug delivery. After a loading period of 16 weeks where patients on brolucizumab or aflibercept were dosed every 8 weeks, patients on brolucizumab could move to 12-week treatment intervals. Patients were followed for 48 weeks with a primary endpoint of noninferiority for mean best corrected visual acuity (BCVA). The primary endpoint was met and 57% and 52% of patients on brolucizumab in the HAWK and HARRIER trials were able adhere to the 12-week treatment interval through week 48, respectively. Secondary analysis demonstrated that patients treated with brolucizumab achieved superior reductions in central subfield thickness compared to aflibercept. Fewer patients treated with brolucizumab had subretinal fluid, inter-retinal fluid and subretinal pigment epithelium fluid than those on aflibercept. Adverse events were comparable between the two treatment groups.
1. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–8.
2. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005–15.
3. Zinkernagel MS, Zysset-Burri DC, Keller I, et al. Association of the intestinal microbiome with the development of neovascular age-related macular degeneration. Sci Rep. 2017;7:40826.
4. Andriessen EM, Wilson AM, Mawambo G, et al. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization. EMBO Mol Med. 2016;8:1366–79.
5. Spark Therapeutics, Inc. LUXTURNA (voretigene neparvovec-rzyl). US prescribing information. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf (accessed 23 September 2018).
6. Xue K, et al. Nature Med. 2018; in press.
7. Barnard AR, Groppe M, MacLaren RE. Gene therapy for choroideremia using an adeno-associated viral (AAV) vector. Cold Spring Harb Perspect Med. 2014;5:a017293.
8. Schmidt-Erfurth U, Sadeghipour A, Gerendas BS, et al. Artificial intelligence in retina. Prog Retin Eye Res. 2018. pii:S1350-9462(18)30011-9. DOI: 10.1016/j.preteyeres.2018.07.004. [Epub ahead of print].
9. Schlegl T, Waldstein SM, Bogunovic H, et al. Fully automated detection and quantification of macular fluid in OCT using deep learning. Ophthalmology. 2018;125:549–58.
10. Khanani A. Phase 3 Randomized, Double-Masked studies of Brolucizumab versus Aflibercept in nAMD: Expanded primary and secondary outcomes from HAWK/HARRIER. Presented at: American Society of Retina Specialists Annual Meeting; July 20–25, 2018; Vancouver, British Columbia.