Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies.

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina. This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options. AREAS COVERED: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management. EXPERT OPINION: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines.Cambridge Eye Trust Research Councils UK - Medical Research Council the Wellcome Trus

Predictors of anti-vascular endothelial growth factor treatment response in neovascular age-related macular degeneration

© 2015 Dr. Sanjeewa WickremasingheThis thesis describes the candidate’s part time work on a project at the Royal Victorian Eye and Ear Hospital and Centre for Eye Research Australia, looking at the predictors of outcome following the use anti vascular endothelial growth factor agents in the treatment of neovascular age related macular degeneration. The work from this thesis is part of the Predictors of outcome in age related macular degeneration study, which is an on-going project that is led by Professor Robyn Guymer (Candidate’s supervisor) looking at various factors that lead to suboptimal outcome in the treatment of neovascular age related macular degeneration, such as individual genetic make up and baseline clinical features

Retinal venular caliber predicts visual outcome after intravitreal ranibizumab injection treatments for neovascular AMD

PurposeTo examine whether baseline retinal vascular caliber predicts visual response to intravitreal ranibizumab injections in patients with neovascular age-related macular degeneration (AMD).MethodsIn this prospective cohort study, patients with neovascular AMD received three monthly intravitreal injections of ranibizumab, followed by as needed dosing up to 1 year. Retinal vascular caliber was measured from digital fundus photographs at baseline and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE), representing average caliber of arterioles and venules, respectively. Visual outcome at 12 months was assessed and the relation to baseline retinal vascular caliber was determined.ResultsA total of 88 eyes were analyzed at baseline. After accounting for age, sex, size of choroidal neovascularization, and number of injections, patients who deteriorated in visual acuity at 12 months had significantly larger baseline CRVE, 243.10 &mu;m (95% confidence interval [CI], 227.01&ndash;259.19), compared with those who were stable, 214.30 &mu;m (95% CI, 205.79&ndash;222.81) and those who improved, 215.26 &mu;m (95% CI, 204.69&ndash;225.84; P = 0.007). Baseline CRAE did not differ significantly from eyes whose vision deteriorated, 150.12 &mu;m (95% CI, 140.67&ndash;159.57), compared with those remaining stable, 143.64 &mu;m (95% CI, 138.64&ndash;148.63), or gaining vision 142.92 &mu;m (95% CI, 136.71&ndash;149.13; P = 0.69).ConclusionsIn eyes with neovascular AMD treated with intravitreal ranibizumab, larger baseline retinal venular caliber was significantly associated with a poorer response to treatment, possibly reflecting increased disease severity.</div

Anti-VEGF treatment in neovascular age-related macular degeneration: A treat-and-extend protocol over 2 years

Purpose: To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti&#8211;vascular endothelial growth factor treatment in age-related macular degeneration. Methods: In this prospective cohort study, 120 age-related macular degeneration patients with choroidal neovascularization received 3 initial monthly ranibizumab or bevacizumab injections; monthly injections were continued until there was no choroidal neovascularization activity (subretinal/intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal hemorrhage). When there was no choroidal neovascularization activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. In the presence of choroidal neovascularization activity, this interval was shortened by 2 weeks. Main outcome measures included the percentage losing <15 letters and the mean visual acuity change after 12 months and 24 months. Results: Mean baseline visual acuity was 51.2 &#0177; 12.1 Early Treatment Diabetic Retinopathy Study scores. Mean visual acuity change from baseline was +9.5 &#0177; 10.9 and +8.0 &#0177; 12.9 letters after 12 months and 24 months, respectively, with, on average, 8.6 &#0177; 1.1 visits/injections in the first year and 5.6 &#0177; 2.0 in the second year. After 12 months and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters. Conclusion: The &#8220;inject-and-extend&#8221; protocol&#8212;with fewer injections and visits&#8212;delivered outcomes comparable to those of the pivotal clinical trials of monthly ranibizumab

Predictors of AMD treatment response

A letter to the editor that refers to the following article :&nbsp; &nbsp; &nbsp;Frank G. Holz, Winfried Amoaku, Juan Donate, Robyn H. Guymer, Ulrich Kellner, Reinier O. Schlingemann, Andreas Weichselberger, Giovanni Staurenghi, SUSTAIN Study Group.&nbsp;Safety and Efficacy of a Flexible Dosing Regimen of Ranibizumab in Neovascular Age-Related Macular Degeneration: The SUSTAIN StudyOphthalmology, Volume 118, Issue 4, April 2011, Pages 663-671</div

Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration

Design Prospective cohort study. Participants We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia. Methods Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of &#8220;as required&#8221; injections based on clinician&#8217;s decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome. Main Outcome Measures The influence of selected SNPs on mean change in visual acuity (VA) at 12 months. Results Mean baseline VA was 51&#0177;16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2&#0177;14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean &#0177; standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was &#8211;2.9&#0177;15.2 letters after 12 months compared with +5.1&#0177;14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose &gt;15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r2 = 0.92). None of the other examined SNPs was associated with outcome. Conclusions The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients&#8217; genotype to achieve optimal treatment response in AMD

Implication of recurrent or retained fluid on optical coherence tomography for visual acuity during active treatment of neovascular age-related macular degeneration with a treat and extend protocol

Purpose: Assess the correlation between optical coherence tomography findings and change in vision for patients receiving "treat and extend" protocol ranibizumab for neovascular age-related macular degeneration. Methods: Optical coherence tomography analysis and best-corrected visual acuity (BCVA) change: mild = 5 to 9 letters, moderate = 10 to 14 letters, and severe >=15 letters. Results: A total of 103 eyes (99 patients, 63% female, 65-91 years) followed for 20.8 +/- 4.9 months. By 12 months, there were 1.38 +/- 0.59 instances of intraretinal fluid (IRF)/subretinal fluid recurrence on optical coherence tomography and 1.25 +/- 1.00 instances of BCVA loss (>=5 letters) per patient. When BCVA was lost, IRF/subretinal fluid was present in 37.3% of cases. Occurrences of severe BCVA loss were less likely to recover vision than when BCVA loss was mild (5.9% vs. 75.6%, P = 0.001). New occurrence of IRF (33.9%) or subretinal fluid (29.6%) was more likely to lead to BCVA loss, compared with dry (16.6%) or persistent IRF (11.9%) or persistent subretinal fluid (14%, P < 0.001). With persistent fluid, any new loss of vision had a lower chance of recovery than when fluid was new in onset (64.3% vs. 85.3%, P = 0.04). Conclusion: During ranibizumab treatment, vision can decrease without signs of fluid. When fluid is present, IRF is associated with poorer vision. New occurrence of any fluid on optical coherence tomography is likely to lead to vision loss, but small amounts of persistent fluid can be tolerated without compromising vision

Polymorphisms in the apoe gene and the location of retinal fluid in eyes with neovascular age-related macular degeneration

Background: Previous reports suggest that the outcome of age-related macular degeneration treatment is dependent on variants in the apolipoprotein E (APOE) gene. We wish to establish if variants in this gene are associated with anatomical location of fluid within the macula on optical coherence tomography imaging before and after three anti-vascular endothelial growth factor treatments. Methods: Patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration were prospectively enrolled and monitored over a 12-month period. Main outcome measures were logMAR best-corrected visual acuity and correlation of qualitative optical coherence tomography features (intraretinal fluid [IRF] and/or subretinal fluid) at baseline and after three anti-vascular endothelial growth factor injections with genetic variants of the APOE gene. Results: One hundred and eighty-six eyes of 186 patients aged 79.4 years (range, 58&#8211;103 years). Subjects with an &#0949;2 allele were more likely to have IRF at baseline compared with the eyes without (odds ratio: 2.98, 95% confidence interval: 1.22&#8211;7.29, P = 0.02). After 3 injections, 184 eyes remained. Of these, 114 of eyes (62.0%) were classified as &#8220;dry&#8221; on optical coherence tomography, whereas 48 eyes (26.1%) still had a component of IRF, and 22 (12.0%) had subretinal fluid alone. There was no statistically significant association between APOE variants and presence of persistent IRF, although there were almost double the number of subjects with &#0949;2 (40%) who had persistent fluid compared with those with &#0949;3/&#0949;4 (23%) (P = 0.06). Conclusion: In patients with neovascular age-related macular degeneration, the presence of the &#0949;2 allele of the APOE gene was associated with having IRF at baseline. Larger studies are required to determine if a greater proportion of those with the &#0949;2 allele retain this fluid after three initial injections