Journal Club 27-2-2021

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

Thales Antonio Cabral de Guimaraes 1 2Michalis Georgiou 1 2James W B Bainbridge 1 2Michel Michaelides 3 2Affiliations expand

Free PMC article

Abstract

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.

Long-term outcomes of treat-and-extend ranibizumab with and without navigated laser for diabetic macular oedema: TREX-DME 3-year results

John F Payne 1Charles C Wykoff 2W Lloyd Clark 3Beau B Bruce 4David S Boyer 5David M Brown 6TREX-DME Study GroupCollaborators, Affiliations expand

Abstract

Background/aims: To evaluate the long-term effects of treat-and-extend dosing of ranibizumab with and without navigated focal laser for diabetic macular oedema (DME).

Methods: This is a multicentre, randomised clinical trial where 150 eyes were randomised into three cohorts; Monthly (n=30), TReat and EXtend without macular laser photocoagulation (TREX; n=60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n=60). During the first 2 years, eyes either received ranibizumab 0.3 mg every 4 weeks or underwent treat-and-extend ranibizumab with or without angiography-guided laser therapy. In the third year, all eyes were treated as needed with ranibizumab for >5 letters vision loss or if the central retinal thickness (CRT) was >325 µm, and all eyes were eligible to receive focal laser.

Results: 109 eyes (73%) completed the 3-year end-point. At week 156, mean best-corrected visual acuity (BCVA) and CRT improved by 6.9, 9.7, 9.5 letters (p=0.60) and 129, 138, 165 µm (p=0.39), in the Monthly, TREX and GILA cohorts, respectively. These improvements were reached prior to week 104 and no significant changes occurred from week 104 to week 156 (BCVA: p=0.34; CRT: p=0.36). The mean number of injections in the third year was 3.0, 3.1, and 2.4 in the Monthly, TREX and GILA cohorts, respectively (p=0.56). 86 eyes (79%) required at least one ranibizumab injection in the third year.

Conclusion: The improvements achieved after 2 years of treat-and-extend ranibizumab for DME were maintained in the third year with a mean of 3 intravitreal injections.

Trial registration number: FDA IND 119146, NCT01934556.

Long-term natural history of visual acuity in eyes with choroideremia: a systematic review and meta-analysis of data from 1004 individual eyes

Liangbo L Shen 1Aneesha Ahluwalia 1Mengyuan Sun 2Benjamin K Young 1Holly K Grossetta Nardini 3Lucian V Del Priore 4Affiliations expand

Abstract

Background/aims: Best-corrected visual acuity (BCVA) is the most common primary endpoint in treatment trials for choroideremia (CHM) but the long-term natural history of BCVA is unclear.

Methods: We searched in seven databases to identify studies that reported BCVA of untreated eyes with CHM. We sought individual-level data and performed segmented regression between BCVA and age. For eyes followed longitudinally, we introduced a horizontal translation factor to each dataset to account for different ages at onset of a rapid BCVA decline.

Results: We included 1004 eyes from 23 studies. BCVA of the right and left eyes was moderately correlated (r=0.60). BCVA as a function of age followed a 2-phase decline (slow followed by rapid decline), with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). After the introduction of horizontal translation factors to longitudinal datasets, BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90). The BCVA decline rate was 0.33 letters/year (95% CI -0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004).

Conclusion: BCVA in eyes with CHM follows a 2-phase linear decline with a transition age of approximately 39 years. Future trials enrolling young patients may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39. BCVA may still have utility as a primary endpoint for patients older than 39 years who have measurable BCVA decline rates.

OCT-A characterisation of recurrent type 3 macular neovascularisation

Riccardo Sacconi 1 2Marco Battista 1 2Enrico Borrelli 1 2Alexandra Miere 3Eleonora Corbelli 1 2Vittorio Capuano 3Lea Querques 2Eric H Souied 3Francesco Bandello 1 2Giuseppe Querques 4 2Affiliations expand

Abstract

Purpose: To investigate optical coherence tomography angiography (OCT-A) findings in recurrent type 3 macular neovascularisation (MNV).

Methods: In this retrospective cohort study, consecutive patients with type 3 MNV secondary to age-related macular degeneration underwent OCT-A at three different time points: baseline, after anti-vascular endothelial growth factor treatment with complete resolution of the exudative signs (ie, non-exudative stage) and at the recurrence of exudation (ie, recurrence stage). Demographics and clinical findings were analysed, including OCT-A features of type 3 MNV recurrence.

Results: Twelve eyes (12 patients, mean age 78±7 years) were included. Using OCT-A, at baseline all type 3 MNVs showed the presence of detectable flow downgrowing from the deep vascular complex (DVC) to the retinal pigment epithelium (RPE)/sub-RPE space. 6/12 eyes (50%) showed anomalous flow under the RPE, while the other 6 eyes showed flow reaching the RPE without anomalous flow in the sub-RPE space. At the non-exudative stage (after treatment), BCVA and CMT significantly improved (p=0.004 and p=0.036), and flow inside the retinal lesions reduced; interestingly the connection to the RPE/sub-RPE space regressed. At the time of recurrence, all type 3 MNVs showed the presence of intra/sub-retinal exudation with restoration of the flow deepening from the DVC to the RPE/sub-RPE space.

Conclusions: Detectable flow deepening from the DVC to the RPE/sub-RPE space using OCT-A is mandatory to have a new exudation secondary to recurrent type 3 MNV. Early detection of type 3 MNV recurrence by OCT-A characterisation may prompt retreatment and potentially prevent progression to late stages of the disease.

Retinal light sensitivity as outcome measure in recessive Stargardt disease

Maximilian Pfau 1 2Frank G Holz 1 3Philipp L Müller 4 3 5Affiliations expand

Abstract

Background/aims: To evaluate the applicability of mesopic light sensitivity measurements obtained by fundus-controlled perimetry (FCP, also termed ‘microperimetry’) as clinical trial endpoint in Stargardt disease (STGD1).

Methods: In this retrospective, monocentre cohort study, 271 eyes of 136 patients (age, 37.1 years) with STGD1 and 87 eyes of 54 healthy controls (age, 41.0 years) underwent mesopic FCP, using a pattern of 50 stimuli (achromatic, 400-800 nm) centred on the fovea. The concurrent validity of mesopic FCP testing using the MAIA device (CenterVue, Italy), the retest variability and its determinants, and the progression of sensitivity loss over time were investigated using mixed-model analyses. The main outcomes were the average pointwise sensitivity loss in dependence of patients’ demographic, functional and imaging characteristics, the intrasession 95% coefficient of repeatability, and the pointwise sensitivity loss over time.

Results: Pointwise sensitivity loss was on average (estimate (95% CI)) 13.88 dB (12.55 to 15.21) along the horizontal meridian and was significantly associated with the electrophysiological subgroup, presence/absence of foveal sparing, best-corrected visual acuity and disease duration. The 95% coefficient of repeatability was 12.15 dB (10.78 to 13.38) and varied in dependence of the underlying mean sensitivity and local sensitivity slope. The global progression rate for the sensitivity loss was 0.45 dB/year (0.13 to 0.78) and was higher for the central and inner ETDRS subfields compared with more peripheral regions.

Conclusions: Mesopic light sensitivity measured by FCP is reliable and susceptible for functional changes. It constitutes a potential clinical outcome for both natural history studies as well as future interventional studies in patients with STGD1.

Prognostic value of intermediate age-related macular degeneration phenotypes for geographic atrophy progression

Sarah Thiele 1Jennifer Nadal 2Maximilian Pfau 3 4Marlene Saßmannshausen 3Monika Fleckenstein 3Frank G Holz 3Matthias Schmid 2Steffen Schmitz-Valckenberg 3Affiliations expand

Free PMC article

Abstract

Background: To characterise early stages of geographic atrophy (GA) development in age-related macular degeneration (AMD) and to determine the prognostic value of structural precursor lesions in eyes with intermediate (i) AMD on the subsequent GA progression.

Methods: Structural precursor lesions for atrophic areas (lesion size at least 0.5 mm² in fundus autofluorescence images) were retrospectively identified based on multimodal imaging and evaluated for association with the subsequent GA enlargement rates (square-root transformed, sqrt). A linear mixed-effects model was used to account for the hierarchical nature of the data with a Tukey post hoc test to assess the impact of the local precursor on the subsequent GA progression rate.

Results: A total of 39 eyes with GA of 34 patients with a mean age of 74.4±6.7 (±SD) years were included in this study. Five precursor lesions (phenotypes 1-5) preceding GA development were identified: large, sub-retinal pigment epithelial drusen (n=19), reticular pseudodrusen (RPD, n=10), refractile deposits (n=4), pigment epithelial detachment (n=4) and vitelliform lesions (n=2). Precursor lesions exhibited a significant association with the subsequent (sqrt) GA progression rates (p=0.0018) with RPD (phenotype 2) being associated with the fastest GA enlargement (2.29±0.52 (±SE) mm/year.

Conclusions: The results indicate the prognostic relevance of iAMD phenotyping for subsequent GA progression highlighting the role of structural AMD features across different AMD stages.

Ocular toxoplasmosis: phenotype differences between toxoplasma IgM positive and IgM negative patients in a large cohort.

British Journal of Ophthalmology ( IF 3.611 ) Pub Date : 2021-02-01, DOI: 10.1136/bjophthalmol-2019-315522
Sofia Ajamil-Rodanes,Joshua Luis,Rabia Bourkiza,Benedict Girling,Angela Rees,Catherine Cosgrove,Carlos Pavesio,Mark Westcott

Purpose To investigate the differences in demographics and clinical characteristics of patients diagnosed with ocular toxoplasmosis according to their IgM status. Methods Retrospective case note analysis was carried out on patients who tested positive for serum Toxoplasma gondii -specific IgM antibodies (IgM+) as well as a comparator group who tested negative for serum IgM (IgM-), but positive for serum IgG. Patient demographics and clinical features were compared between the two groups to evaluate for any significant differences. Results One hundred and six patients were included in the study between March 2011 and June 2018, consisting of 37 in the IgM +group and 69 in the IgM- group. Patients in the IgM +group were significantly older (51.1 vs 34.1 years, p<0.0001), more likely to present with central macular lesions (32% vs 12%, p=0.012), and more likely to develop rhegmatogenous retinal detachment (11% vs 1%, p=0.049). In contrast, patients in the IgM- group were more likely present with pain (20% vs 3%, 0.017) and exhibit more severe inflammation of the anterior chamber and vitreous (p<0.05). Overall, retinal lesions were more likely to be superotemporal (55%) and superonasal (31%). Furthermore, age was associated with larger (p=0.003) and more peripheral lesions (p=0.007). Conclusions This study demonstrated significant differences in clinical characteristics of ocular toxoplasmosis according to serum IgM status. IgM+ patients were older, less likely to report pain, had lower levels of intraocular inflammation, but were more likely to have macular involvement. We also found age to be correlated with larger and more peripheral lesions.

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Retina Ward of Farabi Eye Hospital