Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification: A Split-Person Study

INTRODUCTION: To evaluate the effect pegcetacoplan, a C3 and C3b inhibitor, on the rate of progression of geographic atrophy (GA) as assessed by spectral domain optical coherence tomography (SD-OCT) using a split-person study design and deep-learning quantification. METHODS: A post hoc analysis of phase 2 FILLY trial data comparing study (treated monthly, treated every other month and sham-treated) and fellow (untreated) eyes in a split-person study design was performed. This analysis included 288 eyes from 144 patients with bilateral GA from the FILLY phase 2 trial (Clinical Trials identifier: NCT02503332). Only patients with bilateral GA and without evidence of choroidal neovascularisation in either eye were included. Patient study eyes were treated with sham injections or with pegcetacoplan monthly (PM) or every other month (PEOM) for 12 months. SD-OCT scans of study and fellow eyes taken at baseline and 12 months were used for the analysis. The main outcomes were the annual change in the area of retinal pigment epithelial and outer retinal atrophy (RORA), its constituent features (photoreceptor degeneration [PRD], retinal pigment epithelium [RPE] loss, hypertransmission) and intact macula as compared to the untreated fellow eye. RESULTS: Annual GA growth was reduced in eyes treated with PM versus untreated fellow eyes for OCT features, including RORA (study eye 0.792 vs. fellow eye 1.13 mm2; P = 0.003), PRD (0.739 vs. 1.23 mm2; P = 0.015), RPE-loss (0.789 vs. 1.17 mm2; P = 0.007) and intact macula (- 0.735 vs. - 1.29 mm2; P = 0.011). Similar (but not statistically significant) trends were observed with the PEOM treatment or when GA was quantified with fundus autofluorescence (FAF). The sham treatment demonstrated no effect. Pearson correlation coefficients showed concordance in the enlargement rate of GA between the study and fellow eyes in the sham (R = 0.64) and PEOM (R = 0.68) groups, but not in the PM group (R = 0.21). CONCLUSIONS: Pegcetacoplan-treated eyes demonstrated a reduction in spatial GA progression compared to their untreated counterparts. This effect was more evident on OCT than with FAF. TRIAL REGISTRATION: Clinical Trials identifier: NCT02503332

Deep-learning automated quantification of longitudinal OCT scans demonstrates reduced RPE loss rate, preservation of intact macular area and predictive value of isolated photoreceptor degeneration in geographic atrophy patients receiving C3 inhibition treatment

OBJECTIVE: To evaluate the role of automated optical coherence tomography (OCT) segmentation, using a validated deep-learning model, for assessing the effect of C3 inhibition on the area of geographic atrophy (GA); the constituent features of GA on OCT (photoreceptor degeneration (PRD), retinal pigment epithelium (RPE) loss and hypertransmission); and the area of unaffected healthy macula.To identify OCT predictive biomarkers for GA growth. METHODS: Post hoc analysis of the FILLY trial using a deep-learning model for spectral domain OCT (SD-OCT) autosegmentation. 246 patients were randomised 1:1:1 into pegcetacoplan monthly (PM), pegcetacoplan every other month (PEOM) and sham treatment (pooled) for 12 months of treatment and 6 months of therapy-free monitoring. Only participants with Heidelberg SD-OCT were included (n=197, single eye per participant).The primary efficacy endpoint was the square root transformed change in area of GA as complete RPE and outer retinal atrophy (cRORA) in each treatment arm at 12 months, with secondary endpoints including RPE loss, hypertransmission, PRD and intact macular area. RESULTS: Eyes treated PM showed significantly slower mean change of cRORA progression at 12 and 18 months (0.151 and 0.277 mm, p=0.0039; 0.251 and 0.396 mm, p=0.039, respectively) and RPE loss (0.147 and 0.287 mm, p=0.0008; 0.242 and 0.410 mm, p=0.00809). PEOM showed significantly slower mean change of RPE loss compared with sham at 12 months (p=0.0313). Intact macular areas were preserved in PM compared with sham at 12 and 18 months (p=0.0095 and p=0.044). PRD in isolation and intact macula areas was predictive of reduced cRORA growth at 12 months (coefficient 0.0195, p=0.01 and 0.00752, p=0.02, respectively) CONCLUSION: The OCT evidence suggests that pegcetacoplan slows progression of cRORA overall and RPE loss specifically while protecting the remaining photoreceptors and slowing the progression of healthy retina to iRORA

Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification:A Split-Person Study

Introduction: To evaluate the effect pegcetacoplan, a C3 and C3b inhibitor, on the rate of progression of geographic atrophy (GA) as assessed by spectral domain optical coherence tomography (SD-OCT) using a split-person study design and deep-learning quantification. Methods: A post hoc analysis of phase 2 FILLY trial data comparing study (treated monthly, treated every other month and sham-treated) and fellow (untreated) eyes in a split-person study design was performed. This analysis included 288 eyes from 144 patients with bilateral GA from the FILLY phase 2 trial (Clinical Trials identifier: NCT02503332). Only patients with bilateral GA and without evidence of choroidal neovascularisation in either eye were included. Patient study eyes were treated with sham injections or with pegcetacoplan monthly (PM) or every other month (PEOM) for 12 months. SD-OCT scans of study and fellow eyes taken at baseline and 12 months were used for the analysis. The main outcomes were the annual change in the area of retinal pigment epithelial and outer retinal atrophy (RORA), its constituent features (photoreceptor degeneration [PRD], retinal pigment epithelium [RPE] loss, hypertransmission) and intact macula as compared to the untreated fellow eye. Results: Annual GA growth was reduced in eyes treated with PM versus untreated fellow eyes for OCT features, including RORA (study eye 0.792 vs. fellow eye 1.13 mm2; P = 0.003), PRD (0.739 vs. 1.23 mm2; P = 0.015), RPE-loss (0.789 vs. 1.17 mm2; P = 0.007) and intact macula (− 0.735 vs. − 1.29 mm2; P = 0.011). Similar (but not statistically significant) trends were observed with the PEOM treatment or when GA was quantified with fundus autofluorescence (FAF). The sham treatment demonstrated no effect. Pearson correlation coefficients showed concordance in the enlargement rate of GA between the study and fellow eyes in the sham (R = 0.64) and PEOM (R = 0.68) groups, but not in the PM group (R = 0.21). Conclusions: Pegcetacoplan-treated eyes demonstrated a reduction in spatial GA progression compared to their untreated counterparts. This effect was more evident on OCT than with FAF. Trial Registration: Clinical Trials identifier: NCT02503332.</p

Protein design: on the threshold of functional properties

A review with several refs. The ultimate goal in protein de novo design is the creation of novel macromols. with tailor-made receptor, sensory, and catalytic functions. Despite considerable progress in understanding basic rules of secondary structure formation and protein stability, the well known protein folding problem is still far from being solved and, in general, only a limited no. of designed proteins are folded uniquely. In this article the state-of-the-art in protein design is demonstrated on some selected examples, indicating that the construction of protein-like macromols. mimicking some essential features of natural proteins seems to be within reach. Thus, protein design and mimicry has become an interdisciplinary challenge with most intriguing perspectives. 1998 John Wiley & Sons, Inc. Biopoly 47: 63-73, 1998. [on SciFinder (R)

Design of Oligonucleotide Arrays at Interfaces

The surface attachment and detection of DNA probes are essential in the design of nucleic acid-based biosensors. A new strategy for the covalent immobilization of single-stranded oligonucleotides on gold-covered planar supports is presented. Optimization of the surface d. in the resulting DNA arrays permits a high hybridization efficiency to be achieved. Surface plasmon resonance and, for the first time, ATR-FTIR spectroscopy are used to follow in situ the oligonucleotide layer formation and the subsequent complementary strand hybridization. Such well-defined, covalently immobilized oligonucleotide arrays can find application in the development of novel DNA-based sensors for mutation detection and gene mapping as well as in studies of nucleic acid-ligand interactions. [on SciFinder (R)

Chimeric TASP molecules as biosensors

A chimeric TASP (Template Assembled Synthetic Proteins) mol., consisting of a 4-helix bundle motif and an antibody recognition site, has been covalently attached to a gold surface. The reversible antibody binding to the self-assembled monolayer as monitored by surface plasmon resonance spectroscopy demonstrates the versatility of the TASP concept for the construction of biosensors. [on SciFinder (R)

Construction of molecular devices using the template concept

A symposium report on the construction of regioselectively addressable functionalized template (RAFT) mols., e.g. I [R = Me3CO2C (Boc); R1 = H2C:CHCH2O2C (Alloc)], as conformationally stable cyclopeptide scaffolds in which lysine side chains point to opposite side of the template backbone. Chimeric mol. I [R = H-His, R1 = S(CH2)10CO] was prepd. and complexed to Zn2+, Cu2+, and attached to a gold surface. [on SciFinder (R)

MPI tracer interactions and their effect on signal stability

Nanoparticles tend to agglomerate following their in vivo or in vitro application. This leads to particle interaction and, for magnetic particle imaging (MPI) tracers, to magnetic coupling phenomena. Here, we investigate these effects and their influence on magnetic particle spectroscopy (MPS) and MPI signal stability. Highly magnetic flame-made Zn-ferrites with controlled interparticle distance are suggested as a stable MPI tracer system. Due to their pre-aggregated morphology, additional agglomeration does not substantially alter their magnetic response. This is in strong contrast to frequently investigated polymer-coated iron oxide nanoparticles, which show a massive MPS signal loss in a biologically relevant dispersion medium compared to water. This effect is also shown during MPI and renders these tracers inapplicable to further applications. Our flame-made Zn-ferrites, on the other hand, show sufficient signal stability, which allows their detailed quantification via MPI