Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

Abstract

BackgroundEach inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration.Methods and findingsWe used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients.ConclusionsThese results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

“…Any preventative treatment of this group would need to balance the risk of treating some of these patients who might not lose significant acuity for several years untreated, with the potential benefits to those who eventually do lose their foveal sparing. With the p.N1868I allele accounting for a significant number of patients with Stargardt disease, the relative homogeneity of this group of patients should lend itself to longitudinal studies of visual acuity loss as well as more sensitive biomarkers, such as progression of macular atrophy, 10,30,40 conceivably leading to treatment trials requiring smaller numbers of patients than might otherwise be required to demonstrate efficacy. Delineating the prognosis of these patients may also suggest that one particular avenue of treatment, such as gene therapy, stem-cell transplantation, or pharmacological approaches, 41 may be more appropriate than others for this foveal-sparing form of Stargardt disease.…”

Comparison of Green Versus Blue Fundus Autofluorescence inABCA4-Related Retinopathy

“… 15 , 18 , 19 Furthermore, the identification of RPE atrophy in ABCA4 -related retinopathy appears to be more challenging as it encompasses variable stages toward complete atrophy ranging from questionable (QDAF) to definitely (DDAF) decreased AF. 20 , 21 A previous study correlated OCT-findings in QDAF and DDAF and found significantly thinner outer retinal layers (outer nuclear layer and combined layers between external limiting membrane and Bruch's membrane) in the latter case, considering QDAF as a transition state between healthy retina and DDAF. 22 As both RPE atrophy manifestations may be present within the same eye, more sophisticated measurement approaches are required.…”

“…22 As both RPE atrophy manifestations may be present within the same eye, more sophisticated measurement approaches are required. 20 , 21 …”

Analysis of retinal sublayer thicknesses and rates of change in ABCA4-associated Stargardt disease

“…Microperimetry with static perimetry may provide detailed functional testing in the macula but is also time-consuming, and Stargardt patients have less well-defined correlation between structure and function than patients with age-related macular degeneration 57 – 59 . Thus, combining structural and functional outcomes may be more sensitive to changes than a single mode of testing alone 60 . As above, our data demonstrate an overall slow rate of retinal change (e.g., 3 microns/year for outer retina thinning) in patients with STGD1.…”