Month: 19 Dec 2014
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Quantification of fundus auto-fluorescence (qAF) in recessive Stargardt’s disease (STGD1) patients may contribute to improved outcome measures for clinical trials
Joint research conducted between the Departments of Ophthalmology at Columbia University, New York and Harvard Medical School, Massachusetts has shown that a novel methodology for quantifying auto-fluorescence AF (qAF) in images acquired with a confocal scanning laser ophthalmoscopy (cSLO) may serve as a viable indirect approach to measuring RPE lipofuscin in vivo. As quantitative fundus autofluorescence is significantly increased in Stargardt disease the novel approach may help to establish genotype-phenotype correlations and provide an objective and quantifiable outcome measure in clinical trials.
Several therapeutic trials are currently underway for the treatment of Stargardt’s disease (STGD1) employing small molecule, stem cell and gene therapy approaches. As with any other clinical studies, objectively measuring the impact of such interventions is critical to assessing the efficacy of a new treatment. In a study designed to assess the utility of qAF, researchers found that the benefits of using the technique in Stargardt’s disease (STGD1) was significantly advantageous. The authors of the study suggest that fundus AF imaging is quicker, easier and more cost-effective to perform than a number of other clinical evaluations, in addition to providing a quantifiable readout for the assessment of disease status. The autofluorescence (AF) arises from an accumulation of lipofuscin in the RPE which itself is a consequence of ABCA4 gene insufficiency. While cSLO has shown elevated AF in ABCA4 patients and has been helpful in diagnostics, comparison between patients can be difficult due to unavoidable variability in acquired images. According to the research team, the novel qAF methodology incorporates a fluorescence reference “internal to the imaging device” in such a way that the reference becomes part of the AF image. Subsequent analysis then compares the gray levels in the image with the gray levels of the internal reference, thereby controlling for changes in laser power and detector sensitivity. Additionally, the approach includes corrections for “magnification and optical media density from normative data on lens transmission spectra” and can be used with standardized image acquisition protocols allowing for patient comparison even with data acquired from different devices at different centers.
In their published study (Invest Ophthalmol Vis Sci. 2014;55:2841–2852. DOI:10.1167/ iovs.13-13624) the research team examined qAF in 36 of 42 patients and “TF” in 27 of 42 patients (“TF” or “Texture factor” is a measure of the quantity of small-scale heterogeneity of fundus AF images due to flecks and small patches of partial atrophy). The results indicated that younger patients exhibited the relatively highest qAF, sometimes up to 8-fold higher than that observed in healthy eyes. In addition, the data suggested that the rate of lipofuscin accumulation in STGD1 may be determined in part by the specific ABCA4 mutation. Based on cross-sectional data, the mutations L2027F and L541P/A1038V appeared to confer a faster rate of accumulation, while G1961E and G851D conferred a slower increase in lipofuscin accumulation. Patients carrying the G1916E mutation had lower qAF and TF than most other patients, even in the presence of a second allele associated with severe disease.
Commenting on the initiative, the authors of the IOVS publication stated that, “Quantified fundus autofluorescence is an indirect approach to measuring RPE lipofuscin in vivo. We report that ABCA4 mutations cause significantly elevated qAF, consistent with previous reports indicating that increased RPE lipofuscin is a hallmark of STGD1. Even when qualitative differences in fundus AF images are not evident, qAF can elucidate phenotypic variation. Quantified fundus autofluorescence will serve to establish genotype-phenotype correlations and as an outcome measure in clinical trials”.Back to previous