Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia

Hariri, Amir H; Velaga, Swetha Bindu; Girach, Aniz; Ip, Michael S.; Le, Phuc Van; Lam, Byron L.; Fischer, Manuel; Sankila, Eeva Marja; Pennesi, Mark E.; Holz, Frank G.; MacLaren, Robert E.; Birch, David G.; Hoyng, Carel B.; MacDonald, Ian M.; Black, Graeme C M; Tsang, Stephen H.; Bressler, Neil M.; Larsen, Michael; Gorin, Michael B.; Webster, Andrew R.; Sadda, Srini Vas R.

doi:10.1016/j.ajo.2017.05.002

Cited by 52 publications

(46 citation statements)

References 17 publications

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“…Over the 2-year period and across the whole of 12 patients, The area of retinal autofluorescence is correlated to the area of surviving photoreceptors calculated from multiple slices through the ellipsoid zone. 19,26 Across the whole group of 12 patients who received gene therapy per protocol, similar areas of autofluorescence were preserved in treated and untreated eyes at two years (80.7±3.0% and 80.8±2.1%, respectively) ( Supplementary Fig. S5 and Table S4).…”

Section: Resultsmentioning

confidence: 92%

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

Xue

Jolly

Barnard

et al. 2018

Nat Med

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Retinal gene therapy is increasingly recognised as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology. 1-5 Choroideremia is a chronic X-linked retinal degeneration that was first described in 1872. 6 It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adenoassociated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes two years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, vs 1.5 letter loss, p=0.04), with six treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted.

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Section: Resultsmentioning

confidence: 92%

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

Xue

Jolly

Barnard

et al. 2018

Nat Med

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143

120

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“…Xue et al 2016 documented a correlation between preserved FAF and intact ellipsoid zone, but this observation was qualitative in nature (Xue et al 2016). Hariri et al 2017 used 3D-OCTOR version 3, a custom OCT grading software program, to show that the autofluorescent retinal pigment epithelium region and ellipsoid zone areas are well-correlated, with the preserved ellipsoid zone extending beyond the area of preserved retinal pigment epithelium (Hariri et al 2017). For the RPE layer, it has previously been established that blue fundus autofluorescence is a proxy for RPE health and is predominantly determined by the fluorophore lipofuscin in RPE cells (Delori et al 1995).…”

Section: Discussionmentioning

confidence: 99%

A distinct retinal pigment epithelial cell autofluorescence pattern in choroideremia predicts early involvement of overlying photoreceptors

Stevanovic

Cehajic-Kapetanovic

Jolly

et al. 2019

Acta Ophthalmologica

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Purpose: Choroideremia is an X-linked retinal disease characterized by early retinal pigment epithelium (RPE) loss and subsequent retinal degeneration. The RPE adopts either a smooth or mottled appearance on fundus autofluorescence (FAF). It is not known how RPE changes predict the health of the overlying ellipsoid zone (EZ). Methods: A retrospective review of FAF and optical coherence tomography (OCT) images from 20 patients with choroideremia was performed. The percentage of intact EZ in each smooth and mottled FAF region was determined using one horizontal trans-foveal OCT section. Results: Fourteen out of 20 patients had distinct smooth and mottled areas in both eyes and were included in the sub-analysis. On average, 62.5 AE 10.1% of the EZ in each smooth region of the right eyes was intact compared to 10.0 AE 4.3% in the mottled areas. The same trend was observed in left eyes: 76.5 AE 7.2% of the EZ was intact in the smooth regions versus 9.8 AE 3.9% in the mottled areas (two-way ANOVA, p < 0.0001). Thus, the mottled FAF regions were associated with EZ disruption more so than the smooth areas. Conclusion: Retinal pigment epithelium (RPE) changes correlate with the health of the overlying EZ in choroideremia. The smooth FAF region likely represents early stages of the disease, with most of the area containing preserved EZ, whereas the mottled zone indicates more advanced stages and has mostly disrupted EZ. Because of the clear relationship between FAF findings and EZ integrity, FAF imaging can be used to monitor disease progression and identify areas of preserved EZ that could be rescued by gene therapy.

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“…The subcellular origin of the outer hyperreflective bands, namely B2 and B3, is controversial, 3 , 5 but is critically important to validate, since metrics, such as EZ width, are being used as outcome measures in clinical trials. 10 , 11 Using a cone-dominant species offers a novel contribution toward this debate, but further work correlating OCT with histology is warranted. Using electron microscopy, Remé and Young 16 described three key photoreceptor changes in the 13-LGS that pertain to hypotheses of B2 and B3 hyperreflective band origin.…”

Section: Discussionmentioning

confidence: 99%

“… 4 Some designations remain controversial: adaptive optics (AO)-OCT suggests that the EZ band instead corresponds to an inner segment (IS)/OS junction, and that the IZ band instead corresponds to cone or rod OS tips. 5 , 6 It is critical that we establish a complete understanding of how reflectivity is related to underlying photoreceptor structure as there often is a disconnect between the appearance of residual photoreceptor structure in diseased retinas across imaging modalities, 7 – 9 and EZ outcome measures are being used in clinical trials 10 , 11 despite the lack of consensus of the anatomical origin of the EZ band. This controversy is difficult to solve using human subjects, primarily due to challenges of obtaining samples for histologic correlation and the variability in outer segment length 12 and rod/cone topography 13 of visually normal patients.…”

mentioning

confidence: 99%

Assessment of Outer Retinal Remodeling in the Hibernating 13-Lined Ground Squirrel

Sajdak

Bell

Lewis

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeWe examined outer retinal remodeling of the euthermic and torpid cone-dominant 13-lined ground squirrel (13-LGS) retina using optical coherence tomography (OCT) imaging and histology.MethodsRetinas and corneas of living 13-LGSs were imaged during euthermic and torpid physiological states using OCT. Retinal layer thickness was measured at the visual streak from registered and averaged vertical B-scans. Following OCT, some retinas were collected immediately for postmortem histologic comparison using light microscopy, immunofluorescence, or transmission electron microscopy.ResultsCompared to OCT images from euthermic retinae, OCT images of torpid retinae revealed significantly thicker inner and outer nuclear layers, as well as increases in the distances between outer retinal reflectivity bands 1 and 2, and bands 3 and 4. A significant decrease in the distance between bands 2 and 3 also was seen, alongside significant thinning of the choriocapillaris and choroid. OCT image quality was reduced in torpid eyes, partly due to significant thickening of the corneal stroma during this state.ConclusionsThe torpid retina of the hibernating 13-LGS undergoes structural changes that can be detected by OCT imaging. Comparisons between in vivo OCT and ex vivo histomorphometry may offer insight to the origin of hyperreflective OCT bands within the outer retina of the cone-dominant 13-LGS.

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Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia

Abstract: Quantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia.

Cited by 52 publications

References 17 publications

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

A distinct retinal pigment epithelial cell autofluorescence pattern in choroideremia predicts early involvement of overlying photoreceptors

Assessment of Outer Retinal Remodeling in the Hibernating 13-Lined Ground Squirrel

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