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Retinal Structure Measurements As Inclusion Criteria for Stem Cell–Based Therapies of Retinal Degenerations

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Retinal Structure Measurements As Inclusion Criteria for Stem Cell–Based Therapies of Retinal Degenerations Retina Retinal Structure Measurements as Inclusion Criteria for Stem Cell–Based Therapies of Retinal Degenerations Samuel G. Jacobson, Rodrigo Matsui, Alexander Sumaroka, and Artur V. Cideciyan Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States Correspondence: Samuel G. Jacob- PURPOSE. We reviewed and illustrated the most optimal retinal structural measurements to son, Scheie Eye Institute, University make in stem cell clinical trials. of Pennsylvania, 51 N 39th Street, Philadelphia, PA 19104, USA; METHODS. Optical coherence tomography (OCT) and autofluorescence (AF) imaging were [email protected]. used to evaluate patients with severe visual loss from nonsyndromic and syndromic retinitis pigmentosa (RP), -Stargardt disease, and nonneovascular age-related macular Submitted: July 9, 2015 ABCA4 Accepted: August 21, 2015 degeneration (AMD). Outer nuclear layer (ONL), rod outer segment (ROS) layer, inner retina, ganglion cell layer (GCL), and nerve fiber layer (NFL) thicknesses were quantified. Citation: Jacobson SG, Matsui R, Su- maroka A, Cideciyan AV. Retinal RESULTS. All patients had severely reduced visual acuities. Retinitis pigmentosa patients had structure measurements as inclusion limited visual fields; maculopathy patients had central scotomas with retained peripheral criteria for stem cell–based therapies function. For the forms of RP illustrated, there was detectable albeit severely reduced ONL of retinal degenerations. Invest Oph- across the scanned retina, and normal or hyperthick GCL and NFL. Maculopathy patients had thalmol Vis Sci. 2016;57:ORSFn1– no measurable ONL centrally; it became detectable with eccentricity. Some maculopathy ORSFn9. DOI:10.1167/iovs.15-17654 patients showed unexpected GCL losses. Autofluorescence imaging illustrated central losses of RPE integrity. A hypothetical scheme to relate patient data with different phases of retinal remodeling in animal models of retinal degeneration was presented. CONCLUSIONS. Stem cell science is advancing, but it is not too early to open the discussion of criteria for patient selection and monitoring. Available clinical tools, such as OCT and AF imaging, can provide inclusion/exclusion criteria and robust objective outcomes. Accepting that early trials may not lead to miraculous cures, we should be prepared to know why— scientifically and clinically—so we can improve subsequent trials. We also must determine if retinal remodeling is an impediment to efficacy. Keywords: retinitis pigmentosa, Usher syndrome, Stargardt disease, age-related macular degeneration nherited retinal degenerations (IRDs) have entered an era longstanding concern to those planning stem cell therapies, also I from being incurable to having emerging therapeutic options. is addressed with illustrations of data from patients. An attempt Many previously discussed therapies are in planning stages, is made to relate the patient findings to phases of remodeling whereas others already are in early phase clinical trials.1–3 The postulated from studies of animal models.10 Details of advances expectation of investigators and patients alike is that these efforts in regenerative medicine8,11–16 are not addressed in this article, will lead to robust and safe methods with predictable outcomes but are topics covered by others in this symposium issue. that will improve vision for patients with disabling visual loss. Among current clinical trials of stem cell transplantation for retinal disease,4,5 two types of retinal degenerations are being METHODS enrolled. There are a limited number of trials in patients with forms of retinitis pigmentosa (RP), and there are more trials in Subjects patients with diseases of the macula, whether IRDs or age-related All procedures followed the Declaration of Helsinki and the macular degeneration (AMD). Different sources of stem cells are study was approved by the Institutional Review Board (IRB). being used and different delivery methods are represented.4–9 Informed consent, assent, and parental permission were The main inclusion criterion and common to all of the trials obtained, and the work was Health Insurance Portability and is, of course, seriously impaired visual function. Retinal structural Accountability Act (HIPAA)–compliant. Included were patients inclusion criteria are less well defined than functional criteria, with forms of nonsyndromic or syndromic RP (n ¼ 10; ages, 3– although many trials mention fundus photography, fluorescein 64), Stargardt disease (n ¼ 2; ages 39 and 42), and non- angiography, and optical coherence tomography (OCT). The neovascular AMD (n ¼ 2; ages 67 and 79). current study illustrates the use of segmented cross-sections of OCT to analyze retinal structural details and en face autofluo- Retinal Imaging rescence (AF) imaging to evaluate the integrity of the RPE. Patients representing the two main disease types being targeted Optical Coherence Tomography. Cross-sectional retinal for stem cell–based therapies are shown. Retinal remodeling, a images were obtained with OCT using methods previously iovs.arvojournals.org j ISSN: 1552-5783 ORSFn1 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 10/01/2021 Clinical Plans for Stem Cell Therapies IOVS j Special Issue j Vol. 57 j No. 5 j ORSFn2 described.17–21 Spectral-domain OCT (Optovue, Inc., Fremont, with nearly identical lipofusin autofluorescence on SW-RAFI CA, USA) was used to collect all data. Optical coherence (not shown), it is likely that the central macula and tomography scans were formed by laterally sampling longitu- extramacular regions correspond to severe RPE disease dinal reflectivity profiles (LRPs). High density line scan (HD possibly including complete atrophy. The question of whether line, 4091 LRPs) or line scans (average up to 32 scans, 1019 there was measurable GCL and NFL thicknesses in P1 is LRP each) 9-mm long were used to study the retina along the answered. For P1, the results are either within normal limits or horizontal and vertical meridians through the fovea; only those thickened (Figs. 1B, 1C). scans that included the foveal depression were used for Patient 2 is a 51-year-old man with a clinical diagnosis of unambiguous retinal localization. Circular scans of 3.4-mm Usher syndrome clinical subtype II (genotype unknown). The diameter centered on the optic nerve head (ONH) were ONL is measurable, but abnormally thinned; IS and OS are acquired to quantify the peripapillary retinal NFL. mostly undetectable. NIR-RAFIn shows a macular region of Optical coherence tomograms were analyzed with custom partially retained signal and the SW-RAFI results (not shown) programs (MatLab 7.5; MathWorks, Natick, MA, USA) after the are consistent with retained RPE lipofuscin. Ganglion cell layer LRPs were aligned by straightening the major RPE reflection. and NFL are within normal limits. For retinal sublaminae, signal peak assignments were based on Patient 3, a 17-year-old man with a diagnosis of early-onset our previously published work consistent with hypotheses on RP (unknown genotype), shows reduced, but detectable ONL the correspondence between OCT signals and histologically- thickness across the scan length. The laminar architecture defined layers.17,19 Specifically, the thickness of the following attributable to IS and OS is abnormally thinned. NIR-RAFIn retinal sublaminae (from vitreous to choroid) were quantified shows loss of foveal signal surrounded by detectable, but in patients and normal subjects: hyperreflective NFL, hypore- abnormal signal in the macula. The GCL and NFL are thickened flective ganglion cell layer (GCL), and hyporeflective outer relative to the normal limits (Figs. 1B, 1C). nuclear layer (ONL). Polar plots were used to display All three patients would likely satisfy inclusion criterion in a peripapillary NFL thickness. stem cell–based trial based on abnormally reduced photore- En Face AF. Imaging was performed with a confocal ceptor laminae and RPE losses that would be consistent with scanning laser ophthalmoscope (Spectralis HRA; Heidelberg the visual disturbances. As for postreceptoral inner retinal Engineering, Heidelberg, Germany) to obtain short-wavelength integrity, however, there is complexity without easy interpre- (SW-) excited reduced-illuminance autofluorescence imaging tations. Thickened GCL and/or NFL as in P1 and P3 have been (RAFI), which is based on a signal originating mostly from noted previously in forms of RP.21,24–26 The basis of such inner lipofuscin fluorophores within the RPE.22,23 In addition, near- retinopathy is not clear and it remains uncertain whether there infrared (NIR-) reflectance images and RAFI also were would be any effect of such pathology on efficacy of treatments recorded; normalized NIR-RAFI (NIR-RAFIn) was calculated intended to replace photoreceptors. by pixel-by-pixel division of the registered images. NIR-RAFIn is thought to be based on melanin-based fluorophores within the Quantifying Retinal Laminar Integrity in RPE.23 All images were acquired with the high speed mode Maculopathies wherein a 3083308 square field was sampled onto 768 3 768 pixels. The dilated pupil of the subject was aligned with the Figure 2 illustrates cross-sectional OCT and en face NIR-RAFIn optical axis of the instrument (head position stabilized with results from patients with ABCA4-Stargardt disease (P4, P5) chin and forehead rests) in a
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