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  1. Article ; Online: Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy.

    Morgan, Jessica I W / Jiang, Yu You / Vergilio, Grace K / Serrano, Leona W / Pearson, Denise J / Bennett, Jean / Maguire, Albert M / Aleman, Tomas S

    JAMA ophthalmology

    2022  Volume 140, Issue 4, Page(s) 411–420

    Abstract: Importance: Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells.: Objective: To use ...

    Abstract Importance: Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells.
    Objective: To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia.
    Design, setting, and participants: This longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 1010 vector genome per eye) or high-dose (1 × 1011 vector genome per eye) AAV2-hCHM. Analysis began February 2015.
    Main outcomes and measures: The macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point.
    Results: Nine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM-injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment-related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO.
    Conclusions and relevance: Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.
    MeSH term(s) Adult ; Choroideremia/diagnosis ; Choroideremia/genetics ; Choroideremia/therapy ; Dependovirus/genetics ; Humans ; Male ; Middle Aged ; Ophthalmoscopy/methods ; Retinal Cone Photoreceptor Cells ; Tomography, Optical Coherence/methods
    Language English
    Publishing date 2022-03-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701705-9
    ISSN 2168-6173 ; 2168-6165
    ISSN (online) 2168-6173
    ISSN 2168-6165
    DOI 10.1001/jamaophthalmol.2022.0158
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  2. Article ; Online: A 2-Year Longitudinal Study of Normal Cone Photoreceptor Density.

    Jackson, Kevin / Vergilio, Grace K / Cooper, Robert F / Ying, Gui-Shuang / Morgan, Jessica I W

    Investigative ophthalmology & visual science

    2019  Volume 60, Issue 5, Page(s) 1420–1430

    Abstract: Purpose: Despite the potential for adaptive optics scanning light ophthalmoscopy (AOSLO) to quantify retinal disease progression at the cellular level, there remain few longitudinal studies investigating changes in cone density as a measure of disease ... ...

    Abstract Purpose: Despite the potential for adaptive optics scanning light ophthalmoscopy (AOSLO) to quantify retinal disease progression at the cellular level, there remain few longitudinal studies investigating changes in cone density as a measure of disease progression. Here, we undertook a prospective, longitudinal study to investigate the variability of cone density measurements in normal subjects during a 2-year period.
    Methods: Fourteen eyes of nine subjects with no known ocular pathology were imaged both at a baseline and a 2-year follow-up visit by using confocal AOSLO at five retinal locations. Two-year affine-registered images were created to minimize the effects of intraframe distortions. Regions of interest were cropped from baseline, 2-year manually aligned, and 2-year affine-registered images. Cones were identified (graded masked) and cone density was extracted.
    Results: Mean baseline cone density (cones/mm2) was 87,300, 62,200, 45,500, 28,700, and 18,200 at 190, 350, 500, 900, and 1500 μm, respectively. The mean difference (± standard deviation [SD]) in cone density from baseline to 2-year affine-registered images was 1400 (1700), 100 (1800), 300 (800), 400 (800), and 1000 (2400) cones/mm2 at the same locations. The mean difference in cone density during the 2-year period was lower for affine-registered images than manually aligned images.
    Conclusions: There was no meaningful change in normal cone density during a 2-year period. Intervisit variability in cone density measurements decreased when intraframe distortions between time points were minimized. This variability must be considered when planning prospective longitudinal clinical trials using changes in cone density as an outcome measure for assessing retinal disease progression.
    MeSH term(s) Adult ; Axial Length, Eye/physiology ; Diagnostic Techniques, Ophthalmological ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Ophthalmoscopy/methods ; Prospective Studies ; Retinal Cone Photoreceptor Cells/pathology ; Retinal Diseases/pathology ; Visual Acuity/physiology ; Young Adult
    Language English
    Publishing date 2019-03-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 391794-0
    ISSN 1552-5783 ; 0146-0404
    ISSN (online) 1552-5783
    ISSN 0146-0404
    DOI 10.1167/iovs.18-25904
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: The Reliability of Cone Density Measurements in the Presence of Rods.

    Morgan, Jessica I W / Vergilio, Grace K / Hsu, Jessica / Dubra, Alfredo / Cooper, Robert F

    Translational vision science & technology

    2018  Volume 7, Issue 3, Page(s) 21

    Abstract: Purpose: Recent advances in adaptive optics scanning light ophthalmoscopy (AOSLO) have enabled visualization of cone inner segments through nonconfocal split-detection, in addition to rod and cone outer segments revealed by confocal reflectance. Here, ... ...

    Abstract Purpose: Recent advances in adaptive optics scanning light ophthalmoscopy (AOSLO) have enabled visualization of cone inner segments through nonconfocal split-detection, in addition to rod and cone outer segments revealed by confocal reflectance. Here, we examined the interobserver reliability of cone density measurements in both AOSLO imaging modalities.
    Methods: Five normal subjects (nine eyes) were imaged along the horizontal and vertical meridians using a custom AOSLO with confocal and nonconfocal split-detection modalities. The resulting images were montaged using a previously described semiautomatic algorithm. Regions of interest (ROIs) were selected from the confocal montage at 190 μm, and from split-detection and confocal montages at 900 and 1800 μm from the fovea. Four observers (three experts, one naïve) manually identified cone locations in each ROI, and these locations were used to calculate bound densities. Intraclass correlation coefficients and Dice's coefficients were calculated to assess interobserver agreement.
    Results: Interobserver agreement was high in cone-only images (confocal 190 μm: 0.85; split-detection 900 μm: 0.91; split-detection 1800 μm: 0.89), moderate in confocal images at 900 μm (0.68), and poor in confocal images at 1800 μm (0.24). Excluding the naïve observer data substantially increased agreement within confocal images (190 μm: 0.99; 900 μm: 0.80; 1800 μm: 0.68).
    Conclusions: Interobserver measurements of cone density are more reliable in rod-free retinal images. Moreover, when using manual cell identification, it is essential that observers are trained, particularly for confocal AOSLO images.
    Translational relevance: This study underscores the need for additional reliability studies in eyes containing pathology where identifying cones can be substantially more difficult.
    Language English
    Publishing date 2018-06-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2674602-5
    ISSN 2164-2591
    ISSN 2164-2591
    DOI 10.1167/tvst.7.3.21
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  4. Article ; Online: Visual Function at the Atrophic Border in Choroideremia Assessed with Adaptive Optics Microperimetry.

    Tuten, William S / Vergilio, Grace K / Young, Gloria J / Bennett, Jean / Maguire, Albert M / Aleman, Tomas S / Brainard, David H / Morgan, Jessica I W

    Ophthalmology. Retina

    2019  Volume 3, Issue 10, Page(s) 888–899

    Abstract: Purpose: Recent advances in retinal imaging allow visualization of structural abnormalities in retinal disease at the cellular level. This study used adaptive optics (AO) microperimetry to assess visual sensitivity with high spatial precision and to ... ...

    Abstract Purpose: Recent advances in retinal imaging allow visualization of structural abnormalities in retinal disease at the cellular level. This study used adaptive optics (AO) microperimetry to assess visual sensitivity with high spatial precision and to examine how function varies across 2 phenotypic features observed in choroideremia: atrophic lesion borders and outer retinal tubulations (ORTs).
    Design: Cross-sectional study.
    Participants: Twelve choroideremia patients.
    Methods: A custom AO scanning light ophthalmoscope (AOSLO) equipped with both confocal and nonconfocal split-detection imaging methods was used to image the photoreceptor inner and outer segment mosaics. For AO microperimetry, circular 550-nm stimuli were presented through the AOSLO system; stimuli were either 9.6 or 38.3 arcmin
    Main outcome measure: Visual sensitivity thresholds measured with AO microperimetry at retinal locations corresponding to structural phenotypes observed on AOSLO retinal images.
    Results: In choroideremia, sharp borders between intact central islands of the photoreceptor mosaic and complete atrophy of the outer retina and retinal pigment epithelium were observed in both split-detection and confocal structural images. Adaptive optics microperimetry at locations spanning these borders showed a commensurately sharp decrease in function, with readily measurable visual sensitivity on one side and dense scotoma on the other. These functional transitions often occurred over a distance smaller than the diameter of the Goldman III stimulus. Thresholds measured along ORTs showed dense scotoma over the tubule in all 4 participants, despite the visibility of remnant cone inner segments on the AO images.
    Conclusions: Choroideremia patients exhibited sharp functional transitions that collocated with structural transitions from intact to severely degenerated retina. We found no evidence of visual sensitivity over ORTs. Measuring cone function with high resolution offered insight into disease mechanisms and may enable precise assessment of whether experimental therapies, such as gene therapy, provide a functional benefit.
    MeSH term(s) Adult ; Choroideremia/diagnosis ; Choroideremia/etiology ; Choroideremia/physiopathology ; Cross-Sectional Studies ; Humans ; Male ; Middle Aged ; Ophthalmoscopy/methods ; Retinal Pigment Epithelium/pathology ; Scotoma/complications ; Scotoma/diagnosis ; Scotoma/physiopathology ; Tomography, Optical Coherence/methods ; Visual Acuity ; Visual Fields ; Young Adult
    Language English
    Publishing date 2019-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2468-7219
    ISSN (online) 2468-7219
    DOI 10.1016/j.oret.2019.05.002
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  5. Article ; Online: Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

    Aleman, Tomas S / Huckfeldt, Rachel M / Serrano, Leona W / Pearson, Denise J / Vergilio, Grace K / McCague, Sarah / Marshall, Kathleen A / Ashtari, Manzar / Doan, Tu M / Weigel-DiFranco, Carol A / Biron, Bethany S / Wen, Xiao-Hong / Chung, Daniel C / Liu, Emily / Ferenchak, Kevin / Morgan, Jessica I W / Pierce, Eric A / Eliott, Dean / Bennett, Jean /
    Comander, Jason / Maguire, Albert M

    Ophthalmology

    2022  Volume 129, Issue 10, Page(s) 1177–1191

    Abstract: Purpose: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM.: Design: Prospective, open-label, nonrandomized, dose-escalation, ... ...

    Abstract Purpose: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM.
    Design: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial.
    Participants: Fifteen CHM patients (ages 20-57 years at dosing).
    Methods: Patients received uniocular subfoveal injections of low-dose (up to 5 × 10
    Main outcome measures: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF).
    Results: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships.
    Conclusions: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.
    MeSH term(s) Adult ; Choroideremia/diagnosis ; Choroideremia/genetics ; Choroideremia/therapy ; DNA, Complementary ; Dependovirus/genetics ; Fluorescein Angiography ; Genetic Therapy/methods ; Humans ; Middle Aged ; Prospective Studies ; Retinal Perforations/therapy ; Serogroup ; Tomography, Optical Coherence ; Young Adult
    Chemical Substances DNA, Complementary
    Language English
    Publishing date 2022-06-15
    Publishing country United States
    Document type Clinical Trial ; Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392083-5
    ISSN 1549-4713 ; 0161-6420
    ISSN (online) 1549-4713
    ISSN 0161-6420
    DOI 10.1016/j.ophtha.2022.06.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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