Multimodal Imaging in Choroideremia

Foote, Katharina G.; Roorda, Austin; Duncan, Jacque L.

doi:10.1007/978-3-030-27378-1_23

Cited by 12 publications

(5 citation statements)

References 33 publications

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“…The results suggest the RPE, in addition to rods, is an autonomous site of degeneration in choroideremia. Cones ultimately are lost as well, either by mechanisms that occur in parallel or as a consequence of severe RPE and/or choroidal changes …”

Section: Introductionmentioning

confidence: 99%

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Morgan

Vergilio

et al. 2022

JAMA Ophthalmol

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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 PARTICIPANTSThis 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 × 10 10 vector genome per eye) or high-dose (1 × 10 11 vector genome per eye) AAV2-hCHM. Analysis began February 2015. MAIN OUTCOMES AND MEASURESThe 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. RESULTSNine 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.

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Section: Introductionmentioning

confidence: 99%

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Morgan

Vergilio

et al. 2022

JAMA Ophthalmol

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“…The primary affected cell types and the chronology of retinal cell alterations in choroideremia are still a matter of debate (reviewed by Coussa & Traboulsi, 2012; Foote et al, 2019; Kalatzis et al, 2013) which is hampered by the limitation of animal models (see below). Studies using psychophysics and high resolution multimodal imaging including adaptive optics are discordant.…”

Section: Phenotypic Characteristicsmentioning

confidence: 99%

CHM mutation spectrum and disease: An update at the time of human therapeutic trials

et al. 2021

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Choroideremia is an X‐linked inherited retinal disorder (IRD) characterized by the degeneration of retinal pigment epithelium, photoreceptors, choriocapillaris and choroid affecting males with variable phenotypes in female carriers. Unlike other IRD, characterized by a large clinical and genetic heterogeneity, choroideremia shows a specific phenotype with causative mutations in only one gene, CHM. Ongoing gene replacement trials raise further interests in this disorder. We describe here the clinical and genetic data from a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia families. Most of the variants represent loss‐of‐function mutations with eleven families having large (i.e. ≥6 kb) genomic deletions, 18 small insertions, deletions or insertion deletions, six showing nonsense variants, eight splice site variants and two missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss‐of‐function variants. Recurrent variants are observed worldwide, some of which linked to a common ancestor, others arisen independently in specific CHM regions prone to mutations. Since all exons of CHM may harbor variants, Sanger sequencing combined with quantitative polymerase chain reaction or multiplex ligation‐dependent probe amplification experiments are efficient to achieve the molecular diagnosis in patients with typical choroideremia features.

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“…Although REP-1 is expressed in many cells in the retina as well, RPE are believed to be the first cell affected in CHM (7,8). Recent advances in imaging technology, however, have created controversy as to where degeneration originates (8)(9)(10)(11)(12)(13). Multi-modal imaging studies of CHM patients at varied disease stages revealed early RPE loss followed by photoreceptor outer segment (PR OS) loss and outer retinal tubulations (ORTs) in the affected border region (6,14).…”

Section: Introductionmentioning

confidence: 99%

Glial remodeling and choroidal vascular pathology in eyes from two donors with Choroideremia

et al. 2022

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Choroideremia (CHM) is a recessive, X-linked disease that affects 1 in 50,000 people worldwide. CHM causes night blindness in teenage years with vision loss progressing over the next two to three decades. While CHM is known to cause progressive loss of retinal pigment epithelial (RPE) cells, photoreceptors and choroidal vessels, little attention has been given to retinal glial changes in eyes with CHM. In addition, while choroidal loss has been observed clinically, no histopathologic assessment of choroidal loss has been done. We investigated glial remodeling and activation as well as choriocapillaris changes and their association with RPE loss in postmortem eyes from two donors with CHM. Eyes were fixed and cryopreserved or the retina and choroid/RPE were processed as flatmounts with a small piece cut for transmission electron microscopy. A dense glial membrane, made up of vimentin and GFAP double-positive cells, occupied the subretinal space in the area of RPE and photoreceptor loss of both eyes. The membranes did not extend into the far periphery, where RPE and photoreceptors were viable. A glial membrane was also found on the vitreoretinal surface. Transmission electron microscopy analysis demonstrated prominence and disorganization of glial cells, which contained exosome-like vesicles. UEA lectin demonstrated complete absence of choriocapillaris in areas with RPE loss while some large choroidal vessels remained viable. In the far periphery, where the RPE monolayer was intact, choriocapillaris appeared normal. The extensive glial remodeling present in eyes with CHM should be taken into account when therapies such as stem cell replacement are considered as it could impede cells entering the retina. This gliosis would also need to be reversed to some extent for Müller cells to perform their normal homeostatic functions in the retina. Future studies investigating donor eyes as well as clinical imaging from carriers or those with earlier stages of CHM will prove valuable in understanding the glial changes, which could affect disease progression if they occur early. This would also provide insights into the progression of disease in the photoreceptor/RPE/choriocapillaris complex, which is crucial for identifying new treatments and finding the windows for treatment.

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Multimodal Imaging in Choroideremia

Cited by 12 publications

References 33 publications

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

CHM mutation spectrum and disease: An update at the time of human therapeutic trials

Glial remodeling and choroidal vascular pathology in eyes from two donors with Choroideremia

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