An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus serotype 2 vector encoding the cDNA of Rab escort protein 1, augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element. Up to 0.1 mL of timrepigene emparvovec, containing 1 × 1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intrasurgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec, and 53 completed the study. Visual acuity (VA) was generally maintained in both eyes, independent of intrasurgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post hoc analyses found that these were not associated with clinically significant vision loss at month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of antivector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced VA after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

Choroideremia presenting as vision loss secondary to choroidal neovascularization.

BACKGROUND: Choroidal neovascularization (CNV) is a rare complication of choroideremia that occurs secondary to relative atrophy of the retinal pigment epithelium and eventual rupture of Bruch's membrane. The ideal management of CNV in choroideremia is unclear. MATERIALS AND METHODS: Case report. OBSERVATIONS: A 14-year-old male with no known ocular history presented to the eye emergency department complaining of a central scotoma in the right eye for 4 days. He had no past medical history and family history was unremarkable for known ocular disease. Visual acuity was 20/70 in the right eye and 20/30 in the left eye. Posterior segment exam revealed chorioretinal atrophy extending from the outer macula to the midperiphery in both eyes. There was CNV with associated subretinal hemorrhage in the right eye. Optical coherence tomography demonstrated the presence of CNV with subretinal fluid in the right eye and parafoveal outer retinal atrophy in both eyes. Genetic testing revealed a hemizygous exon 2 deletion on the CHM gene, pathogenic for choroideremia. The patient received a total of 3 injections 4 weeks apart followed by 1 injection 6 weeks later with resolution of the subretinal hemorrhage and reduction in CNV size with improvement in visual acuity to 20/20 at last follow-up exam. CONCLUSIONS AND IMPORTANCE: Choroidal neovascularization is a rare cause of central vision loss in patients with choroideremia. In this report, we demonstrate a good functional and anatomic response to intravitreal bevacizumab in a 14-year-old patient with undiagnosed choroideremia who presented with CNV-induced central vision loss.

Gene Augmentation of CHM Using Non-Viral Episomal Vectors in Models of Choroideremia.

Choroideremia (CHM) is an X-linked chorioretinal dystrophy leading to progressive retinal degeneration that results in blindness by late adulthood. It is caused by mutations in the CHM gene encoding the Rab Escort Protein 1 (REP1), which plays a crucial role in the prenylation of Rab proteins ensuring correct intracellular trafficking. Gene augmentation is a promising therapeutic strategy, and there are several completed and ongoing clinical trials for treating CHM using adeno-associated virus (AAV) vectors. However, late-phase trials have failed to show significant functional improvements and have raised safety concerns about inflammatory events potentially caused by the use of viruses. Therefore, alternative non-viral therapies are desirable. Episomal scaffold/matrix attachment region (S/MAR)-based plasmid vectors were generated containing the human CHM coding sequence, a GFP reporter gene, and ubiquitous promoters (pS/MAR-CHM). The vectors were assessed in two choroideremia disease model systems: (1) CHM patient-derived fibroblasts and (2) chmru848 zebrafish, using Western blotting to detect REP1 protein expression and in vitro prenylation assays to assess the rescue of prenylation function. Retinal immunohistochemistry was used to investigate vector expression and photoreceptor morphology in injected zebrafish retinas. The pS/MAR-CHM vectors generated persistent REP1 expression in CHM patient fibroblasts and showed a significant rescue of prenylation function by 75%, indicating correction of the underlying biochemical defect associated with CHM. In addition, GFP and human REP1 expression were detected in zebrafish microinjected with the pS/MAR-CHM at the one-cell stage. Injected chmru848 zebrafish showed increased survival, prenylation function, and improved retinal photoreceptor morphology. Non-viral S/MAR vectors show promise as a potential gene-augmentation strategy without the use of immunogenic viral components, which could be applicable to many inherited retinal disease genes.

A generation of human-induced pluripotent stem cell line (MUi032-A) from a Choroideremia disease patient carrying a hemizygous mutation on the CHM gene.

Choroideremia (CHM) is a monogenic, X-linked inherited retinal disease caused by mutations in the CHM gene. CHM patients develop progressive loss of vision due to degeneration of cell layers in the retina. In this report, the human-induced pluripotent stem cell, MUi032-A, was generated from CD34+ hematopoietic stem/progenitor cells of a male CHM patient by co-electroporation of non-integration episomal vectors containing OCT4/shp53, Sox-2/KLF4, and L-MYC/LIN-28. The MUi032-A showed normal karyotype and a hemizygous c.715C > T mutation. They expressed pluripotency markers and differentiated into cells derived from three germ layers. This cell line may be useful for disease mechanisms and gene therapy studies.

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.

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 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. 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.

Repair of Rhegmatogenous Retinal Detachment in Choroideremia Secondary to Posterior Extramacular Retinal Hole.

Rhegmatogenous retinal detachment in choroideremia is a rare occurrence. The authors present a case of a 23-year-old man with choroideremia with a near-total rhegmatogenous retinal detachment. Fundus examination did not reveal any retinal breaks, but extensive preoperative optical coherence tomography detected a small posterior hole along the superior arcades. The retinal detachment was successfully managed with vitrectomy, perfluorooctane to confirm the absence of any peripheral breaks, endolaser, and 20% sulfur hexafluoride gas. Similar extramacular holes were found in the patient's other eye. Patients with choroideremia may develop posterior retinal breaks leading to retinal detachment.

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

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.

Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date.

Choroideremia is an inherited retinal disease characterised by a degeneration of the light-sensing photoreceptors, supporting retinal pigment epithelium and underlying choroid. Patients present with the same symptoms as those with classic rod-cone dystrophy: (1) night blindness early in life; (2) progressive peripheral visual field loss, and (3) central vision decline with a slow progression to legal blindness. Choroideremia is monogenic and caused by mutations in CHM. Eight clinical trials (three phase 1/2, four phase 2, and one phase 3) have started (four of which are already finished) to evaluate the therapeutic efficacy of gene supplementation mediated by subretinal delivery of an adeno-associated virus serotype 2 (AAV2/2) vector expressing CHM. Furthermore, one phase 1 clinical trial has been initiated to evaluate the efficiency of a novel AAV variant to deliver CHM to the outer retina following intravitreal delivery. Lastly, a non-viral-mediated CHM replacement strategy is currently under development, which could lead to a future clinical trial. Here, we summarise the rationale behind these various studies, as well as any results published to date. The diversity of these trials currently places choroideremia at the forefront of the retinal gene therapy field. As a consequence, the trial outcomes, regardless of the results, have the potential to change the landscape of gene supplementation for inherited retinal diseases.

Tackling the Challenges of Product Development Through a Collaborative Rare Disease Network: The Foundation Fighting Blindness Consortium.

The Foundation Fighting Blindness, a 501(c)(3) nonprofit organization, established an international consortium of inherited retinal disease specialists in 2016, with a mission to accelerate the development of treatments for rare, inherited retinal degenerations, such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Usher syndrome, choroideremia, and achromatopsia. The Consortium accomplishes its mission by evaluating novel outcome measures, sharing standardized study protocols and datasets, and disseminating findings. Having established research infrastructure in the first 3 years, including 39 global research sites, the network is now poised to expand its infrastructure for trials of new therapies in partnership with industry. This model represents an innovative approach to overcome challenges of therapeutic development for rare diseases.

Choroidal neovascularisation in a predicted female choroideraemia carrier treated with intravitreal anti-vascular endothelial growth factor.

PURPOSE: To report a case of choroidal neovascularisation and leakage in a myopic female predicted to be a choroideraemia carrier treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF). METHODS: Case report. RESULTS: A female magazine editor presented with sudden decrease in vision in her right eye, with Snellen visual acuities (VAs) of 1/60 and 3/60 in the right and left eyes respectively. She was diagnosed with choroidal neovascularisation (CNV) formation and subretinal haemorrhage in her right eye. This is on a background of previous presentations, the first of which was 20 years ago for declining left eye vision. She was subsequently found to be a predicted choroideraemia carrier. However, she also has high myopia, and it is unclear whether the predicted choroideraemia carrier status or high myopia is the main underlying cause of her CNV, although we believe that the former is more likely. The first episode of CNV in her right eye was treated successfully with intravitreal anti-VEGF. However, she experienced four further CNV reactivations in her right eye, all of which were treated successfully with anti-VEGF. At her last follow-up visit to date, Snellen VAs were 6/9 and 3/60 in her right and left eye respectively. CONCLUSION: This is a unique case of CNV formation in a predicted choroideraemia carrier who also has co-existent high myopia. Prompt treatment of CNV activity with anti-VEGF has been efficacious in prevention of subretinal fibrosis and irreversible vision loss and allowed the patient to continue working in her chosen career.

Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies.

Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (-6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (-1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had -17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (-14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.

Properties and Therapeutic Implications of an Enigmatic D477G RPE65 Variant Associated with Autosomal Dominant Retinitis Pigmentosa.

RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function mutations have been identified within the RPE65 gene causing inherited retinal dystrophies, most notably Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (arRP), which are both severe and early onset disease entities. We previously reported a mutation, D477G, co-segregating with the disease in a late-onset form of autosomal dominant RP (adRP) with choroidal involvement; uniquely, it is the only RPE65 variant to be described with a dominant component. Families or individuals with this variant have been encountered in five countries, and a number of subsequent studies have been reported in which the molecular biological and physiological properties of the variant have been studied in further detail, including observations of possible novel functions in addition to reduced RPE65 enzymatic activity. With regard to the latter, a human phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP. Here, we review data accrued from published studies investigating molecular mechanisms of this unique variant and include hitherto unpublished material on the clinical spectrum of disease encountered in patients with the D477G variant, which, in many cases bears striking similarities to choroideremia.

Coroideremia familiar: reporte de caso con énfasis en la evolución clínica y adquisición de discapacidad visual / Familiar choroideremia: case report with emphasis on clinical evolution and acquisition of visual impairment

Resumen La coroideremia es una enfermedad retiniana hereditaria que se caracteriza por la degeneración progresiva coriocapilar de coroides y retina; esta tiene la capacidad de limitar el funcionamiento y generar discapacidad, afectando el desempeño de la persona en el ámbito familiar, social y profesional, al producir dificultades en la comunicación, la movilidad, el desplazamiento y la gestión de su diario vivir. Esta condición de salud ocular se origina por una mutación del gen que codifica la proteína RabEscort-1, ubicada en el cromosoma Xq21. Su fisiopatología no es clara, y los reportes de caso de coroideremia familiar son escasos en Latinoamérica. Se reporta el caso de un hombre de 54 años con nictalopía y pérdida progresiva de agudeza visual, con un hermano menor con coroideremia y primo materno con sospecha de dicha enfermedad, con énfasis en evolución clínica, hallazgos al fondo de ojo y progresión a discapacidad categoría visual, tipo baja visión. MÉD.UIS. 2020;33(2):109-115.

Abstract Choroideremia is a hereditary retinal disease characterized by progressive choroidal and retinal choriocapillary degeneration, it has the ability to limit functioning and generate disability, affecting the persons performance in the family, social and professional environment, by causing difficulties in communication, mobility, displacement and management of your daily life. This eye health condition is caused by a mutation of the gene that encodes the RabEscort-1 protein, located on the Xq21 chromosome. His pathophysiology is not clear, and case reports of familial choroideremia are sparse in Latin America. The case of a 54-year-old man with night blindness and progressive loss of visual acuity is reported, with a younger brother with choroideremia and maternal cousin with suspected disease, with emphasis on clinical evolution, fundus findings and progression to disability category visual, low vision type. MÉD.UIS. 2020;33(2):109-115.

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations.

Purpose: To report combined viewpoints on ocular gene therapy from a select group of clinician scientists and a patient advocacy group. Methods: With the support of Randy Wheelock and Dr. Chris Moen from the Choroideremia Research Foundation (CRF), a special interest group at the 2019 Annual meeting of the Association for Research in Vision and Ophthalmology in Vancouver, Canada, shared their knowledge, experience, concepts, and ideas and provided a forum to discuss therapeutic strategies for the treatment of inherited retinal disorders, using experience in choroideremia (CHM) as a model. Results: A member of the CRF presented the patient perspective and role in clinical trials. Five clinician scientists presented reasons for limited long-term visual improvement in many gene therapy trials, including challenges with dose, incomplete understanding of photoreceptor metabolism, vector delivery, inflammation, and identification of patients likely to benefit from treatment. Conclusions: The shared experience of the five clinician scientists indicates that the results of ocular gene therapy for choroideremia have been less successful than for RPE65-related Leber congenital amaurosis. Improvement in vector delivery and developing a better understanding of gene expression in target tissues, treatment dose and side effects, and inflammation, as well as identifying patients who are most likely to benefit without suffering excessive risk, are necessary to advance the development of effective therapies for inherited retinal degenerations. Translational Relevance: Additional long-term data are required to determine if ocular gene therapy will be sufficient to alter natural progression in choroideremia. Combination therapies may have to be considered, as well as alternative vectors that minimize risk.

CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA.

PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 10 genome particles during vitrectomy. Twelve-month data are reported. RESULTS: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (-4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of -2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (-36.1 [66.9] deg) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure. CONCLUSION: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained.

Optical coherence tomography (OCT) features of cystoid spaces in choroideremia (CHM).

PURPOSE: To investigate the prevalence and features of cystoid spaces (CS) in patients with confirmed genetic diagnosis of choroideremia (CHM) using swept source optical coherence tomography (OCT). METHODS: We retrospectively reviewed CHM patients examined at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence. We took into consideration genetically confirmed CHM patients with ophthalmological and swept source optical coherence tomography (OCT) examinations. The presence/absence and location of cystoid spaces in the retina of each eye were reported. RESULTS: A total of 42 eyes of 21 CHM patients were included in our series. The average age of the patients was 36.5 ± 20.1 (range, 13-73 years). The average best-corrected visual acuity (BCVA) for all patients was 0.63 ± 1.00 logMar (range, 0-2,80). CS were present in 15 eyes of eight patients (8/21, 38%). In all cases, CS were located in inner nuclear layer (INL); in five eyes of three patients, CS were detected also in ganglion cell layer (GCL). CS appeared as microcistoyd abnormalities and were detected in retinal areas characterized by retinal pigment epithelium (RPE) and outer retinal layers atrophy at the transition zone. CONCLUSIONS: Cystoid spaces in choroideremia showed peculiar features; they are clusters of small-size extrafoveal degenerative cysts mainly located in inner nuclear layer at the transition zone where outer retinal layers and RPE are severely damaged.

Chronic Choroidal Neovascular Membrane in Choroideremia Treated With Intravitreal Bevacizumab.

Choroidal neovascular membrane (CNVM) is a rare complication of choroideremia. The authors report a case of a 13-year-old male presenting with metamorphopsia and decreased central vision of 1-year duration. Genetic testing was significant for a pathogenic c.1437dupA mutation in the CHM gene. Fundus biomicroscopy showed a subfoveal membrane; diagnosis of CNVM was substantiated with fluorescein angiography and swept-source optical coherence tomography angiography (SS-OCTA). The patient received six injections of intravitreal bevacizumab during a 13-month period with functional and anatomic improvement. Lesion area on SS-OCTA remained stable. CNVM should be suspected in young patients with choroideremia presenting with acute decrease in central vision. Treatment with anti-vascular endothelial growth factor should be considered even in chronic cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e188-e192.].

Insights into Retinal Development Using Live Imaging in Female Carriers of Choroideremia.

Lineage tracing can provide key insights into the development of tissues, such as the retina. Yet it is not possible to manipulate human cells during embryogenesis. The authors observed a distinct phenotype in female carriers of X-linked disorders, in particular, carriers of choroideremia caused by mutations in CHM, encoding Rab escort protein-1. The authors found that X chromosome inactivation provides a method for retinal lineage tracing in human patients. Live imaging of female carriers displays a developmental pattern that is different within the peripheral retina compared with the posterior retina and provides important insights into the development and migration of retinal cells. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e158-e162.].

High-Resolution Retinal Imaging Reveals Preserved Cone Photoreceptor Density and Choroidal Thickness in Female Carriers of Choroideremia.

BACKGROUND AND OBJECTIVE: To characterize the photoreceptors and choroidal morphology of heterozygous female carriers of choroideremia who typically do not have any visual defects but can have severe funduscopic changes. PATIENTS AND METHODS: This was a clinical case series study. Detailed ophthalmic examinations were performed on six female carriers from four families with choroideremia. The subfoveal choroidal thickness (SFCT) was determined by spectral-domain optical coherence tomography (SD-OCT) and the cone photoreceptor density by adaptive optics (AO) retinal imaging. SFCT and cone densities of the carriers were compared to that of normal eyes of healthy subjects. RESULTS: The mean age of the carriers was 42.5 years. Fundus photographs showed diffuse, patchy depigmentation; however, the SFCT was within the normal limits. AO retinal imaging revealed preserved cone densities at temporal eccentricities from 2 to 8 angular degrees. CONCLUSIONS: The findings indicate that despite the presence of distinctive depigmentation of the retinal pigment epithelium in female carriers of choroideremia, their cone photoreceptor densities and SFCT are well-preserved. These observations may account for the good visual acuity and lack of an awareness of visual disturbances. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:76-85.].