185. Safety Study by Validated Immunoassays in a Phase III Study of Subjects with Inherited Retinal Dystrophy Due to Mutations in the Gene Encoding Human Retinal Pigment Epithelium-Specific Protein 65 (RPE65) Injected with Adeno-Associated Viral Vectors

Aim: We present the case of a 72-year-old male with advanced choroideremia and a left chronic rhegmatogenous retinal detachment, which to our knowledge is the first formal report of a retinal detachment in this disease. Background: Choroideremia is a rare X-linked inherited retinal dystrophy, caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), and affected males typically experience a progressive centripetal loss of vision. The disease pathology is caused by a primary retinal pigment epithelium degeneration, which leads to secondary loss of photoreceptors and choriocapillaris. This in turn leads to fusion of the degenerate outer retinal layers resulting in a retinopexy that is known to make subretinal gene therapy particularly challenging in these patients. Conclusion: Although retinal gene therapy is commonly targeted to the macular area in choroideremia, the observation of a rhegmatogenous retinal detachment indicates that the peripheral retina may not fuse with the residual choroid as occurs in the equatorial and macular regions. If this hypothesis is correct, targeting gene therapy to the retinal periphery even in advanced cases may be feasible and could potentially be used to preserve navigational vision.

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Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-318483 ◽

2021 ◽

pp. bjophthalmol-2020-318483

Author(s):

Malena Daich Varela ◽

Thales Antonio Cabral de Guimaraes ◽

Michalis Georgiou ◽

Michel Michaelides

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Early Onset ◽

Viral Vectors ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Dystrophy ◽

European Medicines Agency ◽

Current Management ◽

Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.

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Diffuse Pigmented Lesions in the Outer Retina: An Unusual Fundus Appearance

Journal of VitreoRetinal Diseases ◽

10.1177/2474126419873547 ◽

2019 ◽

Vol 4 (3) ◽

pp. 243-247

Author(s):

Matthew D. Benson ◽

Uriel Rubin ◽

Marvi Cheema ◽

Ian M. MacDonald ◽

Matthew T.S. Tennant ◽

...

Keyword(s):

Phenotypic Diversity ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Dystrophy ◽

Full Field ◽

Panel Testing ◽

Pigmented Lesions ◽

Hereditary Retinal Dystrophy ◽

Ultrasound Findings ◽

Chest X Ray

Purpose: This report describes and provides a differential diagnosis for a patient with unusual bilateral retinal pigmented lesions. Methods: A 40-year-old woman was found to have multiple flat, gray lesions scattered across her fundi, becoming larger and more confluent toward the periphery. There were small drusenlike deposits in her foveae. The hyperpigmented lesions demonstrated hypoautofluorescence with thickening of the retinal pigment epithelium and disruption of the overlying layers on optical coherence tomography (OCT). Full-field electroretinography revealed generalized reduced a- and b-wave amplitudes. Results: Chest x-ray, breast ultrasound, mammography, and pelvic ultrasound findings were negative for malignant etiologic factors. Panel testing results for hereditary retinal dystrophy were negative. Conclusions: Although the clinical and OCT appearance of the lesions is similar to congenital grouped pigmentation, the symmetric and bilateral nature of ocular findings coupled with electroretinographic changes suggest a possible retinal dystrophy. This case adds to the phenotypic diversity of pigmented fundus lesions.

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902. Neural Retina Limits Delivery Non Viral Vectors to Retinal Pigment Epithelium

Molecular Therapy ◽

10.1016/s1525-0016(16)45108-7 ◽

2007 ◽

Vol 15 ◽

pp. S344-S345

Keyword(s):

Retinal Pigment Epithelium ◽

Viral Vectors ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Neural Retina

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Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium

Human Molecular Genetics ◽

10.1093/hmg/4.4.641 ◽

1995 ◽

Vol 4 (4) ◽

pp. 641-649 ◽

Cited By ~ 71

Author(s):

Aileen Nicoletti ◽

Deborah J. Wong ◽

Kazuhide Kawase ◽

Lisa H. Gibson ◽

Teresa L. Yang-Feng ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Molecular Characterization ◽

Human Gene ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Gene Encoding

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THE ROLE OF THE PIGMENT EPITHELIUM IN THE ETIOLOGY OF INHERITED RETINAL DYSTROPHY IN THE RAT

The Journal of Cell Biology ◽

10.1083/jcb.49.3.664 ◽

1971 ◽

Vol 49 (3) ◽

pp. 664-682 ◽

Cited By ~ 361

Author(s):

Dean Bok ◽

Michael O. Hall

Keyword(s):

Cell Death ◽

Outer Segment ◽

Pigment Epithelium ◽

Retinal Dystrophy ◽

Visual Cell ◽

Sprague Dawley ◽

Inherited Retinal Dystrophy ◽

Rcs Rats ◽

Electron Microscopes ◽

And Control

Visual cell outer segment renewal was studied in eyes of mutant Royal College of Surgeons (RCS) and Sprague-Dawley (control) rats by a combination of microscopy and radioautography with the light and electron microscopes. RCS and control rats were injected with amino acids-3H at 11 days of age. Radioactive rod outer segment discs were assembled at the outer segment base from radioactive proteins synthesized in the rod inner segments. In controls, all radioactive discs assembled at 11 days of age were displaced the length of the outer segments, removed from outer segment tips, and phagocytized by the pigment epithelium by 8 days after injection. In the RCS rats, disc assembly and displacement resembled controls for the first 3 days after injection. However, as disc assembly continued for some time thereafter, a layer of labeled, disorganized, lamellar debris accumulated between the outer segment tips and the pigment epithelium. The buildup of debris was accompanied by visual cell death. At no time during the study was there evidence for phagocytic activity by the pigment epithelium. 61 days after injection, the layer of debris was the only heavily radioactive component in the retina. In the retina of RCS rats, the outer segment renewal mechanism malfunctions because the pigment epithelium does not fulfill its normal phagocytic role. The end result is visual cell death and blindness.

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522. Neural Retina Limits Delivery Non Viral Vectors to Retinal Pigment Epithelium

Molecular Therapy ◽

10.1016/j.ymthe.2006.08.593 ◽

2006 ◽

Vol 13 ◽

pp. S200-S201

Author(s):

Liesbeth Peeters ◽

Niek Sanders ◽

Koen Boussery ◽

Johan Van de Voorde ◽

Joseph Demeester ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Viral Vectors ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Neural Retina

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Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-313672 ◽

2019 ◽

Vol 104 (2) ◽

pp. 173-181 ◽

Cited By ~ 2

Author(s):

Marina Riera ◽

Víctor Abad-Morales ◽

Rafael Navarro ◽

Sheila Ruiz-Nogales ◽

Pilar Méndez-Vendrell ◽

...

Keyword(s):

Visual Acuity ◽

Retinitis Pigmentosa ◽

Pigment Epithelium ◽

Fundus Autofluorescence ◽

Retinal Pigment ◽

Retinal Dystrophy ◽

Macular Dystrophy ◽

Nucleotide Polymorphisms ◽

Autofluorescence Imaging ◽

New Genotype

PurposeThis study aimed to identify the underlying genetic cause(s) of inherited retinal dystrophy (IRD) in 12 families of Kuwaiti origin affected by macular dystrophy and four Spanish patients affected by retinitis pigmentosa (RP).MethodsClinical diagnoses were based on standard ophthalmic evaluations (best-corrected visual acuity, retinography, fundus autofluorescence imaging, optical coherence tomography, electroretinography and visual field tests). Panel-based whole exome sequencing was used to simultaneously analyse 224 IRD genes in one affected member of each family. The putative causative variants were confirmed by Sanger sequencing and cosegregation analyses. Haplotype analysis was performed using single nucleotide polymorphisms.ResultsA homozygous missense mutation c.606C>A (p.Asp202Glu) in RP1 was found to be the molecular cause of IRD in all 12 families from Kuwait. These patients exhibited comparable symptoms, including progressive decline in visual acuity since adolescence. Fundus autofluorescence images revealed bilateral macular retinal pigment epithelium disturbances, with neither perimacular flecks nor peripheral alterations. A shared haplotype spanning at least 1.1 Mb was identified in all families, suggesting a founder effect. Furthermore, RP1 variants involving nonsense and/or frameshifting mutations (three of them novel) were identified in three Spanish autosomal-recessive RP families and one dominant RP pedigree.ConclusionThis study describes, for the first time, a macular dystrophy phenotype caused by an RP1 mutation; establishing a new genotype-phenotype correlation in this gene, expanding its mutation spectrum and further highlighting the clinical heterogeneity associated with IRD.

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Unusual presentation of early-onset X-linked retinoschisis: Report after 1 year of multimodal follow-up

European Journal of Ophthalmology ◽

10.1177/1120672120916722 ◽

2020 ◽

pp. 112067212091672

Author(s):

Andrea Lembo ◽

Giacomo Maria Bacci ◽

Massimiliano Serafino ◽

Stefano Lucentini ◽

Roberto Caputo ◽

...

Keyword(s):

Retinal Detachment ◽

Early Onset ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Dystrophy ◽

Unusual Presentation ◽

Macular Dystrophy ◽

Wide Field ◽

The Right

Purpose: To describe the unusual presentation, diagnosis, and clinical course of an early-onset X-linked infantile retinoschisis Case report: A 6-month-old infant presented with strabismus and poor fixation. After the detection of bilateral intraretinal hemorrhage and diffuse dystrophic retinal pattern at indirect ophthalmoscopy, the patient received a complete evaluation under anesthesia. Retinal wide-field imaging, spectral domain optical coherence tomography, and electroretinogram were performed and revealed a retinoschisis involving the posterior pole and the inferior periphery in the right eye. In the left eye, an inferior retinal detachment extending to the macula was detected. Blood sample and genetic counseling were required in the strong suspicion of an inherited retinal dystrophy. Genetic tests confirmed the diagnosis of X-linked retinoschisis (RS1 gene mutation). After consultation with a pediatric vitreoretinal surgeon, a wait and see strategy was chosen. The follow up visits showed a surprisingly good natural course of the disease. Conclusion: X-linked retinoschisis is a well-known inherited retinal disease potentially affecting young children as early as 3 months old. In this case, the stunning presentation (diffuse retinal pigment epithelium dystrophic changes resembling a macular dystrophy) and the positive course of the disease (resolution of macular retinal detachment in the left eye and stability of schisis in the right eye) arise some interesting considerations about the necessity of an early surgical treatment.

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