Is RPGR-related retinal dystrophy associated with systemic disease? A case series.

BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.

RNA gene editing in the eye and beyond: The neglected tool of the gene editing armatorium?

RNA editing allows correction of pathological point mutations without permanently altering genomic DNA. Theoretically targetable to any RNA type and site, its flexibility and reversibility makes it a potentially powerful gene editing tool. RNA editing offers a host of potential advantages in specific niches when compared to currently available alternative gene manipulation techniques. Unlike DNA editors, which are currently too large to be delivered in vivo using a viral vector, smaller RNA editors fit easily within the capabilities of an adeno-associated virus (AAV). Unlike gene augmentation, which is limited by gene size and viral packaging constraints, RNA editing may correct transcripts too long to fit within a viral vector. In this article we examine the development of RNA editing and discuss potential applications and pitfalls. We argue that, although in its infancy, an RNA editing approach can offer unique advantages for selected retinal diseases.

Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?

INTRODUCTION: Choroideremia is an X-linked inherited retinal degeneration resulting from mutations in the CHM gene, encoding Rab escort protein-1 (REP1), a protein regulating intracellular vesicular transport. Loss-of-function mutations in CHM lead to progressive loss of retinal pigment epithelium (RPE) with photoreceptor and choriocapillaris degeneration, leading to progressive visual field constriction and loss of visual acuity. Three hundred and fifty-four unique mutations have been reported in CHM. While gene augmentation remains an ideal therapeutic option for choroideremia, other potential future clinical strategies may exist. AREAS COVERED: The authors examine the pathophysiology and genetic basis of choroideremia. They summarize the status of ongoing gene therapy trials and discuss CHM mutations amenable to other therapeutic approaches including CRISPR/Cas-based DNA and RNA editing, nonsense suppression of premature termination codons, and antisense oligonucleotides for splice modification. The authors undertook a literature search in PubMed and NIH Clinical Trials in October 2020. EXPERT OPINION: The authors conclude that AAV-mediated gene augmentation remains the most effective approach for choroideremia. Given the heterogeneity of CHM mutations and potential risks and benefits, genome-editing approaches currently do not offer significant advantages. Nonsense suppression strategies and antisense oligonucleotides are exciting novel therapeutic options; however, their clinical viability remains to be determined.

Optimisation of dark adaptation time required for mesopic microperimetry.

BACKGROUND: Macular Integrity Assessment (MAIA) microperimetry is increasingly used in clinical and research settings to assess point retinal sensitivity and fixation stability. Testing occurs under mesopic conditions, commonly after a period of dark adaptation. Our aim was to identify the minimum length of adaptation required to optimise microperimetry performance. METHODS: MAIA microperimetry using the 10-2 grid was performed on 40 right eyes of 40 healthy participants aged 18-73 with no ocular pathology and vision of at least 0.1 logMAR after ambient light exposure, with 0, 5, 10, 15, 20 and 30 min of adaptation in mesopic settings. Ten right eyes of 10 participants with choroideremia were also tested following 0 and 20 min of adaptation. We further tested 10 right eyes of 10 healthy participants after bright light exposure, with 0, 10 and 20 min of adaptation. We compared changes in threshold sensitivity and fixation stability across time points. RESULTS: Microperimetry performance did not improve with increasing adaptation time in healthy participants or patients with choroideremia after ambient light exposure. After bright light exposure, we found microperimetry thresholds improved after 10 min of adaptation, but did not improve further at 20 min. CONCLUSION: Mesopic adaptation is not required before MAIA microperimetry after exposure to ambient light. Ten minutes of adaptation is sufficient after exposure to a bright light stimulus, such as ophthalmoscopy or retinal imaging. The brief time of dark adaptation required corresponds to cone adaptation curves and provides further evidence for cone-mediated central retinal function under mesopic conditions.