X-linked Retinitis Pigmentosa Research Articles

A global survey of visual symptoms in female carriers of choroideremia and X-linked retinitis pigmentosa

PurposeTo investigate self-reported visual impairment in a large cohort of female carriers of X-linked retinal diseases around the world, using the validated Michigan Retinal Degeneration Questionnaire (MRDQ). DesignCross-sectional global survey study MethodsAn online survey collecting demographic and MRDQ data was distributed to self-reported female carriers of X-linked retinal diseases, and healthy controls (females with no eye disease). Respondents indicated their visual symptoms relating to everyday activities in seven visual domains: central vision, colour vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. Mann-Whitney test was used to compared visual disability scores between female carriers and healthy controls. ResultsTwo-hundred and thirty-seven female carriers of X-linked retinal diseases (74.3% choroideremia and 25.7% X-linked retinitis pigmentosa) and 100 age-matched healthy controls completed the questionnaire (median age: 51 vs. 47.5 years of age, respectively). Most female carriers resided in the USA (53.6%) and Australia (17.3%), whilst healthy controls were mostly from Australia (93%). Female carriers had significantly worse visual disability, compared to controls. Female carriers who were older than 50 years had significantly worse visual function impairment for all domains, except photosensitivity, when compared to carriers less than 50 years of age. ConclusionsThis study has shown that female carriers of choroideremia and X-linked RP report significantly worse visual symptoms, compared to healthy controls. Future studies are required to correlate MRDQ responses with clinical findings, to determine the degree of retinal changes required to impact female carriers’ quality of life.

AAV-RPGR Gene Therapy Rescues Opsin Mislocalisation in a Human Retinal Organoid Model of RPGR-Associated X-Linked Retinitis Pigmentosa.

Variants within the Retinitis Pigmentosa GTPase regulator (RPGR) gene are the predominant cause of X-Linked Retinitis Pigmentosa (XLRP), a common and severe form of inherited retinal disease. XLRP is characterised by the progressive degeneration and loss of photoreceptors, leading to visual loss and, ultimately, bilateral blindness. Unfortunately, there are no effective approved treatments for RPGR-associated XLRP. We sought to investigate the efficacy of RPGRORF15 gene supplementation using a clinically relevant construct in human RPGR-deficient retinal organoids (ROs). Isogenic RPGR knockout (KO)-induced pluripotent stem cells (IPSCs) were generated using established CRISPR/Cas9 gene editing methods targeting RPGR. RPGR-KO and isogenic wild-type IPSCs were differentiated into ROs and utilised to test the adeno associated virus (AAV) RPGR (AAV-RPGR) clinical vector construct. The transduction of RPGR-KO ROs using AAV-RPGR successfully restored RPGR mRNA and protein expression and localisation to the photoreceptor connecting cilium in rod and cone photoreceptors. Vector-derived RPGR demonstrated equivalent levels of glutamylation to WT ROs. In addition, treatment with AAV-RPGR restored rhodopsin localisation within RPGR-KO ROs, reducing mislocalisation to the photoreceptor outer nuclear layer. These data provide mechanistic insights into RPGRORF15 gene supplementation functional potency in human photoreceptor cells and support the previously reported Phase I/II trial positive results using this vector construct in patients with RPGR-associated XLRP, which is currently being tested in a Phase III clinical trial.

Assessment of Visual Function With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study

Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized, retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and safety of cotoretigene toliparvovec subretinal gene therapy. Part 2 of the XIRIUS trial (NCT03116113) was a Phase 2/3, 12-month, randomized (1:1:1), dose-expansion study. Males aged ≥10 years with RPGR-associated XLRP were included. Participants were randomized 1:1:1 to subretinal cotoretigene toliparvovec low dose (5 × 1010 vector genomes [vg]/eye), cotoretigene toliparvovec high dose (2.5 × 1011 vg/eye), or untreated control. The primary endpoint was the percentage of participants meeting microperimetry responder criteria (≥7 dB improvement at ≥5 of 16 central loci). Secondary endpoints included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months; and the proportion of eyes with a ≥15 and ≥10 LLVA ETDRS letter change from baseline at month 12. Because of the impact of COVID-19, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low dose n=10, high dose n=10, control n=9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between cotoretigene toliparvovec (low dose, 37.5%, P=0.3181; high dose, 25.0%, P=0.5177) and control (22.2%). Mean change from baseline in microperimetry sensitivity, however, significantly improved with the low dose versus control at month 12 (P=0.0350). Significant improvement in LLVA occurred with low dose versus control at month 12 (33.3% difference [80% CI, 14.7-55.2]; P=0.0498). Three ocular-related serious adverse events occurred in the low-dose group versus 7 in the high-dose group. The primary microperimetry endpoint was not met. Significant improvements in LLVA and mean microperimetry and fewer serious adverse events were observed with low-dose cotoretigene toliparvovec.

Identification of a novel RPGR mutation associated with retinitis pigmentosa and primary ciliary dyskinesia in a Slovak family: a case report

BackgroundThe mutations in the RPGR (retinitis pigmentosa GTPase regulator) gene are the most common cause of X-linked retinitis pigmentosa (XLRP), a rare genetic disorder affecting the photoreceptor cells in the retina. Several reported cases identified this gene as a genetic link between retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), characterised by impaired ciliary function predominantly in the respiratory tract. Since different mutations in the same gene can result in various clinical manifestations, it is important to describe a correlation between the gene variant and the observed phenotype.MethodsTwo young brothers from a non-consanguineous Slovak family with diagnosed retinal dystrophy and recurrent respiratory infections were examined. Suspected PCD was diagnosed based on a PICADAR questionnaire, nasal nitric oxide analysis, transmission electron microscopy, high-speed video microscopy analysis, and genetic testing.ResultsWe identified a novel frameshift RPGR mutation NM_001034853: c.309_310insA, p.Glu104Argfs*12, resulting in a complex X-linked phenotype combining PCD and RP. In our patients, this mutation was associated with normal ultrastructure of respiratory cilia, reduced ciliary epithelium, more aciliary respiratory epithelium, shorter cilia, and uncoordinated beating with a frequency at a lower limit of normal beating, explaining the clinical manifestation of PCD in our patients.ConclusionThe identified novel pathogenic mutation in the RPGR gene expands the spectrum of genetic variants associated with the X-linked PCD phenotype overlapping with RP, highlighting the diversity of mutations contributing to the disorder. The described genotype–phenotype correlation can be useful in clinical practice to recognise a broader spectrum of PCD phenotypes as well as for future research focused on the genetic basis of PCD, gene interactions, the pathways implicated in PCD pathogenesis, and the role of RPGR protein for the proper functioning of cilia in various tissues throughout the body.

HSD42 The Humanistic Impact of X-Linked Retinitis Pigmentosa (XLRP): Results from the Explore Xlrp-2 Retrospective Chart Review and Cross-Sectional Survey of Patients and Caregivers in 10 Countries

HSD42 The Humanistic Impact of X-Linked Retinitis Pigmentosa (XLRP): Results from the Explore Xlrp-2 Retrospective Chart Review and Cross-Sectional Survey of Patients and Caregivers in 10 Countries

HSD119 Patient Pathways, Genetic Testing, and Diagnosis of X-Linked Retinitis Pigmentosa in Europe: Insights from the Cross-Sectional Explore Xlrp-1.2 Physician Survey

HSD119 Patient Pathways, Genetic Testing, and Diagnosis of X-Linked Retinitis Pigmentosa in Europe: Insights from the Cross-Sectional Explore Xlrp-1.2 Physician Survey

HSD14 X-Linked Retinitis Pigmentosa Impacts Patients’ Independence, Work Status, and Quality of Life: Insights from the Cross-Sectional Explore Xlrp-1.2 Physician Survey

HSD14 X-Linked Retinitis Pigmentosa Impacts Patients’ Independence, Work Status, and Quality of Life: Insights from the Cross-Sectional Explore Xlrp-1.2 Physician Survey

Deep Learning-Facilitated Study of the Rate of Change in Photoreceptor Outer Segment Metrics in RPGR-Related X-Linked Retinitis Pigmentosa.

The aim of this retrospective cohort study was to obtain three-dimensional (3D) photoreceptor outer segment (OS) metrics measurements with the assistance of a deep learning model (DLM) and to evaluate the longitudinal change in OS metrics and associated factors in retinitis pigmentosa GTPase regulator (RPGR) X-linked retinitis pigmentosa (XLRP). The study included 34 male patients with RPGR-associated XLRP who had preserved ellipsoid zone (EZ) within their spectral-domain optical coherence tomography volume scans and an approximate 2-year or longer follow-up. Volume scans were segmented using a DLM with manual correction for EZ and apical retinal pigment epithelium (RPE). OS metrics were measured from 3D EZ-RPE layers of volume scans. Linear mixed-effects models were used to calculate the rate of change in OS metrics and the associated factors, including baseline age, baseline OS metrics, and follow-up duration. The mean (standard deviation) of progression rates were -0.28 (0.43) µm/y, -0.73 (0.61) mm2/y, and -0.014 (0.012) mm3/y for OS thickness, EZ area, and OS volume, respectively. In multivariable analysis, the progression rates of EZ area and OS volume were strongly associated with their baseline values, with faster decline in eyes with larger baseline values (P ≤ 0.003), and nonlinearly associated with the baseline age (P ≤ 0.003). OS thickness decline was not associated with its baseline value (P = 0.32). These results provide evidence to support using OS metrics as biomarkers to assess the progression of XLRP and as the outcome measures of clinical trials. Given that their progression rates are dependent on their baseline values, the baseline EZ area and OS volume should be considered in the design and statistical analysis of future clinical trials. Deep learning may provide a useful tool to reduce the burden of human graders to analyze OCT scan images and to facilitate the assessment of disease progression and treatment trials for retinitis pigmentosa.

A novel pathogenic splicing mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa verified by minigene splicing assay.

To report a novel splicing mutation in the RPGR gene (encoding retinitis pigmentosa GTPase regulator) in a three-generation Chinese family with X-linked retinitis pigmentosa (XLRP). Comprehensive ophthalmic examinations including best corrected visual acuity, fundus photography, vision field, and pattern-visual evoked potential were performed to identify the disease phenotype of a six-year-old boy from the family (proband). Genomic DNA was extracted from peripheral blood of five available members of the pedigree. Whole-exome sequencing (WES), Sanger sequencing, and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR. Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants. The proband was diagnosed as having retinitis pigmentosa (RP). He had severe symptoms with early onset. A novel splicing mutation, c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing. Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped, leading to the subsequent deletion of 623 correct amino acids (c.529_619del p.Val177Glnfs*16). We identify a novel splice donor site mutation causing aberrant splicing of RPGR. Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.

Female carriers of X-linked inherited retinal diseases - Genetics, diagnosis, and potential therapies.

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions that cause progressive vision loss, typically due to monogenic mutations. Female carriers of X-linked IRDs have a single copy of the disease-causing gene, and therefore, may exhibit variable clinical signs that vary from near normal retina to severe disease and vision loss. The relationships between individual genetic mutations and disease severity in X-linked carriers requires further study. This review summarises the current literature surrounding the spectrum of disease seen in female carriers of choroideremia and X-linked retinitis pigmentosa. Various classification systems are contrasted to accurately grade retinal disease. Furthermore, genetic mechanisms at the early embryonic stage are explored to potentially explain the variability of disease seen in female carriers. Future research in this area will provide insight into the association between genotype and retinal phenotypes of female carriers, which will guide in the management of these patients. This review acknowledges the importance of identifying which patients may be at high risk of developing severe symptoms, and therefore should be considered for emerging treatments, such as retinal gene therapy.

A novel quantitative targeted analysis of X-chromosome inactivation (XCI) using nanopore sequencing

X-chromosome inactivation (XCI) analyses often assist in diagnostics of X-linked traits, however accurate assessment remains challenging with current methods. We developed a novel strategy using amplification-free Cas9 enrichment and Oxford nanopore technologies sequencing called XCI-ONT, to investigate and rigorously quantify XCI in human androgen receptor gene (AR) and human X-linked retinitis pigmentosa 2 gene (RP2). XCI-ONT measures methylation over 116 CpGs in AR and 58 CpGs in RP2, and separate parental X-chromosomes without PCR bias. We show the usefulness of the XCI-ONT strategy over the PCR-based golden standard XCI technique that only investigates one or two CpGs per gene. The results highlight the limitations of using the golden standard technique when the XCI pattern is partially skewed and the advantages of XCI-ONT to rigorously quantify XCI. This study provides a universal XCI-method on DNA, which is highly valuable in clinical and research framework of X-linked traits.

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials.

To explore which microperimetry sensitivity index (pointwise sensitivity, mean sensitivity, and volume sensitivity) is suitable as a microperimetry outcome measure in patients with X-linked RPGR-associated retinitis pigmentosa (RP). Microperimetry data from patients with RPGR-associated RP were collected and analyzed retrospectively. Fourteen participants completed triplicate microperimetry testing, across 2 consecutive days for the repeatability analyses. Longitudinal data was obtained from 13 participants who completed microperimetry testing at two separate visits. The test-retest coefficients of repeatability (CoR) for pointwise sensitivity were ±9.5 dB and ±9.3 dB, in the right and left eyes, respectively. The mean sensitivity CoR for the right and left eyes was ±0.7 dB and ±1.3 dB. Volume sensitivity CoR was ±144.5dB*deg2 and ±324.2 dB*deg2 for the right and left eyes, respectively. The mean sensitivities were positively skewed toward zero in those with a high number of nonseeing points (arbitrarily assigned to -1.0 dB) and just seen points (0.0 dB). Volume sensitivities were unaffected by the averaging effects of skewed data. Clinical trials should report population-specific test-retest variability to determine a clinically significant change. Pointwise sensitivity indices should be used with caution as outcome measures in clinical trials owing to high levels of test-retest variability. Global indices seem to be less prone to variability. Volume sensitivity indices seem to be superior for use in RPGR-associated RP clinical trials compared with mean sensitivity because they are unaffected by the averaging effects of highly skewed data. Careful selection of sensitivity indices (VA) is required when using microperimetry as a clinical trial outcome measure.

Long-Read Nanopore Sequencing of RPGR ORF15 is Enhanced Following DNase I Treatment of MinION Flow Cells.

RPGR ORF15 is an exon present almost exclusively in the retinal transcript of RPGR. It is purine-rich, repetitive and notoriously hard to sequence, but is a hotspot for mutations causing X-linked retinitis pigmentosa. Long-read nanopore sequencing on MinION and Flongle flow cells was used to sequence RPGR ORF15 in genomic DNA from patients with inherited retinal dystrophy. A flow cell wash kit was used on a MinION flow cell to increase yield. Findings were confirmed by PacBio SMRT long-read sequencing. We showed that long-read nanopore sequencing successfully reads through a 2 kb PCR-amplified fragment containing ORF15. We generated reads of sufficient quality and cumulative read-depth to detect pathogenic RP-causing variants. However, we observed that this G-rich, repetitive DNA segment rapidly blocks the available pores, resulting in sequence yields less than 5% of the expected output. This limited the extent to which samples could be pooled, increasing cost. We tested the utility of a MinION wash kit containing DNase I to digest DNA fragments remaining on the flow cell, regenerating the pores. Use of the DNase I treatment allowed repeated re-loading, increasing the sequence reads obtained. Our customised workflow was used to screen pooled amplification products from previously unsolved inherited retinal disease (IRD) in patients, identifying two new cases with pathogenic ORF15 variants. We report the novel finding that long-read nanopore sequencing can read through RPGR-ORF15, a DNA sequence not captured by short-read next-generation sequencing (NGS), but with a more reduced yield. Use of a flow cell wash kit containing DNase I unblocks the pores, allowing reloading of further library aliquots over a 72-h period, increasing yield. The workflow we describe provides a novel solution to the need for a rapid, robust, scalable, cost-effective ORF15 screening protocol.

Retinal degeneration in rpgra mutant zebrafish.

Introduction: Pathogenic mutations in RPGR ORF15, one of two major human RPGR isoforms, were responsible for most X-linked retinitis pigmentosa cases. Previous studies have shown that RPGR plays a critical role in ciliary protein transport. However, the precise mechanisms of disease triggered by RPGR ORF15 mutations have yet to be clearly defined. There are two homologous genes in zebrafish, rpgra and rpgrb. Zebrafish rpgra has a single transcript homologous to human RPGR ORF15; rpgrb has two major transcripts: rpgrb ex1-17 and rpgrb ORF15, similar to human RPGR ex1-19 and RPGR ORF15, respectively. rpgrb knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. However, the impact of knocking down rpgra in zebrafish remains undetermined. Here, we constructed a rpgra mutant zebrafish model to investigate the retina defect and related molecular mechanism. Methods: we utilized transcription activator-like effector nuclease (TALEN) to generate a rpgra mutant zebrafish. Western blot was used to determine protein expression. RT-PCR was used to quantify gene transcription levels. The visual function of embryonic zebrafish was detected by electroretinography. Immunohistochemistry was used to observe the pathological changes in the retina of mutant zebrafish and transmission electron microscope was employed to view subcellular structure of photoreceptor cells. Results: A homozygous rpgra mutant zebrafish with c.1675_1678delins21 mutation was successfully constructed. Despite the normal morphological development of the retina at 5 days post-fertilization, visual dysfunction was observed in the mutant zebrafish. Further histological and immunofluorescence assays indicated that rpgra mutant zebrafish retina photoreceptors progressively began to degenerate at 3-6 months. Additionally, the mislocalization of cone outer segment proteins (Opn1lw and Gnb3) and the accumulation of vacuole-like structures around the connecting cilium below the OSs were observed in mutant zebrafish. Furthermore, Rab8a, a key regulator of opsin-carrier vesicle trafficking, exhibited decreased expression and evident mislocalization in mutant zebrafish. Discussion: This study generated a novel rpgra mutant zebrafish model, which showed retinal degeneration. our data suggested Rpgra is necessary for the ciliary transport of cone-associated proteins, and further investigation is required to determine its function in rods. The rpgra mutant zebrafish constructed in this study may help us gain a better understanding of the molecular mechanism of retinal degeneration caused by RPGR ORF15 mutation and find some useful treatment in the future.

Asymmetric presentation with a novel RP2 gene mutation in X-Linked retinitis pigmentosa: a case report

BackgroundWe present the detailed multimodal imaging analysis in a case of X-linked retinitis pigmentosa (XLRP) exhibiting a markedly asymmetric presentation with a novel RP2 mutation.Case presentationA 25-year-old woman complained of decreased vision in the right eye as well as night blindness. Her visual acuity was 20/100 (OD) and 20/20 (OS). Fundus examination revealed bone spicule pigmentation with tessellated changes in the fundus within the posterior pole. Optical coherence tomography (OCT) showed generalized disruption of foveal microstructures in the OD. No abnormal findings were identified, but localized ellipsoid zone band losses were observed on OCT in the OS. Fundus autofluorescence revealed multiple patchy hypo-autofluorescent lesions in the OD and a tapetal-like radial reflex against a dark background in the OS. Fluorescein angiography and OCT angiography revealed diffuse mottled hyperfluorescence with reduced retinal vessel density in the OD and no evidence of vascular compromise in the OS. Goldmann perimetry demonstrated a constricted visual field, and electrophysiological assessment revealed an extinguished rod response and a severely impaired cone response in the OD. Molecular genetic tests via next-generation sequencing revealed the pathogenic variant to be a heterozygous frameshift mutation in RP2 (RP2, p.Glu269Glyfs*7), resulting in premature termination of the protein.ConclusionsRandom X-inactivation may be attributed to interocular differences in the severity of XLRP in female carriers. A novel frameshift mutation in the RP2 gene and a comprehensive phenotypic evaluation in the current study may broaden the spectrum of the disease in XLRP carriers.

Nrl:CreERT2 mouse model to induce mosaic gene expression in rod photoreceptors.

Photoreceptors are sensory neurons that capture light within their outer segment, a narrow cylindrical organelle stacked with disc-shaped membranes housing the visual pigment. Photoreceptors are the most abundant neurons in the retina and are tightly packed to maximize the capture of incoming light. As a result, it is challenging to visualize an individual cell within a crowded photoreceptor population. To address this limitation, we developed a rod-specific mouse model that expresses tamoxifen-inducible cre recombinase under the control of the Nrl promoter. We characterized this mouse using a farnyslated GFP (GFPf) reporter mouse and found mosaic rod expression throughout the retina. The number of GFPf-expressing rods stabilized within 3 days post tamoxifen injection. At that time, the GFPf reporter began to accumulate in basal disc membranes. Using this new reporter mouse, we attempted to quantify the time course of photoreceptor disc renewal in WT and Rd9 mice, a model of X-linked retinitis pigmentosa previously proposed to have a reduced disc renewal rate. We measured GFPf accumulation in individual outer segments at 3 and 6 days post-induction and found that basal accumulation of the GFPf reporter was unchanged between WT and Rd9 mice. However, rates of renewal based on the GFPf measurements were inconsistent with historical calculations from radiolabeled pulse-chase experiments. By extending GFPf reporter accumulation to 10 and 13 days we found that this reporter had an unexpected distribution pattern that preferentially labeled the basal region of the outer segment. For these reasons the GFPf reporter cannot be used for measuring rates of disc renewal. Therefore, we used an alternative method that labels newly forming discs with a fluorescent dye to measure disc renewal rates directly in the Rd9 model and found it was not significantly different from WT. Our study finds that the Rd9 mouse has normal rates of disc renewal and introduces a novel Nrl:CreERT2 mouse for gene manipulation of individual rods.

Functional Analysis of a Novel, Non-Canonical RPGR Splice Variant Causing X-Linked Retinitis Pigmentosa.

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is one of the most severe forms of RP due to its early onset and intractable progression. Most cases have been associated with genetic variants within the purine-rich exon ORF15 region of this gene. RPGR retinal gene therapy is currently being investigated in several clinical trials. Therefore, it is crucial to report and functionally characterize (all novel) potentially pathogenic DNA sequence variants. Whole-exome sequencing (WES) was performed for the index patient. The splicing effects of a non-canonical splice variant were tested on cDNA from whole blood and a minigene assay. WES revealed a rare, non-canonical splice site variant predicted to disrupt the wildtype splice acceptor and create a novel acceptor site 8 nucleotides upstream of RPGR exon 12. Reverse-transcription PCR analyses confirmed the disruption of the correct splicing pattern, leading to the insertion of eight additional nucleotides in the variant transcript. Transcript analyses with minigene assays and cDNA from peripheral blood are useful tools for the characterization of splicing defects due to variants in the RPGR and may increase the diagnostic yield in RP. The functional analysis of non-canonical splice variants is required to classify those variants as pathogenic according to the ACMG's criteria.

Management of a unique case of Coats'-like X-linked retinitis pigmentosa associated with a RPGR variant in the era of anti-VEGF.

To describe a unique case of X-linked Coats-like Retinitis Pigmentosa (CLRP), a form of exudative Retinitis Pigmentosa, in association with a RPGR variant, and its management with intravitreal anti-Vascular Endothelium Growth Factor drugs (anti-VEGFs), along with a peculiar OCT finding observed in a late stage of disease. Case report. A 33-year-old man previously treated with anti-VEGFs for macular edema came to our clinic for bilateral visual loss. A hemizygous RPGR variant (c.2442_2445del) was found and a diagnosis of CLRP was made. He was initially treated with carbonic anhydrase inhibitors; when efficacy wore off, he was switched to anti-VEGF injections in both eyes with improvement. After a year without treatment, visual acuity drastically worsened in both eyes; optical coherence tomography displayed disruption and increased hyperreflectivity of the inner retinal layers in the right eye. The c.2442_2445del variant is added to the number of known ORF 15 RPGR mutations associated with CLRP. Anti-VEGF treatment was successful in blocking visual loss in our patient and withholding treatment had a negative impact on his visual outcome.

Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations

X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss. To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study. This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021. Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months. A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred. Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials. ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Thicknesses of the retina and choroid in children with retinitis pigmentosa

PurposeTo compare the retinal thicknesses (RT) and choroidal thicknesses (CT) in retinitis pigmentosa (RP) children with those of healthy children using enhanced depth imaging (EDI) optical coherence tomography (OCT). The RT and CT in different genetic subgroups of autosomal dominant RP (ADRP) and X-linked inheritance RP (XLRP) were further studied to investigate the characteristics of retinal and choroidal changes in the early stages of RP.MethodA retrospective analysis was performed on a group of patients with RP who underwent EDI-OCT. Thirty-two children (64 eyes) with RP and 28 age- and refraction-matched healthy children (56 eyes) were included in the study. Seven of the 32 RP children (14 eyes) had X-linked inheritance RP, and 10 (20 eyes) had autosomal dominant inheritance RP. RT and CT were measured by optical coherence tomography and compared between the 32 children with RP and 28 controls and between 7 XLRP and 10 ADRP children.ResultAmong the 32 children with RP, there were 18 males and 14 females with an average age of 6.6 ± 2.4 years. The mean RT was smaller in the RP group than in the control group at all of the locations. The mean temporal CT was smaller in the RP group (243.76 ± 60.82 μm) than in the control group (275.23 ± 40.92 μm) (P = 0.001), while there was no significant thinning on the foveal or nasal side.The best-corrected visual acuity of the XLRP group (0.40 ± 0.19) was worse than that of the ADRP group (0.68 ± 0.21) (P = 0.001), but the disease duration was the same (P = 0.685). The mean foveal RT was smaller in the XLRP group (173.85 ± 22.87 μm) than in the ADRP group (192.20 ± 9.70 μm) (P = 0.003), while there was no significant thinning at the other locations we studied. The mean temporal CT was smaller in the XLRP group (211.21 ± 69.41 μm) than in the ADRP group (274.45 ± 57.91 μm) (P = 0.007); CT measurements in XLRP children showed a more severe reduction on the temporal side.ConclusionThe choroid in RP children was preferentially smaller on the temporal side of the macula, and retinal thinning was relatively extensive. Children with RP have strong clinical and genetic heterogeneity. The XLRP children demonstrated greater RT reduction at the fovea and greater CT reduction at the temporal side of the macula than the ADRP children. Our findings also provide evidence that the changes in thicknesses may be indicative of the greater severity of XLRP versus ADRP in the early stage.