Training in Cortically Blinded Fields Appears to Confer Patient-Specific Benefit Against Retinal Thinning.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Associations Between Self-Reported Visual and Hearing Functioning and Cognitive Function Among Hispanics/Latino: Hispanic Community Health Study.

Background and Objectives: To investigate the associations between self-reported visual functioning (VF) and hearing functioning with cognition in the Hispanic/Latino population. Research Design and Methods: We utilized data from the Miami Ocular Study of Latinos ancillary study to Hispanic Community Health Study/Study of Latinos with 1,056 participants aged 45 and older. The outcomes were cognitive performances assessed by the Digit Symbol Substitution Test (DSST), Word Fluency, Brief-Spanish English Verbal Learning Test-recall (B-SEVLT recall), words recalled over 3 trials, and the Six-Item Screener. VF was measured by National Eye Institute Visual Function Questionnaire (NEI-VFQ), and hearing function was measured by Hearing Handicap Inventory Screening Questionnaire for Adults and Elderly (HHIA/E-S). Multiple regressions were performed for each cognitive outcome while controlling for covariates and complex sampling design. Results: NEI-VFQ was associated with 3 of the 5 cognitive outcomes. A 4-point NEI-VFQ score difference was associated with a 0.56-point difference in DSST (standard error [SE] = 0.27, p < .001), 0.17 in Word fluency (SE = 0.16, p < .01), and 0.08 in B-SEVLT-recall (SE = 0.07, p < .01). HHIA/E-S was not associated with any of the cognitive measures examined. Discussion and Implications: These data suggest that impaired VF is associated with worse cognition in the Hispanic/Latino population. Although previous work in this cohort indicated hearing loss assessed by pure tone audiometry was associated with worse cognition, we found self-perceived hearing function was not associated with cognition, suggesting the potential limitation of self-reported hearing function as a proxy for hearing loss in epidemiological research in Hispanic/Latino populations. Results also imply impaired VF and hearing function may be linked to cognition differently in the Hispanic population, and more research is needed to better understand the underlying linking mechanisms. Visual and hearing impairments are common and treatable and represent important modifiable risk factors that can be treated to preserve cognitive function in Hispanics/Latinos.

A Prospective, Observational, Noninterventional Clinical Study of Participants With Choroideremia: The NIGHT Study.

PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.

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

PURPOSE: 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. DESIGN: Part 2 of the XIRIUS trial (NCT03116113) was a Phase 2/3, 12-month, randomized (1:1:1), dose-expansion study. PARTICIPANTS: Males aged ≥10 years with RPGR-associated XLRP were included. METHODS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

A SYSTEMATIC LITERATURE REVIEW OF DISEASE PROGRESSION REPORTED IN RPGR -ASSOCIATED X-LINKED RETINITIS PIGMENTOSA.

PURPOSE: Retinitis pigmentosa GTPase regulator-associated X-linked retinitis pigmentosa ( RPGR -associated XLRP) is a rare and severe form of retinitis pigmentosa, resulting in progressive visual impairment; however, disease progression data are limited. A systematic literature review was conducted to assess available data on disease progression in RPGR -associated XLRP. METHODS: PubMed, Embase, and select congress abstracts were evaluated through June 2022. Eligible studies included results specific to RPGR -associated XLRP or populations with ≥80% of patients with retinitis pigmentosa carrying disease-causing RPGR variants. End points of interest included visual acuity, visual field, ellipsoid zone width, progression to blindness, and patient-reported outcomes. RESULTS: Fourteen studies met ≥1 end point of interest. Progressive declines in visual acuity, visual field, and ellipsoid zone width were reported across studies. Nearly all publications reported annual declines in visual acuity (3.5%-8.2%). Annual visual field declines ranged from 4.2% to 13.3%. Changes in retinal structure were also observed (ellipsoid zone width changes: -177 to -830 µ m/year). Most studies measured blindness using visual acuity; visual field-based definitions resulted in blindness by age ∼25 years. Patient-reported outcome data were limited. CONCLUSION: Published evidence shows that patients with RPGR -associated XLRP experience progressive decline in visual acuity, visual field, and ellipsoid zone width, eventually resulting in blindness. Additional longitudinal data with standardized end points and expanded collection of patient-reported outcomes are needed to assess visual decline in RPGR -associated XLRP.

Leber hereditary optic neuropathy gene therapy.

PURPOSE OF REVIEW: To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON). RECENT FINDINGS: Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally. SUMMARY: Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops.

Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures.

PURPOSE: To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). DESIGN: Phase 1 clinical trial. METHODS: This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range = 18-36 months). RESULTS: Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P = .023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial.

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .

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.

Current Assistive Devices Usage and Recommendations for a Future Artificial Vision Prosthesis among Patients with Severe Visual Impairment Due to Inherited Retinal Diseases.

Patients with inherited retinal diseases (IRDs) utilize various adaptive techniques and devices designed to assist them with activities of daily living (ADLs). The purpose of this study was to assess the assistive devices used by patients with IRDs, the difficulties they face despite these devices, and their recommendations for a future visual prosthesis. In collaboration with blind patients, an online survey was developed and administered to adults with IRDs and visual acuities of 20/400 to no light perception in the better-seeing eye. We analyzed data from 121 survey respondents (aged 18 to >80 years). Five respondents were Argus II prosthesis recipients. The most commonly used aids were cellular phones/tablets for reading (63.6%) as well as a sighted guide (75.0%) and a cane (71.4%) for mobility. Despite current assistive devices, participants reported continued difficulty with ADLs. Improved navigation, reading, and facial recognition were ranked the most desirable features for future visual prostheses. Argus II recipients suggested technology with improved ability to recognize objects and obstacles, detect movement, and cut out busy backgrounds. These insights are valuable in shaping the design of future prosthetic devices tailored to the needs of IRD patients.

Bilateral exudative retinal detachments after subretinal gene therapy with voretigene neparvovec-rzyl for RPE65 Leber Congenital Amaurosis.

Purpose: To report panuveitis with exudative retinal detachments in a healthy 27-year-old woman with biallelic mutations in the RPE65 gene, who underwent bilateral sequential gene therapy with subretinal administration of voretigene neparvovec-rzyl. Observations: Visual acuity improved for 30 days after surgery as oral corticosteroids were tapered. At postoperative week 6, vision declined due to sudden onset uveitis and exudative retinal detachments in both eyes. HLA Class II typing revealed the haplotype associated with sympathetic ophthalmia and Vogt-Koyanagi-Harada (VKH). The inflammation improved after corticosteroid, mycophenolate mofetil, and adalimumab therapy while vision remained poor. Conclusions and Importance: Surgically-induced sympathetic ophthalmia is a plausible explanation for the clinical findings; surgery of both eyes within one week would conceal the inciting eye. VKH or inflammation related to the gene therapy are other possible etiologies but severe bilateral panuveitis has not been reported with voretigene neparvovec-rzyl. Informed consent for gene therapy surgery should include a discussion of the rare complication of sympathetic ophthalmia following vitrectomy surgery.

Thrombosed orbital varix of the inferior ophthalmic vein: A rare cause of acute unilateral proptosis.

Background: Orbital varices are rare, accounting for only 0-1.3% of orbital masses. They can be found incidentally or cause mild to serious sequelae, including hemorrhage and optic nerve compression. Case Description: We report a case of a 74-year-old male with progressively painful unilateral proptosis. Imaging revealed the presence of an orbital mass compatible with a thrombosed orbital varix of the inferior ophthalmic vein in the left inferior intraconal space. The patient was medically managed. On a follow-up outpatient clinic visit, he demonstrated remarkable clinical recovery and denied experiencing any symptoms. Follow-up computed tomography scan showed a stable mass with decreased proptosis in the left orbit consistent with the previously diagnosed orbital varix. One-year follow-up orbital magnetic resonance imaging without contrast showed slight increase in the intraconal mass. Conclusion: An orbital varix may present with mild to severe symptoms and management, depending on case severity, ranges from medical treatment to escalated surgical innervation. Our case is one of few progressive unilateral proptosis caused by a thrombosed varix of the inferior ophthalmic vein described in the literature. We encourage further investigation into the causes and epidemiology of orbital varices.

Sirolimus Induced Toxic Optic Neuropathy.

Objective: To describe a case of optic neuropathy after prolonged sirolimus therapy in the setting of cardiac transplant. Background: Sirolimus is an immunosuppressant that inhibits Mechanistic Target of Rapamycin (mTOR) and blocks T-cell activation and B-cell differentiation by preventing response to Interleukin-2 (IL-2). Tacrolimus is another immunosuppressive agent, one of the known but uncommon side effects of which is bilateral optic neuropathy years after taking the medication. To the best of our knowledge, this is the first report of sequential optic neuropathy after years of treatment with sirolimus. Case Presentation: A 69-year-old male with a history of cardiac transplantation presented with progressive, sequential, and painless vision loss. Visual acuity was 20/150 OD and 20/80 OS, with impaired color vision in both eyes (Ishihara 0/10) and bilateral disc pallor and mild optic disc edema in the left eye. Visual field was constricted in both eyes. The patient was on prolonged sirolimus therapy for over 7 years. Orbital MRI revealed bilateral chiasmatic thickness and FLAIR hyperintensity, without optic nerve enhancement post gadolinium. After extensive work up, other etiologies such as infectious, inflammatory, and neoplastic lesions were ruled out. Subsequently, sirolimus was substituted with cyclosporin that led to gradual improvement of vision and visual fields bilaterally. Conclusion: Optic neuropathy is a rare side effect of tacrolimus, which has been seen as sudden, painless, and bilateral vision loss in post-transplant patients. Other concurrent medications influencing the cytochrome P4503A enzyme complexes may alter the pharmacokinetics of tacrolimus and increase the likelihood of toxicity. Discontinuation of offending agent has been shown to improve visual defects. We presented a rare case of optic neuropathy in a patient on sirolimus, whose visual defects improved upon discontinuation of sirolimus and switching to cyclosporin.

Phase I NT-501 Ciliary Neurotrophic Factor Implant Trial for Primary Open-Angle Glaucoma: Safety, Neuroprotection, and Neuroenhancement.

Purpose: To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma. Design: Open-label, prospective, phase I clinical trial. Participants: A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye. Methods: The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics. Main Outcome Measures: Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome. Results: All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA, -5.82 vs. -0.82 letters; and contrast sensitivity, -1.82 vs. -0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (-13.0%, -3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 µm vs. 10.16 µm; and GDx VCC, 1.58 µm vs. 8.36 µm in fellow vs. study eyes, respectively). Conclusions: The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

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

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Training in cortically-blind fields confers patient-specific benefit against retinal thinning after occipital stroke.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of trans-synaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness, and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography (OCT) data in 48 participants with unilateral V1 stroke and homonymous visual defects, who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layers (GCL-IPL), and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ~6 months of daily motion discrimination training in the intact- or blind-field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pre-training, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact-field exhibited increased LIGCL-IPL. Those trained in their blind-field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training, but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

RNA-based therapies in inherited retinal diseases.

Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY DETECTION OF BRUCH MEMBRANE AND CHORIOCAPILLARIS ABNORMALITIES IN SORSBY MACULAR DYSTROPHY.

PURPOSE: Swept-source optical coherence tomography angiography (SS-OCTA) was used to analyze Bruch membrane (BM) and choriocapillaris (CC) abnormalities in undiagnosed family members with Sorsby macular dystrophy (SMD). METHODS: In a family with SMD ( TIMP3 Tyr191Cys), SS-OCTA imaging was performed using the 6 × 6 mm scan patter and previously validated algorithms to detect abnormalities in BM and the CC, as well as the presence of reticular pseudodrusen and macular neovascularization. Genetic analyses were performed for TIMP3 mutations. RESULTS: Of eight family members, two were previously diagnosed with SMD and six were asymptomatic. SS-OCTA imaging of the 33-year-old proband revealed type 1 macular neovascularization in the left eye and bilateral reticular pseudodrusen, thickening of BM, CC thinning, and increases in CC flow deficits. A TIMP3 mutation was confirmed. His niece, despite having no clinical evidence of SMD, showed BM thickening and CC thinning on SS-OCTA. A TIMP3 mutation was confirmed. The proband's younger nephew and niece also carried the TIMP3 mutation without clinical evidence of SMD. Two additional members had normal examinations, unremarkable SS-OCTA findings, and no TIMP3 mutation. CONCLUSION: Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD.