To report on the safety of the first five cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt Dystrophy (SD) due to mutations in ABCA4. Nonrandomized multicenter phase I/IIa clinical trial. Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at three dose levels and were followed for three years after treatment. The primary end point was ocular and systemic adverse events. The secondary endpoints were best-corrected visual acuity (BCVA), static perimetry (SP), kinetic perimetry (KP), total field hill of vision (V_TOT), full field electroretinogram (ffERG), multifocal ERG (mfERG), color fundus photography (CFP), short-wavelength fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT). The subretinal injections were well-tolerated by all 22 patients across three dose levels. There was one case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In one patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared to the untreated eye. However, in six patients hypoautofluorescent changes were worse in the treated eye than the untreated eye. Of these, one patient had retinal pigment epithelium (RPE) atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in BCVA, SP, KP, V_TOT, ffERG, or mfERG attributable to the treatment. Subretinal treatment with EIAV-ABCA4 was well tolerated with only one case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of RPE atrophy on FAF. There was significant reduction in macular flecks in one treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12. Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12. CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe. This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Purpose: The purpose of this study was to evaluate rod-mediated function with two-color dark-adapted perimetry (2cDAP) in patients with RPE65-related retinopathy treated with voretigene neparvovec-rzyl. Methods: Following dilation and dark adaptation, 2cDAP and FST were performed. The 2cDAP was measured on an Octopus 900 perimeter (Haag-Streit) with cyan (500 nm wavelength) and red (650 nm wavelength) stimuli. Hill of vision (HOV) analysis was performed on 2cDAP perimetry with Visual Field Modeling and Analysis (VFMA). Full field threshold stimulus testing (FST) was also measured as a secondary measure of rod-mediated function, and assessed on a Diagnosys Espion with the ColorDome stimulator (Diagnosys LLC). Results: Eight eyes from 4 patients who were treated with voretigene bilaterally had rod function assessed by 2cDAP testing at least 1 year after treatment. There was statistically significant improvement in 2cDAP following gene augmentation therapy. HOV VFMA analysis showed widespread improvements that extended beyond the treatment bleb and statistically significant improvement in HOV analysis volumetric measurements post-treatment to cyan and red stimuli. FST testing performed in six eyes from three patients demonstrated statistically significant improvement to all chromatic stimuli following treatment. Conclusions: These findings demonstrated statistically significant improvement in 2cDAP and FST following treatment with voretigene. Translational Relevance: These findings provide a sensitive method of assessing rod-mediated function in a topographic manner that may be useful in future clinical trials for inherited retinal dystrophies.

Background Microcephaly and chorioretinopathy (MCCRP) is a rare neuro-ophthalmologic disorder that causes microcephaly and chorioretinopathy. In a recessive inheritance pattern, there are three types: MCCRP1; MCCRP2 and MCCRP3. MCCRP3 results from pathogenic variants in the tubulin-gamma complex-associated protein 4 (TUBGCP4) gene. Materials and Methods This is a case report of a patient with a molecular diagnosis defined by mutations in the TUBGCP4 gene. Segregation analyses were carried out. Results The molecular investigation found two heterozygous variants c.1380 G > A (p.Trp460*) a novel nonsense variant, and c.1746 G > T (p Leu582=) a synonymous variant in TUBGCP4. The clinical phenotype was characterized by microcephaly, microphthalmia, chorioretinopathy, a punched-out retinal appearance, dysmorphic facial features, decreased visual acuity, and learning difficulties. The clinical features were similar to those described previously in children with MCCRP3. The proband also had additional features including centripetal obesity, stretch marks, acanthosis nigricans, scoliosis, and hypercholesterolemia. These other features could be part of a ciliopathy syndrome. Conclusions MCCRP2 caused by pathogenic variants in PLK4 is well established as a ciliopathy disease. The role of TUBGCP4 is not well established in the cilium physiology. MCCRP3 may be part of the ciliopathy spectrum.