Perimacular Atrophy Following Voretigene Neparvovec-Rzyl Treatment in the Setting of Previous Contralateral Eye Treatment With a Different Viral Vector.

Purpose: To report on cases of unilateral perimacular atrophy after treatment with voretigene neparvovec-rzyl, in the setting of previous contralateral eye treatment with a different viral vector.

Design: Single-center, retrospective chart review.

Methods: In this case series, four patients between the ages of six and 11 years old with RPE65-related retinopathy were treated unilaterally with rAAV2-CB-hRPE65 as part of a gene augmentation clinical trial (NCT00749957).

Expanding the phenotypic and genotypic spectrum of patients with -related retinopathy.

Background: Variants in HGSNAT have historically been associated with syndromic mucopolysaccharidosis type IIIC (MPSIIIC) but more recent studies demonstrate cases of HGSNAT-related non-syndromic retinitis pigmentosa. We describe and expand the genotypic and phenotypic spectrum of this disease.

Materials And Methods: This is a retrospective, observational, case series of 11 patients with pericentral retinitis pigmentosa due to variants in HGSNAT gene without a syndromic diagnosis of MPSIIIC.

Vitelliform maculopathy in MELAS syndrome.

Purpose: We present a unique case of foveomacular vitelliform lesions in a patient with metabolic encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS).

Observations: After performing large panel next generation sequencing genetic testing, there was no likely alternative genetic etiology for vitelliform maculopathy in this patient.

Conclusions And Importance: We present a rare case of a visually asymptomatic pediatric patient with MELAS and vitelliform maculopathy, which may be part of the spectrum of retinal manifestations in MELAS.

Improved Rod Sensitivity as Assessed by Two-Color Dark-Adapted Perimetry in Patients With RPE65-Related Retinopathy Treated With Voretigene Neparvovec-rzyl.

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.

X-Linked Retinoschisis.

X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas in 1898 and is clinically diagnosed by characteristic intraretinal cysts arranged in a petaloid "spoke-wheel" pattern centered in the macula. When clinical electroretinogram (ERG) testing began in the 1960s, XLRS was noted to have a characteristic reduction of the dark-adapted b-wave amplitude despite normal or usually nearly normal a-wave amplitudes, which became known as the "electronegative ERG response" of XLRS disease.

The new landscape of retinal gene therapy.

Novel therapeutics for inherited retinal dystrophies (IRDs) have rapidly evolved since groundbreaking clinical trials for LCA due to RPE65 mutations led to the first FDA-approved in vivo gene therapy. Since then, advancements in viral vectors have led to more efficient AAV transduction and developed other viral vectors for gene augmentation therapy of large gene targets. Furthermore, significant developments in gene editing and RNA modulation technologies have introduced novel capabilities for treatment of autosomal dominant diseases, intronic mutations, and/or large genes otherwise unable to be treated with current viral vectors.

The Role of ERK1/2 Activation in Sarpogrelate-Mediated Neuroprotection.

Purpose: To characterize the mediators of 5-HT2A serotonin receptor-driven retinal neuroprotection.

Methods: Albino mice were treated intraperitoneally with saline or sarpogrelate, a 5-HT2A antagonist, immediately before light exposure (LE). Following LE, retinas were harvested for a high-throughput phosphorylation microarray to quantify activated phosphorylated proteins in G protein-coupled receptor (GPCR) signaling.

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy.

Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study.

Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology.

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration.

Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.

Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia.

Background: Cobalamin C disease (cblC), which leads to methylmalonic acidemia with homocystinuria, is the most common inherited disorder of vitamin B12 metabolism. Reported ocular findings associated with cblC have been maculopathy, pigmentary retinopathy, and optic nerve atrophy. Cobalamin A disease (cblA) which causes an isolated methylmalonic acidemia without homocystinuria is rarer than cblC.

Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

Purpose: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.

Methods: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin.

Molecular and Clinical Findings in Patients With Knobloch Syndrome.

Importance: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described.

Objective: To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome.

Retinal Gene Therapy: Current Progress and Future Prospects.

Clinical trials treating inherited retinal dystrophy caused by mutations had put retinal gene therapy at the forefront of gene therapy. Both successes and limitations in these clinical trials have fueled developments in gene vectors, which continue to further advance the field. These novel gene vectors aim to more safely and efficiently transduce retinal cells, expand the gene packaging capacity of AAV, and utilize new strategies to correct the varying mechanisms of dysfunction found with inherited retinal dystrophies.

Granulicatella adiacens, an unusual causative agent in chronic dacryocystitis.

Background: Granulicatella adiacens, a recent taxonomic addition, is a commensal organism of the oral, gastrointestinal, and urogenital tracts and is rarely encountered in the orbit and eye.

Findings: We present a 46-year-old Caucasian woman with chronic dacryocystitis who underwent an external dacryocystorhinostomy and was found to have G. adiacens.

Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model.

Defects in aryl hydrocarbon receptor interacting protein-like1 (AIPL1) are associated with blinding diseases with a wide range of severity in humans. We examined the mechanism behind autosomal dominant cone-rod dystrophy (adCORD) caused by 12 base pair (bp) deletion at proline 351 of hAIPL1 (P351Δ12) mutation in the primate-specific region of human AIPL1. Mutant P351Δ12 human isoform, aryl hydrocarbon receptor interacting protein-like 1 (hAIPL1) mice demonstrated a CORD phenotype with early defects in cone-mediated vision and subsequent photoreceptor degeneration.

Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis.

Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease with early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects are characterized at the most severe end of the LCA spectrum. The rapid photoreceptor degeneration and vision loss observed in the LCA patient population are mimicked in a mouse model lacking AIPL1.