Dr. Ver Hoeve is Senior Scientist and Director of Electrodiagnostic Services in the Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health. He is responsible for electroretinographic and visual evoked potential testing in human patients and has conducted research in numerous animal models. He is currently investigating neuroprotection strategies in a non-human primate model of experimental glaucoma.
James Ver Hoeve
A case report of retinal dystrophy in patients with PACS1 syndrome
Ophthalmic Genet. 2023 May 23:1-5. doi: 10.1080/13816810.2023.2216272. Online ahead of print.
PACS1 syndrome, also referred to as Schuurs-Hoeijmakers syndrome, is a multisystemic developmental disorder caused by a specific pathogenic variant in the PACS1 (phosphofurin acidic cluster sorting protein 1) gene. Ocular findings in PACS1 syndrome are known to include iris, retina, optic nerve coloboma, myopia, nystagmus, and strabismus. Here, we present the cases of two patients referred to the University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences for ocular evaluation. The first patient is a 14-month-old female who, at 3 months of age, was found to have a depressed rod and cone response on electroretinogram (ERG), consistent with possible retinal dystrophy (RD). This feature has not been previously described in PACS1 syndrome and joins a growing list of calls for expanding the PACS1 phenotype. The second case illustrates a 5-year-old male referred for ocular screening after diagnosing PACS1 syndrome and underwent ERG without abnormal findings. These cases demonstrate the significant variability in the ophthalmic presentation of PACS1 syndrome and the need for early screening. These novel findings may have implications in understanding the mechanism of the PACS1 protein and its role in retinal ciliary phototransduction in photoreceptors.
Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy
Mol Ther. 2023 Jul 5;31(7):2014-2027. doi: 10.1016/j.ymthe.2023.03.011. Epub 2023 Mar 16.
Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 1010 vg/eye resulted in transduction of 18%-85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM.
Preclinical Evaluation of ADVM-062, a Novel Intravitreal Gene Therapy Vector for the Treatment of Blue Cone Monochromacy
<em>MFRP</em> variant results in nanophthalmos, retinitis pigmentosa, variability in foveal avascular zone
Ophthalmic Genet. 2023 Feb;44(1):83-88. doi: 10.1080/13816810.2022.2103835. Epub 2022 Jul 26.
BACKGROUND: Membrane frizzled-related protein (MFRP) plays a critical role in ocular development. MFRP mutations are known to cause nanophthalmos and, in some cases, retinitis pigmentosa, foveoschisis, and/or optic nerve head (ONH) drusen. The broad clinical spectrum of MFRP mutations necessitates further investigation of specific genotype-phenotype relationships.
MATERIALS AND METHODS: We reviewed ophthalmologic and genetic medical records of two affected siblings and one unaffected sibling.
RESULTS: Genetic testing revealed variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans in the two affected siblings. In both cases, photopic and scotopic responses were markedly reduced on electroretinogram (ERG), with greater decrease in scotopic function. Optical coherence tomography for both siblings revealed non-cystoid thickening. Blunted foveal reflexes were also observed in both siblings. Notably, foveal avascular zone abnormalities were seen on fundus autofluorescence in only one affected sibling.
CONCLUSIONS: MFRP-related ocular disease may be underrecognized due to its presentation with high hyperopia and possibly subtle retinal findings. Presence of variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans resulted in nanophthalmos and retinitis pigmentosa without associated foveoschisis or ONH drusen in our patients, consistent with the incomplete phenotype previously described in Neri et al. Abnormalities in the foveal avascular zone have been noted in other case studies and were inconsistently associated with the variants described here, representing a potential area for future investigation.
Use of sweep visual evoked potential in preverbal children with optic nerve hypoplasia
J AAPOS. 2022 Jun;26(3):131.e1-131.e6. doi: 10.1016/j.jaapos.2022.01.012. Epub 2022 May 13.
PURPOSE: To evaluate sweep VEP (sVEP) in preverbal children with optic nerve hypoplasia (ONH) and to assess associations between sVEP results, patient clinical characteristics and future recognition visual acuity.
METHODS: The medical records of children with ONH who had sVEP testing and documented recognition visual acuity at the University of Wisconsin from 2005 to 2013 were reviewed retrospectively. Optic nerve size, amblyopia treatment, and neurologic diagnoses were collected.
RESULTS: A total of 57 patients were included: 41 (71%) with bilateral ONH and 27 (47%) with neurologic abnormality. Mean age at initial sVEP was 13.3 months (range, 1-32). Mean duration between initial sVEP and final recognition acuity was 5.5 years (range, 3.5-7). Sweep VEP was associated with ONH severity (P < 0.05). Sweep VEP, and the combination of ONH severity and neurologic status, were significant predictors (P < 0.05) of logMAR optotype acuity, together accounting for 54%-61% of the variance in final recognition acuity.
CONCLUSIONS: Sweep VEP in preverbal children with ONH depends on ONH severity and correlates with final recognition visual acuity. Children with milder degrees of ONH without neurologic abnormalities had better final vision, and patients with severe ONH and neurologic diagnoses had worse vision outcomes.
Effect of intraocular pressure (IOP), volume and location on the distribution of aqueous solutions injected into the suprachoroidal (SC) space
Investigative Ophthalmology & Visual Science, 63(7), pp.4152-F0144
Ocular evaluation and genetic test for an early Alström Syndrome diagnosis
Am J Ophthalmol Case Rep. 2020 Aug 12;20:100873. doi: 10.1016/j.ajoc.2020.100873. eCollection 2020 Dec.
PURPOSE: We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease.
OBSERVATIONS: The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants.
CONCLUSIONS AND IMPORTANCE: ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.
Vigabatrin-Induced Retinal Functional Alterations and Second-Order Neuron Plasticity in C57BL/6J Mice
Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):17. doi: 10.1167/iovs.61.2.17.
PURPOSE: Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results.
METHODS: We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry.
RESULTS: No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain.
CONCLUSIONS: No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.
Vigabatrin-induced retinal functional alterations and second-order neuron plasticity in C57BL/6J mice
Investigative Ophthalmology & Visual Science, 61(2), pp.17-17
Evoked potentials as a biomarker of remyelination
Proc Natl Acad Sci U S A. 2019 Dec 26;116(52):27074-27083. doi: 10.1073/pnas.1906358116. Epub 2019 Dec 16.
Multiple sclerosis (MS) is a common cause of neurologic disease in young adults that is primarily treated with disease-modifying therapies which target the immune and inflammatory responses. Promotion of remyelination has opened a new therapeutic avenue, but how best to determine efficacy of remyelinating drugs remains unresolved. Although prolongation and then shortening of visual evoked potential (VEP) latencies in optic neuritis in MS may identify demyelination and remyelination, this has not been directly confirmed. We recorded VEPs in a model in which there is complete demyelination of the optic nerve, with subsequent remyelination. We examined the optic nerves microscopically during active disease and recovery, and quantitated both demyelination and remyelination along the length of the nerves. Latencies of the main positive component of the control VEP demonstrated around 2-fold prolongation during active disease. VEP waveforms were nonrecordable in a few subjects or exhibited a broadened profile which precluded peak identification. As animals recovered neurologically, the VEP latencies decreased in association with complete remyelination of the optic nerve but remained prolonged relative to controls. Thus, it has been directly confirmed that VEP latencies reflect the myelin status of the optic nerve and will provide a surrogate marker in future remyelination clinical trials.
Normative Values for Multifocal ERGs Recorded from Cynomolgus Macaques in a Non-clinical Setting
In Investigative Ophthalmology & Visual Science (Vol. 60, No. 9)
Ocular toxicity of AUY922 in pigmented and albino rats
Toxicol Appl Pharmacol. 2016 Oct 15;309:55-62. doi: 10.1016/j.taap.2016.08.025. Epub 2016 Aug 28.
AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, β-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.
Variability in the Electroretinographic Response of Laboratory Animals
Investigative Ophthalmology & Visual Science, 57(12), pp.5766-5766
Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin
Hum Gene Ther Clin Dev. 2015 Sep;26(3):165-76. doi: 10.1089/humc.2015.076.
Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 × 10(10) or 4 × 10(11) vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.
Functional and Structural Effects of Subretinal Dose Delivery in Mice
Investigative Ophthalmology & Visual Science, 56(7), pp.245-245
Localized retinal manifestations of paraneoplastic autoimmune retinopathy
Retin Cases Brief Rep. 2014 Fall;8(4):318-21. doi: 10.1097/ICB.0000000000000054.
PURPOSE: Systemic neoplastic processes can affect the retina through autoimmune retinopathy. This process may present in a variety of patterns. A novel pattern of paraneoplastic autoimmune retinopathy has been described.
METHODS: Two patients presented with paraneoplastic vision changes. Optical coherence tomography and multifocal electroretinography were performed, which showed a unique focal retinal change in both patients. Case 1 is a 20-year-old woman with history of cutaneous melanoma. Case 2 is 67-year-old woman with history of breast cancer.
RESULTS: Both patients showed a localized area of foveal thinning that corresponded with areas of depression on multifocal electroretinography. Each tested positive for antiretinal antibodies.
CONCLUSION: This is a novel manifestation of paraneoplastic autoimmune retinopathy. Previously described cases have all affected the retina diffusely. These cases highlight the need to consider distant neoplastic processes when evaluating patient with similar presentations to those depicted here.
Gender Differences in Anesthetized Primate ERG and Full-field Flash VEP
Investigative Ophthalmology & Visual Science, 55(13), pp.5130-5130
Inner Nuclear Layer (INL) Cystoid Spaces (Lacunae) Observed in Experimental Glaucoma and Axotomy in Non-Human Primates (NHPs)
Investigative Ophthalmology & Visual Science, 54(15), pp.4818-4818
Emerging Electrophysiological Technologies for Assessing Ocular Toxicity in Laboratory Animals
Collins, M and Weir, A. B. eds., Assessing Ocular Toxicology in Laboratory Animals. Molecular and Integrative Toxicology, Springer, New York, pp 123-158 (2013)
Electrophysiologic Correlates of RNFL Thickness in Experimental Glaucoma
Investigative Ophthalmology & Visual Science, 54(15), pp.794-794
Inter-ocular And Inter-subject Variability In The Full-field Electroretinograms Of Rabbits And Monkeys
Investigative Ophthalmology & Visual Science, 52(14), pp.703-703
Spectral domain OCT segmentation accuracy in monkeys
Investigative Ophthalmology & Visual Science, 51(13), pp.4401-4401
Ocular and systemic safety evaluation of calcium formate as a dietary supplement
Journal of ocular pharmacology and therapeutics, 25(3), pp.223-230
Bilateral optic atrophy: a background finding in cynomolgus macaques used in toxicologic research
Investigative Ophthalmology & Visual Science, 50(13), pp.5344-5344
Evaluation of EIAV Based Lentiviral Vectors Following Ocular Delivery in the Nonhuman Primate Model: Development of RetinoStat®
Investigative Ophthalmology & Visual Science, 49(13), pp.5340-5340
Standardized Full-Field Electroretinography in Cynomolgus Monkeys
Investigative Ophthalmology & Visual Science, 49(13), pp.5816-5816
Measurement of regional choroidal blood flow in rabbits and monkeys using fluorescent microspheres
Archives of Ophthalmology, 124(6), pp.860-868.
Safety evaluation of intravitreal administration of VEGF trap in cynomolgus monkeys for 13 weeks.
Investigative Ophthalmology & Visual Science, 47(13), pp.1751-1751.
Interspecies and gender differences in multifocal electroretinograms of cynomolgus and rhesus macaques
Documenta ophthalmologica, 109, pp.73-86.
26-Week Intravitreal Injection Toxicity Study with rhuFab VEGF in Cynomolgus Monkeys with an 8-Week Recovery
Association for Research in Vision and Ophthalmology Annual Meeting. Invest Ophthalmol Vis Sci., 44 – electronic abstract (2003).
Swelling and loss of photoreceptors in chronic human and experimental glaucomas
Archives of ophthalmology, 118(2), pp.235-245.
Safety Evaluation of Intravitreal Administration of rhuFab VEGF in Cynomolgus Monkeys for 3 Months
Invest Ophthalmol Vis Sci, 41 (4):S142 (2000).
VEP and PERG acuity in anesthetized young adult rhesus monkeys
Visual neuroscience, 16(4), pp.607-617.