Dr. Nork is a founder, serves as a member of the Executive Board, and provides consulting on many aspects of vision science.
Dr. Nork is an Associate Professor of Ophthalmology at the University of Wisconsin School of Medicine and Public Health. He is fellowship trained in ophthalmic pathology, and his clinical specialties include diseases, surgery of the retina and vitreous, and clinical electrophysiology.
His research model incorporates electrophysiologic and histopathologic techniques to assess the effects of glaucoma on the outer retina (the photoreceptors) and possible neuroprotective mechanisms. In collaboration with the University of Wisconsin Department of Ophthalmology Fundus Photograph Reading Center, Dr. Nork grades retina photographs and optical coherence tomographs for toxicologic studies. He also provides surgical expertise on vitrectomy, subretinal injections and retinal laser photocoagulation for animal models of choroidal neovascularization.
Schwartz-Matsuo syndrome: An important cause of secondary glaucoma.
Am J Ophthalmol Case Rep. 2020 Mar;17:100586
Authors: Etheridge T, Larson JC, Nork TM, Momont AC
Purpose: We report a case of Schwartz-Matsuo syndrome that highlights the pathophysiology, diagnostic challenges, and management considerations of this rare disease.
Observations: 31-year-old man with a history of left eye cataract presented with left eye photophobia and elevated intraocular pressure (IOP) of 64 mm Hg. Visual acuity 20/40. Open angles with an increased pigment of trabecular meshwork by gonioscopy, 2 + anterior chamber (AC) cell, superior retinal detachment, and 0.6 cup-to-disc ratio. Electron microscopy of AC fluid demonstrated outer segments of photoreceptors. IOP was lowered with oral and topical ophthalmic antihypertensives. Retinal detachment was treated with pars plana vitrectomy with endolaser, gas tamponade, and AC paracentesis. Follow-up VA 20/20 with normal IOP.
Conclusions and importance: Schwartz-Matsuo syndrome is characterized by elevated IOP with marked fluctuations, open angles, aqueous cells, and retinal detachment. Diagnosis is supported by electron microscopy of AC fluid with outer segments of photoreceptors. Treatment includes retinal detachment repair and antihypertensive therapy.
PMID: 31956728 [PubMed]
EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL.
Retina. 2019 Aug 19;:
Authors: Bantseev V, Schuetz C, Booler HS, Horvath J, Hovaten K, Erickson S, Bentley E, Nork TM, Freeman WR, Stewart JM, Barteselli G
PURPOSE: To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant.
METHODS: Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated.
RESULTS: Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus).
CONCLUSION: In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.
PMID: 31436674 [PubMed - as supplied by publisher]
Effects of Vitrectomy and Lensectomy on Older Rhesus Macaques: Oxygen Distribution, Antioxidant Status, and Aqueous Humor Dynamics.
Invest Ophthalmol Vis Sci. 2017 Aug 01;58(10):4003-4014
Authors: Siegfried CJ, Shui YB, Tian B, Nork TM, Heatley GA, Kaufman PL
Purpose: The purpose of this study is to evaluate effects of vitrectomy (PPV) and lens extraction with intraocular lens implantation (PE/IOL) on molecular oxygen (pO2) distribution, aqueous humor antioxidant-oxidant balance, aqueous humor dynamics, and histopathologic changes in the trabecular meshwork (TM) in the older macaque monkey.
Methods: Six rhesus monkeys underwent PPV followed by PE/IOL. pO2, outflow facility, and intraocular pressure (IOP) were measured. Aqueous and vitreous humor specimens were analyzed for antioxidant status and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage. TM specimens were obtained for immunohistochemical and quantitative PCR analysis.
Results: pO2 at baseline revealed steep gradients in the anterior chamber and low levels in the posterior chamber (PC) and around the lens. Following PPV and PE/IOL, pO2 significantly increased in the PC, around the IOL, and angle. IOP increased following both surgical interventions, with no change in outflow facility. Histopathologic analysis did not show changes in TM cell quantification, but there was an increase in 8-OHdG. Quantitative PCR did not reveal significant differences in glaucoma-related gene expression. Aqueous and vitreous humor analysis revealed decreased ascorbate and total reactive antioxidant potential and increased 8-OHdG in the aqueous humor only in the surgical eyes.
Conclusions: Oxygen distribution in the older rhesus monkey is similar to humans at baseline and following surgical interventions. Our findings of histopathologic changes of TM oxidative damage and alterations in the oxidant-antioxidant balance suggest a potential correlation of increased oxygen exposure with oxidative stress/damage and the development of open angle glaucoma.
PMID: 28800647 [PubMed - in process]
TWO CASES OF ACUTE RETINAL NECROSIS DUE TO VARICELLA ZOSTER DESPITE PRIOR SHINGLES VACCINATION.
Retin Cases Brief Rep. 2017 Mar 13;:
Authors: Weinlander EJ, Wang AL, Jaru-Ampornpan P, Altaweel MM, Nork TM
PURPOSE: To review two cases of acute retinal necrosis in adults due to varicella zoster virus despite prior shingles vaccination.
METHODS: Retrospective chart review.
PATIENTS: A 62-year-old man and a 64-year-old man with unilateral acute retinal necrosis who had shingles vaccinations 16 and 7 months before their ocular symptoms.
RESULTS: Polymerase chain reaction confirmation of varicella zoster virus in the anterior chambers of both patients. Both patients had good responses to oral antiviral therapy and topical and/or oral steroids.
DISCUSSION: These two cases demonstrate that singles vaccination is not an absolute protection against varicella zoster virus-related acute retinal necrosis. However, such vaccination may reduce the severity of the acute retinal necrosis.
PMID: 28291069 [PubMed - as supplied by publisher]
Microglia in the primate macula: specializations in microglial distribution and morphology with retinal position and with aging.
Brain Struct Funct. 2017 Feb 17;:
Authors: Singaravelu J, Zhao L, Fariss RN, Nork TM, Wong WT
Microglia, the principal resident immune cell in the retina, play constitutive roles in immune surveillance and synapse maintenance, and are also associated with retinal disease, including those occurring in the macula. Perspectives on retinal microglia function have derived largely from rodent models and how these relate to the macula-bearing primate retina is unclear. In this study, we examined microglial distribution and cellular morphology in the adult rhesus macaque retina, and performed comparative characterizations in three retinal locations along the center-to-periphery axis (parafoveal, macular, and the peripheral retina). We found that microglia density peaked in the parafoveal retina and decreased in the peripheral retina. Individual microglial morphology reflected macular specialization, with macular microglia demonstrating the largest and most complex dendritic arbors relative to other retinal locations. Comparing retinal microglia between young and middle-aged animals, microglial density increased in the macular, but not in the peripheral retina with age, while microglial morphology across all locations remained relatively unchanged. Our findings indicate that microglial distribution and morphology demonstrate regional specialization in the retina, correlating with gradients of other retinal cell types. As microglia are innate immune cells implicated in age-related macular diseases, age-related microglial changes may be related to the increased vulnerability of the aged macula to immune-related neurodegeneration.
PMID: 28213784 [PubMed - as supplied by publisher]
Single ocular injection of a sustained-release anti-VEGF delivers 6months pharmacokinetics and efficacy in a primate laser CNV model.
J Control Release. 2016 Dec 28;244(Pt A):1-13
Authors: Adamson P, Wilde T, Dobrzynski E, Sychterz C, Polsky R, Kurali E, Haworth R, Tang CM, Korczynska J, Cook F, Papanicolaou I, Tsikna L, Roberts C, Hughes-Thomas Z, Walford J, Gibson D, Warrack J, Smal J, Verrijk R, Miller PE, Nork TM, Prusakiewicz J, Streit T, Sorden S, Struble C, Christian B, Catchpole IR
A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in ocular VEGF-driven efficacy models in vivo. The dual dAb is highly potent, showing a lower IC50 than aflibercept in VEGF receptor binding assays (RBAs) and retaining activity upon release from microparticles over 12months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6months at sufficient levels to protect Cynomolgus against laser-induced grade IV choroidal neovascularisation (CNV). This demonstrates proof of concept for delivery of an anti-VEGF molecule within a sustained-release system, showing protection in a pre-clinical primate model of wet AMD over 6months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.
PMID: 27810558 [PubMed - in process]
Toluene inhalation exposure for 13 weeks causes persistent changes in electroretinograms of Long-Evans rats.
Neurotoxicology. 2016 Mar;53:257-70
Authors: Boyes WK, Bercegeay M, Degn L, Beasley TE, Evansky PA, Mwanza JC, Geller AM, Pinckney C, Nork TM, Bushnell PJ
Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000ppm toluene by inhalation (6hr/d, 5d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not significantly changed by toluene exposure. Four to five weeks after completion of exposure, rats were dark-adapted overnight, anesthetized, and several sets of electroretinograms (ERG) were recorded. In dark-adapted ERGs recorded over a 5-log (cd-s/m(2)) range of flash luminance, b-wave amplitudes were significantly reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A second set of rats, exposed concurrently with the first set, was tested approximately one year after the termination of 13 weeks of exposure to toluene. Again, dark-adapted ERG b-wave amplitudes were reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A third set of rats was exposed to the same concentrations of toluene for only 4 weeks, and a fourth set of rats exposed to 0 or 1000ppm toluene for 4 weeks were tested approximately 1year after the completion of exposure. No statistically significant reductions of ERG b-wave amplitude were observed in either set of rats exposed for 4 weeks. No significant changes were observed in ERG a-wave amplitude or latency, b-wave latency, UV- or green-flicker ERGs, or in photopic flash ERGs. There were no changes in the density of rod or M-cone photoreceptors. The ERG b-wave reflects the firing patterns of on-bipolar cells. The reductions of b-wave amplitude after 13 weeks of exposure and persisting for 1year suggest that alterations may have occurred in the inner nuclear layer of the retina, where the bipolar cells reside, or the outer or inner plexiform layers where the bipolar cells make synaptic connections. These data provide experimental evidence that repeated exposure to toluene may lead to subtle persistent changes in visual function. The fact that toluene affected ERGs, but not VEPs, suggests that elements in the rat retina may be more sensitive to organic solvent exposure than the rat visual cortex.
PMID: 26899397 [PubMed - in process]
Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate.
Regul Toxicol Pharmacol. 2014 Jul;69(2):187-200
Authors: Eichenbaum G, Zhou J, Kelley MF, Roosen W, Costa-Giomi P, Louden C, Di Prospero NA, Pandina G, Singh JB, Ford L, Moyer JA, Nork TM, Ver Hoeve JN, Aguirre GD
The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring.
PMID: 24680767 [PubMed - indexed for MEDLINE]
Quantifying optic nerve axons in a cat glaucoma model by a semi-automated targeted counting method.
Mol Vis. 2014;20:376-85
Authors: Teixeira LB, Buhr KA, Bowie O, Duke FD, Nork TM, Dubielzig RR, McLellan GJ
PURPOSE: To describe and validate a semi-automated targeted sampling (SATS) method for quantifying optic nerve axons in a feline glaucoma model.
METHODS: Optic nerve cross sections were obtained from 15 cats, nine with mild to severe glaucoma and six with normal eyes. Optic nerves were dissected, fixed in paraformaldehyde and glutaraldehyde, and processed for light microscopy by resin embedding, sectioning, and staining of axon myelin sheaths with 1% p-phenylenediamine before axon quantification. Commercially available image analysis software was used as a semi-automated axon counting tool (SCT) and was first validated by comparison with a manual axon count (MAC). This counting tool was then used in a SATS method performed by three masked raters and in a semi-automated full count (SAFC) method performed by a single observer. Correlation was assessed between the SCT and MAC using a linear model and analysis of covariance (ANCOVA). Correlation between the SATS and SAFC methods was calculated and the bias, systematic errors, and variance component assessed. The intraclass correlation coefficient (ICC) was determined to establish inter-rater agreement. In addition, the time required to perform the SATS and SAFC methods was evaluated.
RESULTS: Correlation between the axon counts obtained by the SCT and MAC was strong (r = 0.9985). There was evidence of an overcounting of axons by the SCT compared to the MAC with a percentage error rate of 13.0% (95% confidence interval [CI] 11.0%, 15.1%). Both the correlation of SATS count (average per rater) to SAFC (r = 0.9891) and inter-rater agreement (ICC = 0.986) were high. The SATS method presented an overall positive counting error (p<0.001) when compared to the SAFC, consistent with a fixed percentage overestimation of 11.2% (95% CI 8.3%, 14.2%) of the full count. The average time required to quantify axons by the SATS method was 10.9 min, only 27% of that required to conduct the SAFC.
CONCLUSIONS: Our data demonstrate that the SATS method provides a practical, rapid, and reliable means of estimating axon counts in the optic nerves of cats with glaucoma.
PMID: 24715755 [PubMed - indexed for MEDLINE]
Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(®), for age-related macular degeneration.
Hum Gene Ther. 2012 Sep;23(9):980-91
Authors: Binley K, Widdowson PS, Kelleher M, de Belin J, Loader J, Ferrige G, Carlucci M, Esapa M, Chipchase D, Angell-Manning D, Ellis S, Mitrophanous K, Miskin J, Bantseev V, Nork TM, Miller P, Naylor S
RetinoStat(®) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ∼1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.
PMID: 22716662 [PubMed - indexed for MEDLINE]
AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits angiogenesis in models of ocular neovascular diseases.
Invest Ophthalmol Vis Sci. 2012 Apr;53(4):2170-80
Authors: Oliner JD, Bready J, Nguyen L, Estrada J, Hurh E, Ma H, Pretorius J, Fanslow W, Nork TM, Leedle RA, Kaufman S, Coxon A
PURPOSE: To determine whether systemic treatment with AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits neovascular processes in animal models of ocular disease.
METHODS: AMG 386 was tested in a laser-induced choroidal neovascularization (CNV) model in monkeys using fluorescein angiography. The biodistribution of (125)I-AMG 386 was determined in cynomolgus monkeys by whole-body autoradiography and radioanalysis of ocular tissues. A murine retinopathy of prematurity (ROP) model was used to examine the effect of AMG 386 on established and newly formed retinal vessels, either as a single agent or when combined with VEGF inhibition.AMG 386 pharmacokinetics were evaluated in each model.
RESULTS: In the CNV model, AMG 386 significantly decreased fluorescent angiographic leakage and reduced fibroplasia, indicating an impaired healing response consistent with angiogenesis blockade. Radiolabeled AMG 386 was widely distributed across ocular tissues, with highest concentrations in the choroid, cornea, retinal pigmented epithelium, iris/ciliary body, and sclera. In the ROP model, AMG 386 prevented pathologic retinal angiogenesis when administered from P8 to P16 but transiently impeded regression of these abnormal vessels when administered from P17 to P23. Combining AMG 386 with VEGF inhibition led to cooperative prevention of retinal angiogenesis in this model. No AMG 386-related ocular toxicities occurred, and no treatment-related clinical observations were made in any of the studies.
CONCLUSIONS: In this study, AMG 386 inhibited angiogenesis in animal models of CNV and ROP, supporting investigation of AMG 386 for the treatment of ocular neovascular diseases in the clinical setting.
PMID: 22410553 [PubMed - indexed for MEDLINE]
The effect of pentobarbital sodium and propofol anesthesia on multifocal electroretinograms in rhesus macaques.
Doc Ophthalmol. 2012 Feb;124(1):59-72
Authors: Kim CB, Ver Hoeve JN, Nork TM
We compared the suitability of pentobarbital sodium (PB) and propofol (PF) anesthetics for multifocal electroretinograms (mfERGs) in rhesus macaques. mfERGs were collected from 4 ocularly normal rhesus macaques. All animals were pre-anesthetized with intramuscular ketamine (10-15 mg/kg). Intravenous PB induction/maintenance levels were 15 mg/kg/2-10 mg/kg and for PF, 2-5 mg/kg/6-24 mg/kg/h. There were 3 testing sessions with PB anesthesia and 5-7 testing sessions with PF anesthesia. All PB sessions were carried out before PF. First-order (K1) and second-order (first slice) kernels (K2.1) response density amplitude (RDA), implicit time (IT), and root mean square signal-to-noise ratios (RMS SNR) of the low-frequency (LFC) and high-frequency (HFC) components were evaluated. The use of PF or PB anesthesia resulted in robust, replicable mfERGs in rhesus macaques; however, RMS SNR of K1 LFC in ring and quadrant analyses was significantly larger for PF than for PB. Additionally, K1 RDA under PF was significantly larger than under PB for N1, P1, and P2 components (ring and quadrant) and for N2 (quadrant). PF IT was significantly prolonged (<1 ms) relative to PB IT for N1, P1 (ring), and N1 (quadrant), while PB IT was significantly prolonged (0.8-4.2 ms) relative to PF IT for N2 and P2 (ring and quadrant). K1 HFC and K2.1 LFC did not differ significantly between PB and PF in the ring or quadrant analyses. The response differences found with PB and PF anesthesia likely arise from variable relative effects of the anesthetics on retinal γ-aminobutyric acid (GABA(A)) receptors, and in part, on glycine and on glutamate receptors. Given the advantages of a stable anesthetic plane with continuous intravenous infusion and a smoother, more rapid recovery, PF is an appealing alternative for mfERG testing in rhesus macaques.
PMID: 22200766 [PubMed - indexed for MEDLINE]
Massive spontaneous suprachoroidal hemorrhage in a young woman with cystic fibrosis and diabetes mellitus on anticoagulants.
Retin Cases Brief Rep. 2012;6(2):216-8
Authors: Nguyen HN, Nork TM
PURPOSE: To report a case of massive spontaneous suprachoroidal hemorrhage in a young woman with cystic fibrosis and proliferative diabetic retinopathy on anticoagulant therapy.
METHODS: Single case report.
RESULTS: A 24-year-old woman with cystic fibrosis and diabetes mellitus developed a massive spontaneous suprachoroidal hemorrhage in the left eye after two months of warfarin therapy and recent treatment with heparin. Fundus examination and B-scan ultrasonography of the left eye revealed a hemorrhagic choroidal detachment. Elevated intraocular pressure was controlled with brimonidine, but four months later the left eye ceased to perceive light.
CONCLUSION: Massive spontaneous suprachoroidal hemorrhage (SSCH) is a rare event that occurs almost exclusively in patients of advanced age. To our knowledge, this is the youngest patient with SSCH described in the literature. Regardless of age or other medical conditions, anticoagulant therapy appears to be a strong risk factor. SSCH carries a poor visual prognosis with or without surgical intervention.
PMID: 22685615 [PubMed]
Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates.
Arch Ophthalmol. 2011 Aug;129(8):1042-52
Authors: Nork TM, Dubielzig RR, Christian BJ, Miller PE, Miller JM, Cao J, Zimmer EP, Wiegand SJ
OBJECTIVE: To evaluate the efficacy of systemic and intravitreous administration of VEGF Trap (aflibercept) in a nonhuman primate model of choroidal neovascularization (CNV).
METHODS: VEGF Trap treatment on laser-induced CNV was evaluated in 48 adult cynomolgus monkeys. In the prevention arms of the study, VEGF Trap was administered by intravenous injection (3 or 10 mg/kg weekly) or intravitreous injection (50, 250, or 500 μg/eye every 2 weeks) beginning before laser injury. In the treatment arm, a single intravitreous injection (500 μg) was given 2 weeks following laser injury. Laser-induced lesions were scored from grade 1 (no hyperfluorescence) to grade 4 (clinically relevant leakage). Representative lesions were evaluated histologically.
RESULTS: Grade 4 leakage developed at 32.4% and 45.4% of the laser sites in animals receiving intravitreous or intravenous administration of placebo at 2 weeks following laser injury, respectively. In contrast, the development of grade 4 lesions was completely or nearly completely prevented in all groups receiving intravenous or intravitreous injections of VEGF Trap. A single intravitreous injection of VEGF Trap (500 μg) administered following the development of CNV reduced the frequency of grade 4 lesions from 44.4% to 0% within 14 days of treatment. Intravitreous VEGF Trap was well tolerated with either no or only mild ocular inflammation. Histological evaluation showed decreased scores for morphologic features of tissue proliferation in the VEGF Trap prevention groups.
CONCLUSIONS: VEGF Trap prevented the development of clinically relevant CNV leakage when administered at the lowest doses tested. Moreover, a single intravitreous injection induced inhibition of active CNV leakage.
CLINICAL RELEVANCE: The animal model used in this study has an established track record as a predictor of pharmacologic efficacy of antineovascular drugs in humans having the neovascular, or wet, form of age-related macular degeneration.
PMID: 21825187 [PubMed - indexed for MEDLINE]
Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing the efficacy of bevacizumab, adalimumab, and ESBA105.
Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4738-45
Authors: Lichtlen P, Lam TT, Nork TM, Streit T, Urech DM
PURPOSE: To compare the relative contribution of VEGF and TNF-alpha in the development of laser-induced choroidal neovascularization (CNV) in monkeys and to exploit the feasibility of topical use of suitable antibody fragments for the prevention of experimental CNV.
METHODS: To induce experimental CNV, small high-energy laser spots were used to treat several areas of the macula in the retinas of cynomolgus monkeys according to previously published protocols. To prevent abnormalities, bevacizumab (a potent VEGF inhibitor) and adalimumab or ESBA105 (potent TNF-alpha inhibitors) were given by intravitreal injection 1 week before and 1 week and 3 weeks after laser treatment. ESBA105 was also applied topically in a separate group. Control animals were treated with either intravitreal or topical saline. Eyes were monitored by ophthalmic examination, color photography, and fluorescein angiography.
RESULTS: Inhibition of VEGF by bevacizumab completely blocked the formation of CNV. Both TNF-alpha inhibitors also significantly reduced laser-induced CNV abnormalities after intravitreal administration. Most important, topical use of the anti-TNF-alpha single-chain antibody fragment ESBA105 also reduced the formation of CNV.
CONCLUSIONS: TNF-alpha contributes to laser-induced CNV formation, and its inhibition can be a new therapeutic target for CNV. This study suggests TNF-alpha as another therapeutic target for the prevention and treatment of CNV and adds to the emerging clinical data suggesting the therapeutic value of TNF-alpha inhibitors in age-related macular degeneration (AMD). Further, this study shows that topical therapy with suitable antibody fragments has the potential of being introduced to retinal disease treatment regimens.
PMID: 20393113 [PubMed - indexed for MEDLINE]