Publications by authors named "Thaddeus P Dryja"

72 Publications

Overlapping immunohistochemical features of adenocarcinoma of the nonpigmented ciliary body epithelium and renal cell carcinoma.

Am J Ophthalmol 2021 Jan 30. Epub 2021 Jan 30.

David G Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School.

Purpose: To find immunohistochemical markers that distinguish adenocarcinoma of the nonpigmented ciliary epithelium (NPCE) from metastatic carcinoma, especially metastatic renal cell carcinoma.

Design: Retrospective case series.

Method: Three cases of adenocarcinoma of the NPCE were examined histologically with hematoxylin-eosin and immunohistochemical stains including vimentin, AE1/AE3, Cam 5.2, CK7, PAX2, PAX8, AMACR, and CAIX. We also reviewed previously reported cases of this tumor.

Result: We found that the immunohistochemical profile of adenocarcinoma of the NPCE can overlap with renal cell carcinoma. Both tumors can express vimentin, cytokeratin AE1/AE3, Cam 5.2, PAX2, PAX8, and AMACR. One of the adenocarcinomas of the NPCE in our series also expressed CD10 and the renal cell carcinoma marker (RCC Ma). Carbonic anhydrase IX (CAIX) was not detected in any of the three tumors.

Conclusion: Adenocarcinomas arising in phthisical eyes can be diagnostically challenging. We have found it particularly difficult to distinguish adenocarcinoma of the NPCE from metastatic carcinoma, especially metastatic clear cell renal cell carcinoma and papillary renal cell carcinoma. Because of the immunophenotypic overlap, most patients will require systemic workup including imaging of the kidneys to be certain of the diagnosis.
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http://dx.doi.org/10.1016/j.ajo.2021.01.020DOI Listing
January 2021

Molecular Genetics of Intraocular Tumors.

Semin Ophthalmol 2020 Apr 7;35(3):174-181. Epub 2020 Jun 7.

David G Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School , Boston, MA, USA.

Purpose: To explore the value of molecular technologies in the pathologic evaluation, diagnosis, and treatment of retinoblastoma and uveal melanoma.

Methods: Review of the peer-reviewed literature on the molecular pathology of primary intraocular tumors.

Conclusion: Molecular tests are playing an increasingly important role in the diagnosis of intraocular tumors. They provide information valuable for diagnosis, prognosis, screening regimens, genetic counselling, and treatment. These technologies are becoming easier, faster, and with higher sensitivity and accuracy.
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http://dx.doi.org/10.1080/08820538.2020.1776343DOI Listing
April 2020

Isolated orbital amyloidosis causing internal and external ophthalmoplegia.

J AAPOS 2020 02 9;24(1):48-51.e1. Epub 2019 Dec 9.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Amyloid is a protein precursor known to deposit in ocular tissue. Although its presentation is protean, it is rarely seen in the orbit. We report the case of an 85-year-old woman with primary orbital amyloidosis causing internal and external ophthalmoplegia. Strabismus surgery with muscle biopsy alleviated her symptoms and assisted with solving the diagnostic challenge.
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http://dx.doi.org/10.1016/j.jaapos.2019.11.003DOI Listing
February 2020

The Story: Characterization and Cloning of the First Tumor Suppressor Gene.

Genes (Basel) 2019 11 1;10(11). Epub 2019 Nov 1.

Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada.

The gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.
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http://dx.doi.org/10.3390/genes10110879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895859PMC
November 2019

Complement Proteins in the Retina in Cancer-Associated Retinopathy.

JAMA Ophthalmol 2019 Oct 31. Epub 2019 Oct 31.

Department of Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1001/jamaophthalmol.2019.4405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824225PMC
October 2019

A Review of Next-Generation Sequencing (NGS): Applications to the Diagnosis of Ocular Infectious Diseases.

Semin Ophthalmol 2019 6;34(4):223-231. Epub 2019 Jun 6.

a David G Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary , Harvard Medical School , Boston , MA , USA.

: To review the value of next-generation sequencing (NGS) in identifying the pathogens which cause ocular infections, thereby facilitating prompt initiation of treatment with an optimal anti-microbial regimen. Both contemporary and futuristic approaches to identifying pathogens in ocular infections are covered in this brief overview. : Review of the peer reviewed literature on conventional and advanced methods as applied to the diagnosis of infectious diseases of the eye. : NGS is a novel technology for identifying the pathogens responsible for ocular infections with the potential to improve the accuracy and speed of diagnosis and hastening the selection of the best therapy.
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http://dx.doi.org/10.1080/08820538.2019.1620800DOI Listing
July 2019

A Review of the Role of Cytogenetics in the Diagnosis of Orbital Rhabdomyosarcoma.

Semin Ophthalmol 2019 30;34(4):243-251. Epub 2019 May 30.

a David G. Cogan Laboratory of Ophthalmic Pathology , Massachusetts Eye and Ear Infirmary/Harvard Medical School , Boston , MA , USA.

Rhabdomyosarcoma (RMS) is the most common sarcoma of childhood and adolescence. Approximately 10% arise in the orbit, where the embryonal type is most common variant. The alveolar variant is less frequent and has a worse prognosis. Cytogenetic studies have revealed that most alveolar rhabdomyosarcomas have translocations involving the PAX and the FOX01 genes, giving rise to fusion genes that contribute to lack of differentiation and proliferation of the tumor cells. However, approximately 20% of alveolar rhabdomyosarcomas lack translocations and have been found to behave more similarly to embryonal cases. Histopathology remains the basis of diagnosis, but cytogenetic features and molecular signatures are becoming part of the routine analysis of RMS, since they determine not only prognosis, but also management and treatment regimens. A comprehensive review of the recent published literature in relation to orbital rhabdomyosarcomas and their cytogenetic features as well as clinical and therapeutic implications will be discussed.
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http://dx.doi.org/10.1080/08820538.2019.1620802DOI Listing
July 2019

Using Healthcare Databases to Refine Understanding of Exploratory Associations Between Drugs and Progression of Open-Angle Glaucoma.

Clin Pharmacol Ther 2019 10 14;106(4):874-883. Epub 2019 Jun 14.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

We sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs.
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http://dx.doi.org/10.1002/cpt.1490DOI Listing
October 2019

Induction of Ocular Complement Activation by Inflammatory Stimuli and Intraocular Inhibition of Complement Factor D in Animal Models.

Invest Ophthalmol Vis Sci 2018 02;59(2):940-951

Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

Purpose: Genome-wide association studies suggest a role for the complement system in age-related macular degeneration (AMD). We characterized ocular complement activation and evaluated a complement factor D (FD) neutralizing antibody.

Methods: Mice were treated with toll-like receptor (TLR) ligands, intravitreal injection (IVT), or corneal debridement. Levels of complement proteins and mRNA were measured. A FD neutralizing antibody was administered IVT into eyes of rabbits that were challenged with LPS (lipopolysaccharide) administered intravenously.

Results: Levels of C3 and factor B (FB) mRNA and protein in the eye were increased following intraperitoneal injection of TLR4 ligand LPS. Increased levels of C3 and FB breakdown products were observed in both eye tissues and plasma. Complement activation products were markedly reduced in C3-/- and Cfb-/- mice challenged with LPS. Ocular complement levels were also elevated in mice treated systemically with TLR2 and -3 ligands, injured by IVT injection or corneal debridement, or even in normal aging. IVT administration of a complement FD neutralizing antibody in rabbits inhibited LPS-induced complement activation in the posterior segment of the eye, but not in the anterior segment of the eye or in plasma.

Conclusions: Systemic TLR stimulation and eye tissue injury induced time-dependent alternative complement pathway activation in the eye. Ocular complement levels were also gradually elevated during aging. An anti-FD antibody IVT potently inhibited LPS-induced complement activation in the posterior segment of the eye. This study provides insights into the dynamic profile of ocular complement activation, which is valuable for complement research in eye diseases and for developing complement therapeutics for AMD.
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http://dx.doi.org/10.1167/iovs.17-22605DOI Listing
February 2018

Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma.

Ophthalmology 2018 07 9;125(7):984-993. Epub 2018 Feb 9.

NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom. Electronic address:

Purpose: To identify associations between systemic medications and primary open-angle glaucoma (POAG) requiring a procedure using United States insurance claims data in a hypothesis-generating study.

Design: Database study.

Participants: In total, 6130 POAG cases (defined as patients with POAG undergoing a glaucoma procedure) were matched to 30 650 controls (defined as patients undergoing cataract surgery but without a coded glaucoma diagnosis, procedure, or medication) by age, gender, and region of residence.

Methods: Participant prescription drug use was calculated for the 5-year period before the glaucoma procedure or cataract surgery. Separately for individual generic drugs and drug classes, logistic regression was used to assess the association with POAG status. This was done across all generic drugs and drug classes that were prescribed in at least 1% of cases and controls. Analyses were adjusted for age, sex, region of residence, employment status, insurance plan type, and the total number of drugs prescribed.

Main Outcome Measures: Odds ratio (OR) and 95% confidence intervals (CIs) for the association between each drug or drug class and POAG.

Results: The median age of participants was 72 years, and 52% were women. We tested for associations of POAG with 423 drug classes and 1763 generic drugs, resulting in a total of 2186 statistical tests and a Bonferroni-adjusted significance threshold of P < 2.3 × 10. Selective serotonin reuptake inhibitors (SSRIs) were strongly associated with a reduced risk of POAG (OR, 0.70; 95% CI, 0.64-0.76; P = 1.0 × 10); the most significant drug in this class was citalopram (OR, 0.66; 95% CI, 0.57-0.77; P = 1.2 × 10). Calcium channel blockers were strongly associated with an increased risk of POAG (OR, 1.26; 95% CI, 1.18-1.35; P = 1.8 × 10); the most significant drug in this class was amlodipine (OR, 1.27; 95% CI, 1.18-1.37; P = 5.9 × 10).

Conclusions: We present data documenting potential associations of SSRIs and calcium channel blockers with POAG requiring a procedure. Further research may be indicated to better evaluate any associates of serotonin metabolism or calcium channels in glaucoma, or establish whether the associations are due to variations in the patterns for prescribing these drugs.
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http://dx.doi.org/10.1016/j.ophtha.2018.01.007DOI Listing
July 2018

Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma.

Ophthalmic Plast Reconstr Surg 2018 May/Jun;34(3):e83-e85

Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA and Associate Eye Physicians and Surgeons, Quincy, Massachusetts, U.S.A.

A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf-Schulz-Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz-Gorlin) syndrome with apocrine cysts but again without neoplasia.
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http://dx.doi.org/10.1097/IOP.0000000000001069DOI Listing
July 2018

Mild Complications or Unusual Persistence of Porcine Collagen and Hyaluronic Acid Gel Following Periocular Filler Injections.

Ophthalmic Plast Reconstr Surg 2018 Sep/Oct;34(5):e143-e146

Ophthalmic Plastic and Reconstructive Surgery Service, Department of Ophthalmology of the Massachusetts Eye and Ear Infirmary and the Harvard Medical School, Boston, Massachusetts, U.S.A.

The purpose of this study was to describe the histopathologic appearance of dermal eyelid fillers that were unexpectedly encountered in ophthalmic plastic surgery samples from patients with mild eyelid disfigurements, and to review eyelid cases with complications that had previously been described in the literature. A retrospective histopathologic study with Alcian blue, elastic, and Masson trichrome stains of 2 cases that were submitted to the Ocular Pathology Department was conducted, and a critical review of previously published cases of the histopathologic characteristics of dermal filler material in the periocular region was also conducted. Two periocular tissue samples were found to contain dermal filler material. In one case, porcine collagen appeared as amorphous or indistinctly microfibrillar aggregates that stained light blue with the Masson trichrome method. In the other case, hyaluronic acid gel appeared as vivid blue amorphous pools of material in extracellular locules after staining with the Alcian blue method. An inflammatory response was not observed in either case. Patients who undergo facial filler procedures may, at a later time, require a surgical excisional procedure from which a specimen is generated. Previously injected dermal filler that the patient neglected to mention may be present in the pathologic sample, potentially perplexing the unsuspecting pathologist. Both ophthalmic plastic surgeons and ocular pathologists should be aware of the histopathologic features of dermal fillers. It is helpful if a surgeon who submits a specimen to the pathology service makes note of any known prior use of facial filler material or is alert to its possible presence when unfamiliar foreign material is discovered in the dermis of the eyelids.
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http://dx.doi.org/10.1097/IOP.0000000000001029DOI Listing
September 2018

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of .

Mol Vis 2017 14;23:318-333. Epub 2017 Jun 14.

Department of Ophthalmology; NIBR Informatics, Novartis Institutes for Biomedical Research, Cambridge, MA.

Purpose: A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplotype that confers high risk for age-related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs.

Methods: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype-Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs.

Results: There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, , , and varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For , 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10 in ovary). With regard to , the variation is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10). For , the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 × 10 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high-AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of and but not that of ; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells.

Conclusions: SNPs in chromosome 10q26 that influence the expression of only or are not associated with risk for AMD, while most SNPs that influence the expression of are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in expression. Modulating activity might be a potential therapy for AMD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479693PMC
April 2018

A Compact Whole-Eye Perfusion System to Evaluate Pharmacologic Responses of Outflow Facility.

Invest Ophthalmol Vis Sci 2017 06;58(7):2991-3003

Department of Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States.

Purpose: To discover novel therapies that lower IOP by increasing aqueous humor outflow facility, ex vivo ocular perfusion systems provide a valuable tool. However, currently available designs are limited by their throughput. Here we report the development of a compact, scalable perfusion system with improved throughput and its validation using bovine and porcine eyes.

Methods: At a fixed IOP of 6 mm Hg, flow rate was measured by flow sensors. We validated the system by measuring the outflow responses to Y-39983 (a Rho kinase inhibitor), endothelin-1 (ET-1), ambrisentan (an antagonist for endothelin receptor A [ETA]), sphigosine-1-phosphate (S1P), JTE-013 (antagonist for S1P receptor 2 [S1P2]), S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide [NO] donor), and 3-Morpholino-sydnonimine (SIN-1, another NO donor).

Results: The instrument design enabled simultaneous measurements of 20 eyes with a footprint of 1 m2. Relative to vehicle control, Y-39983 increased outflow by up to 31% in calf eyes. On the contrary, ET-1 decreased outflow by up to 79%, a response that could be blocked by pretreatment with ambrisentan, indicating a role for ETA receptors. Interestingly, the effect of ET-1 was also inhibited by up to 70% to 80% by pretreatment with NO donors, SNAP and SIN-1. In addition to testing in calf eyes, similar effects of ET-1 and ambrisentan were observed in adult bovine and porcine eyes.

Conclusions: The compact eye perfusion platform provides an opportunity to efficiently identify compounds that influence outflow facility and may lead to the discovery of new glaucoma therapies.
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http://dx.doi.org/10.1167/iovs.16-20974DOI Listing
June 2017

Long-acting protein drugs for the treatment of ocular diseases.

Nat Commun 2017 03 23;8:14837. Epub 2017 Mar 23.

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3-4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3-4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.
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http://dx.doi.org/10.1038/ncomms14837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376645PMC
March 2017

Early Insight Into Neovascular Age-Related Macular Degeneration.

Authors:
Thaddeus P Dryja

JAMA Ophthalmol 2016 11;134(11):1281-1282

Novartis Institutes for Biomedical Research, Cambridge, Massachusetts2Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.

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http://dx.doi.org/10.1001/jamaophthalmol.2016.3031DOI Listing
November 2016

Dry Eye Signs and Symptoms Persist During Systemic Neutralization of IL-1β by Canakinumab or IL-17A by Secukinumab.

Cornea 2015 Dec;34(12):1551-6

*Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, MA; †Biometrics Matters Ltd, Hamilton, New Zealand; and ‡Ophthalmology Research, Novartis Institutes for Biomedical Research, Cambridge, MA.

Purpose: To evaluate whether inhibition of the proinflammatory cytokines IL-1β or IL-17A by canakinumab or secukinumab, respectively, influence the signs and symptoms of dry eye.

Methods: In a randomized, double-masked, placebo-controlled, outpatient clinical trial, 72 patients with moderate to severe dry eye were randomly assigned in a 1:1:1 ratio to treatment with a single intravenous dose of canakinumab, of secukinumab, or of placebo. Signs and symptoms of dry eye were evaluated on the treatment day and 1 week, 4 weeks, and 8 weeks after treatment. The prespecified primary efficacy endpoint was corneal staining in the study eye 4 weeks after treatment. Secondary endpoints included tear production (Schirmer test), tear film breakup time, conjunctival redness, the ocular surface disease index (OSDI), the frequency of a desire for a topical ocular lubricant, and visual acuity.

Results: Of the 71 patients included in the analysis of safety, the rate of adverse events was similar between treatment groups. The course of corneal staining scores from baseline to 4 weeks, respectively, were for canakinumab 1.46 to 1.33 (P = 0.62 compared with placebo), for secukinumab 1.46 to 1.23 (P = 0.22), and for placebo 1.68 to 1.42. There were no changes in the other measures of efficacy beyond what was within the range expected for stochastic day-to-day variation.

Conclusions: The results suggest that the inhibition of IL-1β or IL-17A obtained by systemic administration of neutralizing drugs does not influence the severity of dry eye.
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http://dx.doi.org/10.1097/ICO.0000000000000627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633966PMC
December 2015

AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice.

Mol Ther Methods Clin Dev 2015 8;2:15022. Epub 2015 Jul 8.

Ophthalmology Disease Area, Novartis Institutes for BioMedical Research , Cambridge, Massachusetts, USA.

Recessive mutations in RLBP1 cause a form of retinitis pigmentosa in which the retina, before its degeneration leads to blindness, abnormally slowly recovers sensitivity after exposure to light. To develop a potential gene therapy for this condition, we tested multiple recombinant adeno-associated vectors (rAAVs) composed of different promoters, capsid serotypes, and genome conformations. We generated rAAVs in which sequences from the promoters of the human RLBP1, RPE65, or BEST1 genes drove the expression of a reporter gene (green fluorescent protein). A promoter derived from the RLBP1 gene mediated expression in the retinal pigment epithelium and Müller cells (the intended target cell types) at qualitatively higher levels than in other retinal cell types in wild-type mice and monkeys. With this promoter upstream of the coding sequence of the human RLBP1 gene, we compared the potencies of vectors with an AAV2 versus an AAV8 capsid in transducing mouse retinas, and we compared vectors with a self-complementary versus a single-stranded genome. The optimal vector (scAAV8-pRLBP1-hRLBP1) had serotype 8 capsid and a self-complementary genome. Subretinal injection of scAAV8-pRLBP1-hRLBP1 in Rlbp1 nullizygous mice improved the rate of dark adaptation based on scotopic (rod-plus-cone) and photopic (cone) electroretinograms (ERGs). The effect was still present after 1 year.
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http://dx.doi.org/10.1038/mtm.2015.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495722PMC
July 2015

Reliability of the mouse model of choroidal neovascularization induced by laser photocoagulation.

Invest Ophthalmol Vis Sci 2014 Sep 9;55(10):6525-34. Epub 2014 Sep 9.

Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

Purpose: We attempted to reproduce published studies that evaluated whether the following factors influence choroidal neovascularization (CNV) induced by laser photocoagulation in murine retinas: small interfering RNA (siRNA), cobra venom factor, complement factors C3 and C5, and complement receptor C5aR. In addition, we explored whether laser-induced CNV in mice was influenced by the vendor of origin of the animals.

Methods: Reagents or genotypes reported by others to influence CNV in this model were assessed using our standard procedures. Retrospective analyses of control or placebo mice in many experiments were done to evaluate whether the CNV area induced by laser photocoagulation varied according to vendor.

Results: Administration of the following agents did not have a substantial impact on the CNV induced by laser burns in mice: siRNA, low-molecular-weight inhibitor of the C5a receptor (PMX53), or cobra venom factor. Jackson Laboratory (JAX) mice lacking either C3 or C5 had increased neovascularization compared to non-littermate JAX wild-type controls. Taconic mice lacking C3 had reduced CNV compared to non-littermate Taconic wild-type control mice. A retrospective analysis of vehicle-treated wild-type C57BL/6 mice used as controls across 132 experiments conducted from 2007 to 2010 revealed that mice purchased from JAX or from Charles River produced less neovascularization than mice from Taconic.

Conclusions: We present our recommended methods for conducting experiments with the mouse laser-induced CNV model to enhance reproducibility and minimize investigator bias.
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http://dx.doi.org/10.1167/iovs.14-15067DOI Listing
September 2014

Interview with Thaddeus P. Dryja, MD. Interviewed by George B. Bartley.

Authors:
Thaddeus P Dryja

Arch Ophthalmol 2012 Jan;130(1):111-2

Department of Ophthalmology, Harvard Medical School, , Cambridge, MA, USA.

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http://dx.doi.org/10.1001/archophthalmol.2011.382DOI Listing
January 2012

Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.

J Med Genet 2010 Jul 27;47(7):499-506. Epub 2010 May 27.

Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.

Background: Usher syndrome type II (USH2) is an autosomal recessive disorder characterised by retinitis pigmentosa (RP) and mild to moderate sensorineural hearing loss. Mutations in the USH2A gene are the most common cause of USH2 and are also a cause of some forms of RP without hearing loss (ie, non-syndromic RP). The USH2A gene was initially identified as a transcript comprised of 21 exons but subsequently a longer isoform containing 72 exons was identified.

Methods: The 51 exons unique to the long isoform of USH2A were screened for mutations among a core set of 108 patients diagnosed with USH2 and 80 patients with non-syndromic RP who were all included in a previously reported screen of the short isoform of USH2A. For several exons, additional patients were screened.

Results: In total, 35 deleterious mutations were identified including 17 nonsense mutations, 9 frameshift mutations, 5 splice-site mutations, and 4 small in-frame deletions or insertions. Twenty-seven mutations were novel. In addition, 65 rare missense changes were identified. A method of classifying the deleterious effect of the missense changes was developed using the summed results of four different mutation assessment algorithms, SIFT, pMUT, PolyPhen, and AGVGD. This system classified 8 of the 65 changes as 'likely deleterious' and 9 as 'possibly deleterious'.

Conclusion: At least one mutation was identified in 57-63% of USH2 cases and 19-23% of cases of non-syndromic recessive RP (calculated without and including probable/possible deleterious changes) thus supporting that USH2A is the most common known cause of RP in the USA.
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http://dx.doi.org/10.1136/jmg.2009.075143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070405PMC
July 2010

Response of choroidal leiomyoma to treatment with proton beam radiation.

Retin Cases Brief Rep 2010 ;4(2):168-73

From the *Department of Ophthalmology, Weill Cornell Eye Associates, Weill Cornell Medical School, New York, New York; †Department of Ophthalmology, Retina Service, Massachusetts Eye and Ear Infirmary, Boston; ‡Department of Ophthalmology, Novartis Institute for Biomedical Research, Inc, Cambridge; and §Department of Ophthalmology, David G. Cogan Eye Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

Purpose: Uveal leiomyoma is a rare, benign smooth muscle neoplasm usually diagnosed only after local resection or enucleation. We describe a single interventional case report with clinicopathologic correlation of an intraocular leiomyoma responding to proton beam radiation.

Case Report: A 51-year-old woman presented with a choroidal mass in the left eye that was initially diagnosed as a choroidal melanoma. The neoplasm was treated with a total of 70 cobalt gray equivalents of external proton beam radiation in 5 fractions over 7 days. Biannual follow-up examinations over 3 years showed a funduscopically and ultrasonographically regressing tumor. The left eye was enucleated approximately 3 years postradiotherapy because of progressively increasing pain secondary to elevated intraocular pressure from neovascular glaucoma. Microscopic and immunohistochemical examination of the mass revealed a choroidal neoplasm expressing smooth muscle antigens consistent with a uveal leiomyoma.

Conclusion: Uveal leiomyoma appears to be responsive to proton beam radiation, and radiotherapy may serve as an alternative to primary enucleation or local resection. Additional studies are necessary to determine whether radiotherapy of smaller tumors might render better results for vision and globe preservation.
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http://dx.doi.org/10.1097/ICB.0b013e3181a7d066DOI Listing
November 2014

Search for a correlation between telomere length and severity of retinitis pigmentosa due to the dominant rhodopsin Pro23His mutation.

Mol Vis 2009 27;15:592-7. Epub 2009 Mar 27.

Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Purpose: Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa (RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, and apoptosis. We evaluated whether the length of telomeres in leukocytes correlated with the severity of RP in patients with the Pro23His rhodopsin mutation who have shown marked heterogeneity in disease severity.

Methods: We evaluated 122 patients with the Pro23His rhodopsin mutation. The patients' retinal function was stratified according to their 30-Hz cone electroretinogram (ERG). The length of telomeres in leukocytes was measured by the quantitative real time polymerase chain reaction (qRT-PCR) method in the 15 patients with the highest age-adjusted 30-Hz ERG amplitudes and in the 15 patients with the lowest amplitudes.

Results: Mean leukocyte telomere length was similar in the 15 patients with the highest cone ERG amplitudes (median: 0.40 units; interquartile range 0.36-0.56) and the 15 patients with the lowest cone amplitudes (median: 0.41 units; inter quartile range 0.34 -0.64; p=0.95).

Conclusions: We found no evidence for an association between telomere length and the severity of RP as monitored by the cone ERG in patients with the Pro23His rhodopsin mutation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661004PMC
April 2009

A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa.

Invest Ophthalmol Vis Sci 2009 Apr 13;50(4):1864-72. Epub 2008 Dec 13.

Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Massachusetts 02114, USA.

Purpose: Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP gene (RBP3) are associated with photoreceptor degeneration.

Methods: A consanguineous family was ascertained in which four children had autosomal recessive retinitis pigmentosa (RP). Homozygosity mapping performed with SNP microarrays revealed only one homozygous region shared by all four affected siblings. Sequencing of RBP3, contained in this region, was performed in this family and others with recessive RP. Screening was also performed on patients with various other forms of retinal degeneration or malfunction.

Results: Sequence analysis of RBP3 revealed a homozygous missense mutation (p.Asp1080Asn) in the four affected siblings. The mutation affects a residue that is completely conserved in all four homologous modules of the IRBP protein of vertebrate species and in C-terminal-processing proteases, photosynthesis enzymes found in bacteria, algae, and plants. Based on the previously reported crystal structure of Xenopus IRBP, the authors predict that the Asp1080-mediated conserved salt bridge that appears to participate in scaffolding of the retinol-binding domain is abolished by the mutation. No RBP3 mutations were detected in 395 unrelated patients with recessive or isolate RP or in 680 patients with other forms of hereditary retinal degeneration.

Conclusions: Mutations in RBP3 are an infrequent cause of autosomal recessive RP. The mutation Asp1080Asn may alter the conformation of the IRBP protein by disrupting a conserved salt bridge.
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http://dx.doi.org/10.1167/iovs.08-2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823395PMC
April 2009

Diagnosis in a patient with fundus albipunctatus and atypical fundus changes.

Doc Ophthalmol 2009 Jun 24;118(3):233-8. Epub 2008 Oct 24.

Department of Ophthalmology and Visual Sciences (MC 648), Eye and Ear Infirmary, University of Illinois at Chicago, 1855 W Taylor Street, Chicago, IL 60612-7234, USA.

We report a case of an 11-year old Caucasian female with nyctalopia since early childhood with an atypical clinical presentation of fundus albipunctatus (FA), and a novel mutation in the RDH5 gene. In addition to white spots in the fundus, patchy areas of hypopigmentation were noted, which were reminiscent for an early stage of retinitis punctata albescens (RPA). Electroretinographic testing (ERG) showed a non-detectable, dark adapted, isolated rod response and a markedly decreased combined rod and cone response to an achromatic stimulus. After patching one eye overnight, both the isolated rod response and combined rod and cone scotopic white flash response were normal. A Goldmann-Weekers dark adapted final threshold response was also within the normal range. The patient showed a previously reported heterozygous mutation for Gly238Trp, and a novel Arg157Gln mutation. Genetic testing and extended ERG and psychophysical testing may be necessary to diagnose FA from early stages of progressive RPA.
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http://dx.doi.org/10.1007/s10633-008-9151-8DOI Listing
June 2009

Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle.

Nat Genet 2008 Oct 21;40(10):1230-4. Epub 2008 Sep 21.

Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts 02114, USA.

Here we describe two families with retinitis pigmentosa, a hereditary neurodegeneration of rod and cone photoreceptors in the retina. Affected family members were homozygous for loss-of-function mutations in IDH3B, encoding the beta-subunit of NAD-specific isocitrate dehydrogenase (NAD-IDH, or IDH3), which is believed to catalyze the oxidation of isocitrate to alpha-ketoglutarate in the citric acid cycle. Cells from affected individuals had a substantial reduction of NAD-IDH activity, with about a 300-fold increase in the K(m) for NAD. NADP-specific isocitrate dehydrogenase (NADP-IDH, or IDH2), an enzyme that catalyzes the same reaction, was normal in affected individuals, and they had no health problems associated with the enzyme deficiency except for retinitis pigmentosa. These findings support the hypothesis that mitochondrial NADP-IDH, rather than NAD-IDH, serves as the main catalyst for this reaction in the citric acid cycle outside the retina, and that the retina has a particular requirement for NAD-IDH.
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http://dx.doi.org/10.1038/ng.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596605PMC
October 2008

Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration.

Mol Vis 2008 Aug 11;14:1487-95. Epub 2008 Aug 11.

Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Purpose: To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort.

Methods: We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified.

Results: Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified.

Conclusions: We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515825PMC
August 2008

Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.

Invest Ophthalmol Vis Sci 2008 Dec 18;49(12):5532-9. Epub 2008 Jul 18.

The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

Purpose: To estimate the mean rates of ocular function loss in patients with autosomal recessive retinitis pigmentosa due to USH2A mutations.

Methods: In 125 patients with USH2A mutations, longitudinal regression was used to estimate mean rates of change in Snellen visual acuity, Goldmann visual field area (V4e white test light), and 30-Hz (cone) full-field electroretinogram amplitude. These rates were compared with those of previously studied cohorts with dominant retinitis pigmentosa due to RHO mutations and with X-linked retinitis pigmentosa due to RPGR mutations. Rates of change in patients with the Cys759Phe mutation, the USH2A mutation associated with nonsyndromic disease, were compared with rates of change in patients with the Glu767fs mutation, the most common USH2A mutation associated with Usher syndrome type II (i.e., retinitis pigmentosa and hearing loss).

Results: Mean annual exponential rates of decline for the USH2A patients were 2.6% for visual acuity, 7.0% for visual field area, and 13.2% for electroretinogram amplitude. The rate of acuity loss fell between the corresponding rates for the RHO and RPGR patients, whereas the rates for field and ERG amplitude loss were faster than those for the RHO and RPGR patients. No significant differences were found for patients with the Cys759Phe mutation versus patients with the Glu767fs mutation.

Conclusions: On average, USH2A patients lose visual acuity faster than RHO patients and slower than RPGR patients. USH2A patients lose visual field and cone electroretinogram amplitude faster than patients with RHO or RPGR mutations. Patients with a nonsyndromic USH2A mutation have the same retinal disease course as patients with syndromic USH2A disease.
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http://dx.doi.org/10.1167/iovs.08-2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588642PMC
December 2008

Alleles in the HtrA serine peptidase 1 gene alter the risk of neovascular age-related macular degeneration.

Ophthalmology 2008 Jul 27;115(7):1209-1215.e7. Epub 2007 Dec 27.

Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.

Objective: To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.

Design: Retrospective matched-pair case-control study.

Participants: Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).

Methods: Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations.

Main Outcome Measure: Neovascular AMD status.

Results: Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10(-15)). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.

Conclusions: Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.
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http://dx.doi.org/10.1016/j.ophtha.2007.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242506PMC
July 2008