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2014

Cruz N, Yuan Y, Leehy B, Baid R, Kompella U, Deangelis M, Escher P, Haider N. Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease. PLoS One. 2014;9(1):e87942.
Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.
Damico FM, Takahashi B, Acquesta F. Transscleral delivery of Nd: YLF laser at 1,047 nm causes vascular occlusion in experimental pigmented choroidal melanoma. Retina. 2014;34(4):792–800.
PURPOSE: The aims of this study were to determine the scleral attenuation of focused neodymium: yttrium-lanthanum-fluoride laser at 1,047 nm applied transsclerally and whether transscleral delivery can close the vascular supply at the base of experimental choroidal melanoma in rabbits. METHODS: Fifty-two New Zealand albino rabbits were included. Scleral laser attenuation was measured across fresh sclera. B16F10 melanomas were established in the subchoroidal space of 49 rabbits. Twenty-one animals were killed immediately after transscleral treatment, 14 were followed for 2 weeks to 4 weeks, and 14 were followed without treatment. Ophthalmoscopy, fundus photographs, and fluorescein angiography were performed before treatment, immediately after, and weekly during the follow-up. Eyes were examined by light microscopy. RESULTS: Sclera attenuated laser energy by 31% ± 7%. Immediately after treatment, angiography showed diffuse hypofluorescence in 71% (15 of 21 rabbits). Light microscopy showed vascular occlusion extending at least two thirds of the tumor thickness from the base. Seven of the 14 tumors followed for 15 days ± 8 days were eradicated. There was no correlation between tumor height and eradication. CONCLUSION: Rabbit sclera attenuated 31% ± 7% of laser energy. A single transscleral treatment causes tumor vascular closure at the base and may serve as an adjuvant therapy to ensure destruction of deep and intrascleral tumor cells.
Ding J, Sullivan D. The effects of insulin-like growth factor 1 and growth hormone on human meibomian gland epithelial cells. JAMA Ophthalmol. 2014;132(5):593–9.
IMPORTANCE: A phase 1 study has reported that dry eye disease is the most common adverse effect of human exposure to the antibody figitumumab, an anticancer drug that prevents insulin-like growth factor 1 (IGF-1) from binding to its receptor. We hypothesized that the mechanism underlying this effect is the inhibition of IGF-1 action in epithelial cells of the meibomian gland. OBJECTIVES: To test the hypothesis that IGF-1 stimulates meibomian gland function in vitro and to examine whether growth hormone, a closely related hormone of IGF-1, has the same effect. DESIGN, SETTING, AND MATERIAL: Immortalized human meibomian gland epithelial cells were cultured in the presence or the absence of IGF-1, growth hormone, and an IGF-1 receptor-blocking antibody. Signaling pathways, cell proliferation, neutral lipid staining, and a key protein involved in lipid biogenesis were evaluated. INTERVENTION: Application of IGF-1 and growth hormone to human meibomian gland epithelial cells. MAIN OUTCOMES AND MEASURES: Immunoblotting, cell counting, and neutral lipid staining. RESULTS Insulin-like growth factor 1 activated the phosphoinositol 3-kinase/Akt and forkhead box O1 pathways (showing a dose-dependent effect on immunoblotting), stimulated cellular proliferation (about 1.8-fold increase in cell number), increased sterol regulatory element-binding protein 1 expression (about 3-fold increase on immunoblotting), and promoted lipid accumulation in human meibomian gland epithelial cells (about 2-fold increase in lipid staining). These IGF-1 actions, which may be blocked by cotreatment with the anti-IGF-1 antibody, were accompanied by inconsistent effects on extracellular signal-regulated kinase phosphorylation. We were not able to demonstrate activation of Akt, forkhead box O1, extracellular signal-regulated kinase, Janus kinase 2, or signal transducers and activators of transcription 5, induced cell proliferation, or lipid accumulation in these cells by growth hormone application. CONCLUSIONS AND RELEVANCE: Our results support the hypothesis that IGF-1 acts on human meibomian gland epithelial cells and may explain why treatment with figitumumab, the IGF-1 inhibitor, causes dry eye disease. Ophthalmic care for dry eye disease may be needed when patients with cancer undergo treatment with drugs that inhibit IGF-1 action.
Benaglio P, San Jose PF, Avila-Fernandez A, Ascari G, Harper S, Manes G, Ayuso C, Hamel C, Berson E, Rivolta C. Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.. Mol Vis. 2014;20:843–51.

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.

Bujakowska K, Consugar M, Place E, Harper S, Lena J, Taub D, White J, Navarro-Gomez D, Weigel DiFranco C, Farkas M, Gai X, Berson E, Pierce E. Targeted exon sequencing in Usher syndrome type I.. Invest Ophthalmol Vis Sci. 2014;55(12):8488–96.

PURPOSE: Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. METHODS: The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. RESULTS: With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. CONCLUSIONS: We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study.

Simon S, Chee Y, Haddadin R, Veldman P, Borboli-Gerogiannis S, Brauner S, Chang K, Chen S, Gardiner M, Greenstein S, Kloek C, Chen T. Achieving target refraction after cataract surgery.. Ophthalmology. 2014;121(2):440–4.
PURPOSE: To evaluate the difference between target and actual refraction after phacoemulsification and intraocular lens implantation at an academic teaching institution's Comprehensive Ophthalmology Service. DESIGN: Retrospective study. PARTICIPANTS: We examined 1275 eye surgeries for this study. METHODS: All consecutive cataract surgeries were included if they were performed by an attending or resident surgeon from January through December 2010. Postoperative refractions were compared with preoperative target refractions. Patients were excluded if they did not have a preoperative target refraction documented or if they did not have a recorded postoperative manifest refraction within 90 days. MAIN OUTCOME MEASURES: The main outcome measure was percentage of cases achieving a postoperative spherical equivalent ± 1.0 diopter (D) of target spherical equivalent. RESULTS: We performed 1368 cataract surgeries from January through December of 2010. Of these, 1275 (93%) had sufficient information for analysis. Of the included cases, 94% (1196 of 1275) achieved ± 1.0 D of target refraction by 90 days after cataract surgery. CONCLUSIONS: This paper establishes a new benchmark for a teaching hospital, where 94% of patients achieved within 1.0 D of target refraction after cataract surgery. The refractive outcomes after cataract surgery at this academic teaching institution were higher than average international benchmarks.
Wan M, Adebona O, Benson L, Gorman M, Heidary G. Visual outcomes in pediatric optic neuritis. Am J Ophthalmol. 2014;158(3):503–7.e2.
PURPOSE: To describe the visual outcomes of a large cohort of pediatric patients presenting to a tertiary care pediatric hospital with first-episode optic neuritis. DESIGN: Retrospective, observational cohort study. METHODS: In a tertiary care pediatric hospital, patients with first-episode optic neuritis and at least 3 months of follow-up over a 10-year period were assessed and followed-up in the ophthalmology department. The main outcome measures were visual acuity at 3 months and 1 year of follow-up, with analysis of risk factors for poor visual outcomes and the time course of visual recovery. RESULTS: Of the 59 pediatric patients with first-episode optic neuritis, 46 had at least 3 months of follow-up and 36 had at least 1 year of follow-up. The mean age was 12.6 years old; 72% were female, 41% had bilateral involvement, 52% had or developed an underlying diagnosis (39% multiple sclerosis, 7% acute disseminated encephalomyelitis, 7% neuromyelitis optica), and 91% received treatment (85% steroids, 7% multimodal). At 1 year, 81% were at least 20/20 and 89% were at least 20/40. A poor visual outcome at 1 year (<20/40) was associated with vision of <20/20 at 3 months (P = 0.041). Other clinical characteristics, including visual acuity at presentation, sex, bilateral involvement, optic nerve edema, and underlying diagnoses were not significantly associated with poor visual outcomes. CONCLUSIONS: In this cohort of pediatric patients with optic neuritis, the majority of patients regained normal visual acuity at 1 year, regardless of baseline clinical characteristics.
Yonekawa Y, Hacker H, Lehman R, Beal C, Veldman P, Vyas N, Shah A, Wu D, Eliott D, Gardiner M, Kuperwaser M, Rosa R, Ramsey J, Miller J, Mazzoli R, Lawrence M, Arroyo J. Ocular blast injuries in mass-casualty incidents: the marathon bombing in Boston, Massachusetts, and the fertilizer plant explosion in West, Texas. Ophthalmology. 2014;121(9):1670–6.e1.
PURPOSE: To report the ocular injuries sustained by survivors of the April 15, 2013, Boston Marathon bombing and the April 17, 2013, fertilizer plant explosion in West, Texas. DESIGN: Multicenter, cross-sectional, retrospective, comparative case series. PARTICIPANTS: Seventy-two eyes of 36 patients treated at 12 institutions were included in the study. METHODS: Ocular and systemic trauma data were collected from medical records. MAIN OUTCOME MEASURES: Types and severity of ocular and systemic trauma and associations with mechanisms of injury. RESULTS: In the Boston cohort, 164 of 264 casualties were transported to level 1 trauma centers, and 22 (13.4%) required ophthalmology consultations. In the West cohort, 218 of 263 total casualties were transported to participating centers, of which 14 (6.4%) required ophthalmology consultations. Boston had significantly shorter mean distances to treating facilities (1.6 miles vs. 53.6 miles; P = 0.004). Overall, rigid eye shields were more likely not to have been provided than to have been provided on the scene (P<0.001). Isolated upper body and facial wounds were more common in West largely because of shattered windows (75.0% vs. 13.6%; P = 0.001), resulting in more open-globe injuries (42.9% vs. 4.5%; P = 0.008). Patients in Boston sustained more lower extremity injuries because of the ground-level bomb. Overall, 27.8% of consultations were called from emergency rooms, whereas the rest occurred afterward. Challenges in logistics and communications were identified. CONCLUSIONS: Ocular injuries are common and potentially blinding in mass-casualty incidents. Systemic and ocular polytrauma is the rule in terrorism, whereas isolated ocular injuries are more common in other calamities. Key lessons learned included educating the public to stay away from windows during disasters, promoting use of rigid eye shields by first responders, the importance of reliable communications, deepening the ophthalmology call algorithm, the significance of visual incapacitation resulting from loss of spectacles, improving the rate of early detection of ocular injuries in emergency departments, and integrating ophthalmology services into trauma teams as well as maintaining a voice in hospital-wide and community-based disaster planning.
Yang S, MacKinnon S, Dagi L, Hunter D. Superior rectus transposition vs medial rectus recession for treatment of esotropic Duane syndrome. JAMA Ophthalmol. 2014;132(6):669–75.
IMPORTANCE: Superior rectus transposition (SRT) with or without medial rectus recession (MRc) has been introduced as an alternative to MRc alone for treatment of esotropic Duane syndrome; however, the effectiveness of these procedures has not been compared previously. OBJECTIVE: To compare the safety and efficacy of MRc and SRT in treatment of Duane syndrome. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of all patients with esotropic Duane syndrome who underwent surgical treatment from January 1, 2006, through December 31, 2012, in a multispecialty, hospital-based pediatric ophthalmology/adult strabismus practice at Boston Children's Hospital. Patients in the SRT group underwent SRT with or without MRc; those in the non-SRT group underwent unilateral or bilateral MRc. EXPOSURES: Surgical treatment of esotropic Duane syndrome. MAIN OUTCOMES AND MEASURES: Binocular alignment, ocular ductions, head position, stereopsis, and fundus torsion were recorded before surgery and at the 2-month and final postoperative visits. We also evaluated postoperative drift. RESULTS: The medical record review identified 36 patients who underwent 37 procedures, including 19 in the SRT group (13 SRT + MRc and 6 SRT alone) and 18 in the non-SRT group (11 unilateral MRc and 7 bilateral medial rectus resession). Mean MRc was smaller when performed with SRT (3.3 vs 5.3 mm; P = .004). Although the initial deviation was larger in the SRT group, both groups had a similar improvement in esotropia and head turn. Abduction improved by at least 1 unit in 15 of 19 patients in the SRT group (79%) vs 5 of 18 in the non-SRT group (28%). In 24 patients followed up for more than 6 months, mean esotropia decreased from 8.2 to 6.1 prism diopters (Δ) in the SRT group (n = 12) but increased from 7.2 to 10.9Δ in the non-SRT group (n = 12). CONCLUSIONS AND RELEVANCE: The combination of SRT and MRc was more effective than MRc or bilateral medial rectus resession at improving abduction while allowing for a smaller recession to align the eyes and eliminate a compensatory head posture. Although any surgery on the vertical rectus muscles should in theory increase the risk for vertical or torsional complications, to date this theory has not been borne out in our patients. Patients treated with SRT appear to have a reduced likelihood of long-term undercorrection. We therefore recommend SRT with adjustable MRc for treatment of Duane syndrome in patients with larger amounts of esotropia.