Brydon EM, Bronstein R, Buskin A, Lako M, Pierce EA, Fernandez-Godino R. AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31 iPSC-Derived RPE Cells. Mol Ther Methods Clin Dev 2019;15:392-402.Abstract
Retinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 () cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild-type allele among patients. Thus, we hypothesize that -related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSCs) with mutations in and differentiated them into RPE cells. The mutant iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant iPSC-RPE cells with AAV- restored normal phagocytosis and cilia formation, and it partially restored structure and barrier function. These results suggest that AAV-based gene therapy targeting RPE cells holds therapeutic promise for patients with -related RP.
Bulka CM, Dammann O, Santos HP, VanderVeen DK, Smeester L, Fichorova R, O'Shea MT, Fry RC. Placental CpG Methylation of Inflammation, Angiogenic, and Neurotrophic Genes and Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 2019;60(8):2888-2894.Abstract
Purpose: Extremely preterm infants are at increased risk for retinopathy of prematurity (ROP). We previously identified several inflammatory proteins that were expressed early in life and are associated with an increased risk of ROP and several angiogenic and neurotrophic growth factors in the neonatal systemic circulation that are associated with a lower risk of ROP. In this paper, we report the results of a set of analyses designed to test the hypothesis that placental CpG methylation levels of 12 inflammation-, angiogenic-, and neurotrophic-associated genes predict the occurrence of prethreshold ROP in extremely preterm newborns. Methods: We used placental CpG methylation data from 395 newborns from the Extremely Low Gestational Age Newborns study. Results: Multivariable regression models revealed that placental DNA methylation of 16 CpG sites representing 8 genes were associated with prethreshold ROP. Specifically, CpG methylation in the serum amyloid A SAA1 and SAA2, brain-derived neurotrophic factor (BDNF), myeloperoxidase (MPO), C-reactive protein (CRP), angiopoietin 1 (ANGPT1), and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) genes was associated with a lower risk of prethreshold ROP. Conversely, CpG methylation at three probes within tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and in two alternative probes within the BDNF and ANGPT1 genes was associated with an increased risk of ROP. Conclusions: CpG methylation may be a useful marker for improving ROP prediction, opening the opportunity for early intervention to lessen disease severity.
Burstein R, Noseda R, Fulton AB. Neurobiology of Photophobia. J Neuroophthalmol 2019;39(1):94-102.Abstract
BACKGROUND: Photophobia is commonly associated with migraine, meningitis, concussion, and a variety of ocular diseases. Advances in our ability to trace multiple brain pathways through which light information is processed have paved the way to a better understanding of the neurobiology of photophobia and the complexity of the symptoms triggered by light. PURPOSE: The purpose of this review is to summarize recent anatomical and physiological studies on the neurobiology of photophobia with emphasis on migraine. RECENT FINDINGS: Observations made in blind and seeing migraine patients, and in a variety of animal models, have led to the discovery of a novel retino-thalamo-cortical pathway that carries photic signal from melanopsinergic and nonmelanopsinergic retinal ganglion cells (RGCs) to thalamic neurons. Activity of these neurons is driven by migraine and their axonal projections convey signals about headache and light to multiple cortical areas involved in the generation of common migraine symptoms. Novel projections of RGCs into previously unidentified hypothalamic neurons that regulate parasympathetic and sympathetic functions have also been discovered. Finally, recent work has led to a novel understanding of color preference in migraine-type photophobia and of the roles played by the retina, thalamus, and cortex. SUMMARY: The findings provide a neural substrate for understanding the complexity of aversion to light in patients with migraine and neuro-ophthalmologic other disorders.
Busch C, Fraser-Bell S, Zur D, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, Fung AT, Gabrielle P-H, Giancipoli E, Chaikitmongkol V, Okada M, Laíns I, Santos AR, Kunavisarut P, Sala-Puigdollers A, Chhablani J, Ozimek M, Hilely A, Unterlauft JD, Loewenstein A, Iglicki M, Rehak M, Rehak M. Real-world outcomes of observation and treatment in diabetic macular edema with very good visual acuity: the OBTAIN study. Acta Diabetol 2019;56(7):777-784.Abstract
AIMS: To describe and compare the functional and anatomical outcomes of untreated and treated diabetic macular edema (DME) in eyes with very good baseline visual acuity (VA) in a real-world setting. METHODS: A 12-month, retrospective, multicenter, observational cohort study, including DME patients with baseline visual acuity (VA) ≤ 0.1 logMAR (≥ 20/25 Snellen) and central subfield thickness (CST) > 250 µm with intra- and/or subretinal fluid seen on optical coherence tomography. RESULTS: A total of 249 eyes were included, of which 155 were treated and 94 were non-treated during follow-up. Most eyes maintained vision (VA gain or VA loss < 5 letters) at 12 months (treated: 58.1%; non-treated: 73.4%). In non-treated eyes with stable VA within the first 6 months, VA was maintained throughout the follow-up in most cases (86.3%). In non-treated eyes with VA loss ≥ 5 letters within 6 months (36.7%), further observation led to worse visual outcome than treatment (- 4.2 vs. - 7.8 letters, p = 0.013). In eyes in which treatment was initiated at baseline (n = 102), treatment with 8-12 anti-VEGF injections led to better visual outcome compared to treatment with less injections (- 0.3 ± 3.6 letters vs. - 3.8 ± 6.2 letters, p = 0.003). CONCLUSION: In a real-world setting, the majority of DME patients with very good VA maintained vision at 12 months, regardless of whether the DME was treated or not. This study supports close observation of eyes with DME and very good VA with consideration of treatment when a one line drop in vision is observed.
Busch C, Iglicki M, Okada M, Gabrielle P-H, Cohen S, Mariussi M, Amphornphruet A, Cebeci Z, Chaikitmongkol V, Couturier A, Fraser-Bell S, Fung AT, Iannetta D, Radecka L, Laíns I, Rodrigues TM, Lupidi M, Ozimek M, Sala-Puigdollers A, Rehak M, Loewenstein A, Zur D, Zur D. Causative Pathogens of Endophthalmitis after Intravitreal Anti-VEGF Injection: An International Multicenter Study. Ophthalmologica 2019;241(4):211-219.Abstract
PURPOSE: The main objective of this study was to investigate the microbiological spectrum of endophthalmitis after anti-VEGF injections and to compare streptococcal with non-streptococcus-associated cases with regard to baseline characteristics and injection procedure. METHODS: Retrospective, international multicenter study of patients with culture-positive endophthalmitis after intravitreal anti-VEGF injection at 17 different retina referral centers. RESULTS: Eighty-three cases with 87 identified pathogens were included. Coagulase-negative staphylococci (59%) and viridans streptococci (15%) were the most frequent pathogens found. The use of postoperative antibiotics and performance of injections in an operating room setting significantly reduced the rate of streptococcus-induced endophthalmitis cases (p = 0.01 for both). CONCLUSION: We found a statistically significant lower rate of postinjectional local antibiotic therapy and operating room-based procedures among the streptococcus-induced cases compared to cases caused by other organisms.
Busch C, Fraser-Bell S, Iglicki M, Lupidi M, Couturier A, Chaikitmongkol V, Giancipoli E, Rodríguez-Valdés PJ, Gabrielle P-H, Laíns I, Santos AR, Cebeci Z, Amphornphruet A, Degenhardt V, Unterlauft J-D, Cagini C, Mané-Tauty V, Ricci GD'A, Hindi I, Agrawal K, Chhablani J, Loewenstein A, Zur D, Rehak M, Rehak M. Real-world outcomes of non-responding diabetic macular edema treated with continued anti-VEGF therapy versus early switch to dexamethasone implant: 2-year results. Acta Diabetol 2019;56(12):1341-1350.Abstract
AIMS: To provide 2-year follow-up data on eyes with diabetic macular edema (DME) that were non-responsive after three initial anti-vascular endothelial growth factor (VEGF) injections, comparing functional and anatomical outcomes under continued anti-VEGF therapy versus dexamethasone (DEX) implant. METHODS: Multicenter, retrospective chart review comparing eyes with treatment-naïve DME and a suboptimal response to a loading phase of anti-VEGF therapy (3 injections given monthly) which were then treated with (a) further anti-VEGF (n = 72) or (b) initially switched to DEX implant (n = 38). Main outcome measures were change in visual acuity (VA) and central subfield thickness (CST) from the end of the loading phase to 24 months. RESULTS: In 79% of the 12-month study population (87/110 eyes), 24-month data were available. One quarter of eyes in each group switched treatments during the second year. Eyes that were switched early to DEX implant maintained the functional and anatomical improvements at 24 months which were seen in the first year (from month 3: + 8.9 letters, - 214 µm). Eyes that were switched from anti-VEGF therapy to steroids in the second year improved VA and reduced CST at 24 months (from month 12: + 6.8 letters, p = 0.023; - 226 µm, p = 0.004). In eyes continued on anti-VEGF therapy, VA and CST were stable at 24 months (from month 3: + 2.8 letters, p = 0.254; - 24 µm, p = 0.243). Eyes that were non-responsive to anti-VEGF therapy for 12 months had similar chances to experience a VA gain from further therapy as eyes that were non-responsive for 3 months only (23.8 vs. 31.0%, p = 0.344). CONCLUSIONS: The beneficial effect of an early switch to DEX implant in DME non-responders seen at month 12 was maintained during the second year. A later switch from anti-VEGF to steroids still provided significant improvement. Eyes continued on anti-VEGF over a period of 24 months maintained vision. A quarter of eyes, which had not improved vision at 12 months, exhibited a delayed response to treatment.
Caron-Cantin M, Cestari DM, Fortin E. Clinical and radiologic approach to 'typical' versus antibody-related optic neuritis. Curr Opin Ophthalmol 2019;30(6):412-417.Abstract
PURPOSE OF REVIEW: Optic neuritis is an autoimmune optic neuropathy that has been associated with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and more recently antimyelin oligodendrocyte glycoprotein (anti-MOG)-positive disorder. At initial presentation, it is often difficult to differentiate these entities given their significant overlap in clinical presentation and MRI findings. This review summarizes the distinguishing clinical and radiological features of MS, NMOSD, and anti-MOG disorders to help clinicians accurately diagnose and manage patients affected by these conditions. RECENT FINDINGS: Antiaquaporin-4 (AQP4) and more recently anti-MOG antibodies are both associated with central nervous system demyelinating diseases that often initially present with optic neuritis. Serologic testing now allows for a new classification of these overlapping conditions that can help to differentiate 'typical' optic neuritis that is often associated with MS from 'atypical' optic neuritis associated with NMOSD and anti-MOG-positive disorder. SUMMARY: Optic neuritis associated with MS, NMOSD, and anti-MOG-positive disease can have a similar clinical presentation. However, some clinical and radiologic findings can help clinicians to differentiate these entities so that they can be properly managed to optimize visual prognosis.
Chan W, Wiggs JL, Sobrin L. The Genetic Influence on Corticosteroid-Induced Ocular Hypertension: A Field Positioned for Discovery. Am J Ophthalmol 2019;202:1-5.Abstract
PURPOSE: To provide evidence that corticosteroid-induced ocular hypertension has a genetic component. DESIGN: Evidence-based perspective. METHODS: We conducted a comprehensive literature search for studies exploring genetic influences on intraocular pressure responses to corticosteroid treatment. RESULTS: Studies demonstrating increased risk of corticosteroid-induced ocular hypertension among first-degree relatives of affected individuals support a genetic contribution to the disease. Family and personal history of primary open-angle glaucoma also increases the risk of corticosteroid-induced intraocular pressure elevation, suggesting common genetic etiologies. A number of studies have attempted to identify predisposing genetic factors; however, reproducible findings have not yet been reported. The recent availability of large data sets with clinical and genetic data for patients affected by corticosteroid-induced ocular hypertension and glaucoma provides new opportunities to study the genetic underpinnings of this important condition. CONCLUSIONS: There is substantial evidence suggesting a genetic component to corticosteroid-related ocular hypertension and glaucoma, but specific genetic risk factors have yet to be identified. The current confluence of large genetic data sets and affordable genetic sequencing technologies has great potential for discovering the genes that increase risk for this blinding complication of corticosteroid therapy.
Chantarasorn Y, Oellers P, Eliott D. Choroidal Thickness Is Associated with Delayed Subretinal Fluid Absorption after Rhegmatogenous Retinal Detachment Surgery. Ophthalmol Retina 2019;3(11):947-955.Abstract
PURPOSE: To investigate the association between choroidal thickness and persistent subretinal fluid (PSF) after surgery for recent-onset rhegmatogenous retinal detachment (RRD). DESIGN: Case-control study. PARTICIPANTS: Fourteen eyes with macula-off RRD (with fovea on and off) that achieved retinal reattachment on funduscopy and demonstrated PSF after surgery (PSF group) were compared with 62 eyes with macula-off RRD (with fovea on and off) that did not demonstrate PSF after surgery (non-PSF group). METHODS: The diagnosis of PSF was made by the detection of subretinal fluid pockets on OCT beyond 6 weeks after surgery. Covariates included baseline demographics, duration of RRD, area of RRD, foveal status, method of subretinal fluid drainage, retinal pigment epithelium (RPE) changes, and choroidal thickness in both eyes. Multivariate regression analysis was performed by adding gender, age, and pathologic myopia into the model. The secondary outcomes included postoperative vision and time to resolution of PSF. MAIN OUTCOME MEASURES: Subfoveal choroidal thickness in affected eyes, measured by enhanced depth imaging OCT images. RESULTS: The percentage of eyes that underwent vitrectomy, scleral buckle surgery, and pneumatic retinopexy were 71.4%, 14.3%, and 14.3% in the PSF group, respectively, and 87.1%, 11.3%, and 1.6% in the non-PSF group, respectively. Eyes with PSF showed significantly thicker subfoveal choroid than eyes without PSF (305±61 μm vs. 200±70 μm, respectively; adjusted difference, 78.6±19.1 μm; 95% confidence interval [CI], 40.3-116.8 μm; P < 0.001). The PSF group demonstrated a greater proportion of RPE changes in fellow eyes (30.8% vs. 1.7%; P = 0.03) and significantly worse best-corrected visual acuity at the 12-month follow-up (P = 0.03). Multiple logistic regression analysis revealed that choroidal thickness of 280 μm or more was a significant factor associated with the presence of PSF (adjusted odds ratio [AOR], 13.4; 95% CI, 3.1-34.7 [P = 0.001]. CONCLUSIONS: Persistent subretinal fluid is associated with increased subfoveal choroidal thickness in surgical and fellow eyes and with RPE changes in the fellow eye. This indicates that PSF likely belongs to the pachychoroid spectrum. In affected eyes, PSF tends to persist for more than 1 year and results in delayed visual recovery.
Charles NC, Jakobiec FA, Ma L, Belinsky I. Steatocystoma Simplex of the Caruncle: Case Report and Immunohistologic Study. Ophthalmic Plast Reconstr Surg 2019;35(2):e45-e47.Abstract
A yellow cystic lesion of the caruncle in a 23-year-old woman proved to be a solitary steatocystoma, a rare occurrence in that location. While the histopathologic diagnosis was evident from clusters of sebaceous cells within the cyst wall, a panel of immunohistochemical stains further distinguished the lesion from a keratinous cyst. The most useful stains for differentiating the two conditions were carcinoembryonic antigen, epithelial membrane antigen, cytokeratins 17 and 19, and calretinin. Only three previous cases of caruncular steatocystoma simplex have been reported, none of which included immunohistochemical studies. The current findings support the origin of the cyst from the small duct that connects the unilobular sebaceous gland associated with vellus hairs to the follicular canal.
Charles NC, Jakobiec FA, Ma L, Belinsky I. Angiofibroma of the Eyelid: A Rare Clinical and Histologic Variant. Ophthalmic Plast Reconstr Surg 2019;35(4):e199-e102.Abstract
A flesh-colored, supraciliary lesion of the left upper eyelid in a 47-year-old man was excised for cosmetic reasons. Histopathology and immunohistochemistry demonstrated CD34-positive benign spindle cells, factor XIIIa-positive dendritic cells, and CD163-positive histiocytes, all dispersed within a diffuse collagenous background. Prominent loose perivascular cuffs of fibroblastic cells and collagen surrounded small blood vessels. Interpreted as an angiofibroma, the histopathology bore resemblance to that of a single previously-reported forearm lesion termed a "dermal fibroma with a distinctive perivascular cell arrangement." The lesion represents the first eyelid example of an unusual variant of angiofibroma.
Chekuri A, Zientara-Rytter K, Soto-Hermida A, Borooah S, Voronchikhina M, Biswas P, Kumar V, Goodsell D, Hayward C, Shaw P, Stanton C, Garland D, Subramani S, Ayyagari R. Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1. Aging Cell 2019;18(6):e13011.Abstract
Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5 ), and homozygous knock-in (Ctrp5 ) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5 and Ctrp5 mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology.
Chen E, Parikh R. Re: Gong et al.: Comparison of United States and international ophthalmic drug pricing (Ophthalmology. 2019;126:1358-1365. Ophthalmology 2019;126(12):e94-e95.
Chen T-C, She P-Y, Chen DF, Lu J-H, Yang C-H, Huang D-S, Chen P-Y, Lu C-Y, Cho K-S, Chen H-F, Su W-F. Polybenzyl Glutamate Biocompatible Scaffold Promotes the Efficiency of Retinal Differentiation toward Retinal Ganglion Cell Lineage from Human-Induced Pluripotent Stem Cells. Int J Mol Sci 2019;20(1)Abstract
Optic neuropathy is one of the leading causes of irreversible blindness caused by retinal ganglion cell (RGC) degeneration. The development of induced pluripotent stem cell (iPSC)-based therapy opens a therapeutic window for RGC degeneration, and tissue engineering may further promote the efficiency of differentiation process of iPSCs. The present study was designed to evaluate the effects of a novel biomimetic polybenzyl glutamate (PBG) scaffold on culturing iPSC-derived RGC progenitors. The iPSC-derived neural spheres cultured on PBG scaffold increased the differentiated retinal neurons and promoted the neurite outgrowth in the RGC progenitor layer. Additionally, iPSCs cultured on PBG scaffold formed the organoid-like structures compared to that of iPSCs cultured on cover glass within the same culture period. With RNA-seq, we found that cells of the PBG group were differentiated toward retinal lineage and may be related to the glutamate signaling pathway. Further ontological analysis and the gene network analysis showed that the differentially expressed genes between cells of the PBG group and the control group were mainly associated with neuronal differentiation, neuronal maturation, and more specifically, retinal differentiation and maturation. The novel electrospinning PBG scaffold is beneficial for culturing iPSC-derived RGC progenitors as well as retinal organoids. Cells cultured on PBG scaffold differentiate effectively and shorten the process of RGC differentiation compared to that of cells cultured on coverslip. The new culture system may be helpful in future disease modeling, pharmacological screening, autologous transplantation, as well as narrowing the gap to clinical application.
Chen X, Sullivan BD, Rahimi Darabad R, Liu S, Kam WR, Sullivan DA. Are BALB/c Mice Relevant Models for Understanding Sex-Related Differences in Gene Expression in the Human Meibomian Gland?. Cornea 2019;38(12):1554-1562.Abstract
BACKGROUND: A compelling feature of dry eye disease is that it occurs predominantly in women. We hypothesize that this female prevalence is linked to sex-related differences in the meibomian gland (MG). This gland plays a critical role in maintaining the tear film, and its dysfunction is a major cause of dry eye disease. To understand the factors that underlie MG sexual dimorphism and promote dry eye in women, we seek to identify an optimal model for the human MG. Our goal was to determine whether a murine MG is such a model. Toward that end, we examined whether sex differences in MG gene expression are the same in BALB/c mice and humans. METHODS: Eyelid tissues were collected from humans (n = 5-7/sex) and BALB/c mice (n = 9/sex). MGs were isolated and processed for the evaluation of gene expression by using microarrays and bioinformatics software. RESULTS: Our analysis of the 500 most highly expressed genes from human and mouse MGs showed that only 24.4% were the same. Our comparison of 100 genes with the greatest sex-associated differences in human and mouse MGs demonstrated that none were the same. Sex also exerted a significant impact on numerous ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, and chromosomes, but these effects were primarily species-specific. CONCLUSIONS: Our results indicate that BALB/c mice are not optimal models for understanding sex-related differences in gene expression of the human MG.
Chen N, Hu Z, Yang Y, Han H, Lei H. Inactive Cas9 blocks vitreous-induced expression of Mdm2 and proliferation and survival of retinal pigment epithelial cells. Exp Eye Res 2019;186:107716.Abstract
Mouse double minute (MDM)2 single nucleotide polymorphism (SNP) 309G allele in the second promoter of MDM2 enhances vitreous-induced expression of Mdm2 and degradation of the tumor suppressor protein p53. This MDM2 contributes to certain cancer development and experimental proliferative vitreoretinopathy. The goal of this study is to discover a novel strategy to only block vitreous-induced expression of Mdm2 for preventing vitreous-induced cell proliferation and survival and thus find a potential novel strategy to treat proliferation-related diseases. We created two mutations (D10A and H840A) in Streptococcus pyogenes (Sp)Cas9 within the nuclease domains (RuvC1 and HNH, respectively) to render this SpCas9 nuclease dead named as dCas9 in a lentiCRISPR v2 vector. Then an MDM2-sgRNA targeting the second promoter of human MDM2 gene was cloned into this vector for producing lentivirus to infect human retinal pigment epithelial (RPE) cells with, which carry a heterozygous genotype of MDM2. lacZ-sgRNA was used as a control. As a result, we discovered that vitreous from experimental rabbits induced a 1.9 ± 0.2 fold increase in Mdm2 and a 2.0 ± 0.2 fold decrease in p53 in the RPE cells with dCas9/lacZ-sgRNA compared to those with dCas9/MDM2-sgRNA, suggesting that dCas9 under the guidance of the MDM2-sgRNA prevented RV-stimulated increase in Mdm2. In addition, we found that the rabbit vitreous significantly enhanced cell proliferation (1.5 ± 0.2 fold), survival against apoptosis (2.2 ± 0.2 fold), migration (10 ± 1.5%) and contraction (112.7 ± 14.1 mm) of the cells with dCas9/lacZ-sgRNA compared with those with dCas9/MDM2-sgRNA. These results indicated that application of the dCas9 targeted to the P2 of MDM2 is a potential therapeutic approach to diseases due to the P2-driven aberrant expression of Mdm2 - such as proliferative vitreoretinopathy.
Chen X, Lei F, Wang L, Xiong X, Song J. Generation of Tumor Antigen-Specific Cytotoxic T Lymphocytes from Pluripotent Stem Cells. Methods Mol Biol 2019;1884:43-55.Abstract
Immunotherapy is a developing but very promising arsenal to treat cancer. Acquiring a more potent and effective approach in cancer immunotherapy is always the ultimate pursuance. CTL-based therapies are highly acclaimed recently due to its direct killing property. However, difficulty in obtaining adequate number of CTLs is still a major obstacle. In previous studies, it is shown that pluripotent stem cell-derived cytotoxic T lymphocytes (CTL)-especially the genetically engineered tumor antigen-specific CTLs-may serve as a good candidate for this goal. Here we introduce a novel approach in generating tumor antigen-specific CTLs from induced pluripotent stem cells (iPSCs) by using both in vitro and in vivo priming mechanisms for the tumor management in a murine melanoma model.
Cheung CS, VanderVeen DK. Intraocular Lens Techniques in Pediatric Eyes with Insufficient Capsular Support: Complications and Outcomes. Semin Ophthalmol 2019;:1-10.Abstract
Intraocular lens (IOL) implantation in pediatric eyes with insufficient capsular support is challenging and there are multiple IOL options. These include placement of an IOL within the capsular bag with a capsular tension ring, a scleral-fixated posterior-chamber IOL (PCIOL) with or without capsular tension segment or ring, an intra-scleral fixated IOL, an iris-sutured PCIOL, or an anterior chamber iris-fixated IOL. We reviewed 48 articles and 1 published abstract describing the surgical techniques, complications and visual outcomes of different IOL options in the management of aphakic pediatric eyes with insufficient capsular support. The present review found that the visual acuity outcomes of various IOLs are comparable. Furthermore, each .
Chew EY, Clemons TE, Jaffe GJ, Johnson CA, Farsiu S, Lad EM, Guymer R, Rosenfeld P, Hubschman J-P, Constable I, Wiley H, Singerman LJ, Gillies M, Comer G, Blodi B, Eliott D, Yan J, Bird A, Friedlander M, Group MTT 2-PCNTFR2. Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients with Macular Telangiectasia Type 2: A Randomized Clinical Trial. Ophthalmology 2019;126(4):540-549.Abstract
PURPOSE: To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. DESIGN: Randomized sham-controlled clinical trial. PARTICIPANTS: Ninety-nine study eyes of 67 eligible participants were enrolled. METHODS: Single-masked randomized clinical trial of 24 months' duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. MAIN OUTCOME MEASURES: The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. RESULTS: Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group. CONCLUSIONS: In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.
Chi Z-L, Adini A, Birsner AE, Bazinet L, Akula JD, D'Amato RJ. PR1P ameliorates neurodegeneration through activation of VEGF signaling pathway and remodeling of the extracellular environment. Neuropharmacology 2019;148:96-106.Abstract
Neurodegenerative diseases affect millions of people worldwide. Optic neuropathies are the most commonly occurring neurodegenerative diseases, characterized by progressive retinal ganglion cell (RGC) degeneration. We recently reported that Prominin-1, a protein found on the surface of stem cells, interacts with VEGF and enhances its activity. VEGF is known to have various protective roles in the nervous system. Subsequently, we have developed a 12-mer peptide derived from Prominin-1, named PR1P, and investigated its effects on neuronal survival of damaged RGCs in a rat model of optic nerve crush (ONC). PR1P prevented RGC apoptosis resulting in improvement of retinal function in the rat ONC model. PR1P treatment significantly increased phosphorylation of ERK and AKT and expression its downstream proteins c-fos and Egr-1 in the retina. Additionally, PR1P beneficially increased the MMP-9/TIMP-1 ratio and promoted glial activation in the retina of ONC rats. Thus, PR1P displayed neuroprotective effects through enhanced VEGF-driven neuronal survival and reconstruction of the extracellular environment in ONC model. Our data indicate that PR1P may be a promising new clinical candidate for the treatment of neurodegenerative diseases.