Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders.

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.

Small Leucine-Rich Proteoglycans (SLRPs) in the Retina.

Retinal diseases such as age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and diabetic retinopathy (DR) are the leading causes of visual impairment worldwide. There is a critical need to understand the structural and cellular components that play a vital role in the pathophysiology of retinal diseases. One potential component is the family of structural proteins called small leucine-rich proteoglycans (SLRPs). SLRPs are crucial in many fundamental biological processes involved in the maintenance of retinal homeostasis. They are present within the extracellular matrix (ECM) of connective and vascular tissues and contribute to tissue organization and modulation of cell growth. They play a vital role in cell-matrix interactions in many upstream signaling pathways involved in fibrillogenesis and angiogenesis. In this comprehensive review, we describe the expression patterns and function of SLRPs in the retina, including Biglycan and Decorin from class I; Fibromodulin, Lumican, and a Proline/arginine-rich end leucine-rich repeat protein (PRELP) from class II; Opticin and Osteoglycin/Mimecan from class III; and Chondroadherin (CHAD), Tsukushi and Nyctalopin from class IV.

Photothermal optical coherence tomography of indocyanine green in ex vivo eyes.

Indocyanine green (ICG) is routinely used during surgery to stain the inner limiting membrane (ILM) and provide contrast on white light surgical microscopy. While translation of optical coherence tomography (OCT) for intraoperative imaging during ophthalmic surgery has enhanced visualization, the ILM remains difficult to distinguish from underlying retinal structures and ICG does not provide additional OCT contrast. We present photothermal OCT (PT-OCT) for high-specificity detection of ICG on retinal OCT images. We demonstrate our technique by performing an ILM peel in ex vivo eyes using low ICG concentrations and laser powers. These results establish the feasibility of PT-OCT for intraoperative guidance during retinal surgery.

Gene therapy for red-green colour blindness in adult primates.

Red-green colour blindness, which results from the absence of either the long- (L) or the middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here we explore the possibility of curing colour blindness using gene therapy in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young. However, here we show that the addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.

Outer retinal structure after closed-globe blunt ocular trauma.

PURPOSE: To evaluate outer retinal structural abnormalities in patients with visual deficits after closed-globe blunt ocular trauma. METHODS: Nine subjects with visual complaints after closed-globe blunt ocular trauma were examined between 1 month after trauma and 6 years after trauma. Spectral domain optical coherence tomography was used to assess the outer retinal architecture, whereas adaptive optics scanning light ophthalmoscopy was used to analyze the photoreceptor mosaic integrity. RESULTS: Visual deficits ranged from central scotomas to decreased visual acuity. Spectral domain optical coherence tomography defects included focal foveal photoreceptor lesions, variable attenuation of the interdigitation zone, and mottling of the outer segment band, with one subject having normal outer retinal structure. Adaptive optics scanning light ophthalmoscopy revealed disruption of the photoreceptor mosaic in all subjects, variably manifesting as foveal focal discontinuities, perifoveal hyporeflective cones, and paracentral regions of selective cone loss. CONCLUSION: We observe persistent outer retinal disruption in subjects with visual complaints after closed-globe blunt ocular trauma, albeit to a variable degree. Adaptive optics scanning light ophthalmoscopy imaging allows the assessment of photoreceptor structure at a level of detail not resolvable using spectral domain optical coherence tomography or other current clinical imaging tools. Multimodal imaging seems to be useful in revealing the cause of visual complaints in patients after closed-globe blunt ocular trauma. Future studies are needed to better understand how photoreceptor structure changes longitudinally in response to various traumas.

Intensity-based optoretinography reveals sub-clinical deficits in cone function in retinitis pigmentosa.

Introduction: Clinical tools have been widely used in the diagnosis, description, and monitoring the progression of retinitis pigmentosa (RP); however, many of these methods have inherently low sensitivity and specificity, and significant photoreceptor disruption can occur before RP progression has clinically manifest. Adaptive optics scanning light ophthalmoscopy (AOSLO) has shown promise as a powerful tool for assessing photoreceptor disruption both structurally and functionally due to its increased resolution. Methods: Here we assess photoreceptor structure and function at the cellular level through AOSLO by acquiring intensity based optoretinography (iORG) in 15 individuals with no reported retinal pathology and 7 individuals with a prior clinical diagnosis of RP. Photoreceptor structure was quantified by calculating cone nearest neighbor distance (NND) across different retinal eccentricities from the AOSLO images. Cone outer segment length was measured across different retinal eccentricities using optical coherence tomography (OCT) derived longitudinal reflectivity profiles (LRPs). Finally, iORG measures of photoreceptor function were compared to retinal sensitivity as measured using the macular integrity assessment (MAIA) microperimeter. Results: Broadly, participants with RP exhibited increasing cone nearest neighbor distances and decreasing cone outer segment length as a function of retinal eccentricity, consistent with prior reports for both controls and individuals with RP. Nearly all individuals with RP had reduced iORG amplitudes for all retinal eccentricities when compared to the control cohort, and the reduction was greater in eccentricities further from the fovea. Comparing iORG amplitudes to MAIA retinal sensitivity, we found that the iORG was more sensitive to early changes in photoreceptor function whereas MAIA was more sensitive to later stages of disease. Discussion: This highlights the utility of iORG as a method to detect sub-clinical deficits in cone function in all stages of disease progression and supports the future use of iORG for identifying cells that are candidates for cellular based therapies.

Human iPSC-derived photoreceptor transplantation in the cone dominant 13-lined ground squirrel.

Several retinal degenerations affect the human central retina, which is primarily comprised of cones and is essential for high acuity and color vision. Transplanting cone photoreceptors is a promising strategy to replace degenerated cones in this region. Although this approach has been investigated in a handful of animal models, commonly used rodent models lack a cone-rich region and larger models can be expensive and inaccessible, impeding the translation of therapies. Here, we transplanted dissociated GFP-expressing photoreceptors from retinal organoids differentiated from human induced pluripotent stem cells into the subretinal space of damaged and undamaged cone-dominant 13-lined ground squirrel eyes. Transplanted cell survival was documented via noninvasive high-resolution imaging and immunohistochemistry to confirm the presence of human donor photoreceptors for up to 4 months posttransplantation. These results demonstrate the utility of a cone-dominant rodent model for advancing the clinical translation of cell replacement therapies.

Next-Generation Nanomedicine Approaches for the Management of Retinal Diseases.

Retinal diseases are one of the leading causes of blindness globally. The mainstay treatments for these blinding diseases are laser photocoagulation, vitrectomy, and repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) or steroids. Unfortunately, these therapies are associated with ocular complications like inflammation, elevated intraocular pressure, retinal detachment, endophthalmitis, and vitreous hemorrhage. Recent advances in nanomedicine seek to curtail these limitations, overcoming ocular barriers by developing non-invasive or minimally invasive delivery modalities. These modalities include delivering therapeutics to specific cellular targets in the retina, providing sustained delivery of drugs to avoid repeated intravitreal injections, and acting as a scaffold for neural tissue regeneration. These next-generation nanomedicine approaches could potentially revolutionize the treatment landscape of retinal diseases. This review describes the availability and limitations of current treatment strategies and highlights insights into the advancement of future approaches using next-generation nanomedicines to manage retinal diseases.

Long-term retinal imaging of a case of suspected congenital rubella infection.

PURPOSE: Many retinal disorders present with pigmentary retinopathy, most of which are progressive conditions. Here we present over nine years of follow up on a case of stable pigmentary retinopathy that is suspected to stem from a congenital rubella infection. Parafoveal cone photoreceptors were tracked through this period to gain insight into photoreceptor disruption in this pigmentary retinopathy. METHODS: The patient was examined at 8 visits spanning a total of 111 months. Examination at baseline included clinical fundus examination, full-field electroretinography (ERG), kinetic visual field assessment (Goldmann), and best corrected visual acuity; all of these except ERG were repeated at follow up visits. Imaging was performed with fundus photography, spectral-domain optical coherence tomography (SD-OCT) and confocal adaptive optics scanning light ophthalmoscopy (AOSLO). For the latter four time points AOSLO imaging also included split-detector imaging. RESULTS: There were no defects in hearing or cardiac health found in this patient. There were minimal visual deficits found at baseline, with mild rod suppression on ERG; best corrected visual acuity was 20/25 OD and 20/20 OS at baseline, which was stable throughout the follow-up period. Retinal thickness as measured by OCT was within the normal range, though foveal hypoplasia was present and outer nuclear layer thickness was slightly below the normal range at all time points. Cone density was relatively stable throughout the follow-up period. A number of cones were non-reflective when observed with confocal AOSLO imaging and density was markedly lower than expected values (foveal cone density was 43,782 cones/mm2 on average). Genetic analysis revealed no causative variations explaining the phenotype. CONCLUSIONS AND IMPORTANCE: This patient appears to have a stable pigmentary retinopathy. This case is likely due to a congenital insult, rather than progressive retinal disease. This finding of stability agrees with other reports of rubella pigmentary retinopathy. Imaging with AOSLO enabled observation of two notable phenotypic features. First is the observation of dark cones, which are seen in many retinal disorders including color vision defects and degenerative retinal disease. Second, the cone density is well below what is expected - this is especially interesting as this patient has near-normal visual acuity despite this greatly decreased number of normally-waveguiding cones in the fovea.

Development of a Preclinical Laser Speckle Contrast Imaging Instrument for Assessing Systemic and Retinal Vascular Function in Small Rodents.

Purpose: To develop and test a non-contact, contrast-free, retinal laser speckle contrast imaging (LSCI) instrument for use in small rodents to assess vascular anatomy, quantify hemodynamics, and measure physiological changes in response to retinal vascular dysfunction over a wide field of view (FOV). Methods: A custom LSCI instrument capable of wide-field and non-contact imaging in small rodents was constructed. The effect of camera gain, laser power, and exposure duration on speckle contrast variance was standardized before the repeatability of LSCI measurements was determined in vivo. Finally, the ability of LSCI to detect alterations in local and systemic vascular function was evaluated using a laser-induced branch retinal vein occlusion and isoflurane anesthesia model, respectively. Results: The LSCI system generates contrast-free maps of retinal blood flow with a 50° FOV at >376 frames per second (fps) and under a short exposure duration (>50 µs) with high reliability (intraclass correlation R = 0.946). LSCI was utilized to characterize retinal vascular anatomy affected by laser injury and longitudinally measure alterations in perfusion and blood flow profile. Under varied doses of isoflurane, LSCI could assess cardiac and systemic vascular function, including heart rate, peripheral resistance, contractility, and pulse propagation. Conclusions: We present a LSCI system for detecting anatomical and physiological changes in retinal and systemic vascular health and function in small rodents. Translational Relevance: Detecting and quantifying early anatomical and physiological changes in vascular function in animal models of retinal, systemic, and neurodegenerative diseases could strengthen our understanding of disease progression and enable the identification of new prognostic and diagnostic biomarkers for disease management and for assessing treatment efficacies.

Examining Whether AOSLO-Based Foveal Cone Metrics in Achromatopsia and Albinism Are Representative of Foveal Cone Structure.

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.

Photobiomodulation preserves mitochondrial redox state and is retinoprotective in a rodent model of retinitis pigmentosa.

Photobiomodulation (PBM) by far-red (FR) to near-infrared (NIR) light has been demonstrated to restore the function of damaged mitochondria, increase the production of cytoprotective factors and prevent cell death. Our laboratory has shown that FR PBM improves functional and structural outcomes in animal models of retinal injury and retinal degenerative disease. The current study tested the hypothesis that a brief course of NIR (830 nm) PBM would preserve mitochondrial metabolic state and attenuate photoreceptor loss in a model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated with 830 nm light (180 s; 25 mW/cm2; 4.5 J/cm2) using a light-emitting diode array (Quantum Devices, Barneveld, WI) from postnatal day (p) 10 to p25. Sham-treated rats were restrained, but not treated with 830 nm light. Retinal metabolic state, function and morphology were assessed at p30 by measurement of mitochondrial redox (NADH/FAD) state by 3D optical cryo-imaging, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), and histomorphometry. PBM preserved retinal metabolic state, retinal function, and retinal morphology in PBM-treated animals compared to the sham-treated group. PBM protected against the disruption of the oxidation state of the mitochondrial respiratory chain observed in sham-treated animals. Scotopic ERG responses over a range of flash intensities were significantly greater in PBM-treated rats compared to sham controls. SD-OCT studies and histological assessment showed that PBM preserved the structural integrity of the retina. These findings demonstrate for the first time a direct effect of NIR PBM on retinal mitochondrial redox status in a well-established model of retinal disease. They show that chronic proteotoxic stress disrupts retinal bioenergetics resulting in mitochondrial dysfunction, and retinal degeneration and that therapies normalizing mitochondrial metabolism have considerable potential for the treatment of retinal degenerative disease.

Transconjunctival 20-gauge pars plana vitrectomy using a single entry cannulated sutureless system.

PURPOSE: Pars plana vitrectomy with a 20-gauge transconjunctival cannulated sutureless (TCS) system has the potential of combining the advantages of smaller-gauge vitrectomy systems with the economical advantage of not needing to purchase any additional handheld instruments. However, the sclerotomy size is much larger, and self-sealing sclerotomies may be more difficult to construct. Therefore, we evaluated the need for sclerotomy suturing after performing 20-gauge TCS vitrectomy. METHODS: A retrospective chart review was performed on the first consecutive 55 eyes of 54 patients who underwent 20-gauge TCS vitrectomy. The main outcome measure was the number of sclerotomies requiring suturing and complications. RESULTS: Of the 164 sclerotomies made, 101 sclerotomies (62%) were not sutured, whereas the remaining 63 sclerotomies (38%) were closed with a single transconjunctival- scleral suture. The reasons for suturing included leakage and gaping at the sclerotomy, conjunctiva not covering the sclerotomy site, and prevention of gas leak. Complications noted include premature dislodging of cannulas, retinal tear, hypotony, hemorrhagic choroidals, subconjunctival gas, and less than full gas fill. CONCLUSION: Twenty-gauge transconjunctival sutureless vitrectomy is associated with risks similar to other cannulated systems while retaining most of the functionality and handheld instrumentation of the 20-gauge approach. A possibly higher sclerotomy suturing rate relative to smaller-gauge approaches is a disadvantage of this technique.

Physician assessment of changing lesion size of predominantly classic choroidal neovascular membranes in age-related macular degeneration.

BACKGROUND AND OBJECTIVE: To quantify the interpretation of fluorescein angiograms of evolving predominantly classic choroidal neovascularization in age-related macular degeneration. PATIENTS AND METHODS: Thirty-six fluorescein angiograms of predominantly classic choroidal neovascularization were used to define 22 fluorescein angiogram pairs. Imaging software was used to measure surface area and greatest linear dimension (GLD). Six retina physicians estimated the change in surface area and GLD for each pair before and after demarcation of the lesions' borders and GLD. RESULTS: For enlarging lesions, the smallest changes consistently detected by physicians were a 5% to 15% increase in surface area and a 5% to 15% increase in GLD; for shrinking lesions, they were a 5% to 15% decrease in surface area and a 5% to 15% decrease in GLD. Linear regression demonstrated moderate correlation between physician and software estimates of surface area and GLD change (r(2) = 0.50 and 0.67, respectively; P < .001), which was higher with lesion demarcation (r(2) = 0.91 and 0.93, respectively; P < .001). CONCLUSION: Computer-assisted demarcation of lesion surface area and GLD reduced variability in physicians' estimates of choroidal neovascularization size change and improved correlation with software measurements.

Microbiological spectrum of organisms isolated from explanted scleral buckles.

Scleral buckle removal is an uncommon procedure performed for various reasons. Microbiological information on explanted scleral buckles remains limited. The authors identified 37 cases of scleral buckle removal during an 18-year period. Bacterial cultures isolated an organism in 4 of 9 patients (44%) with clinical infection. Organisms identified included methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium abscessus, and coagulase-negative Staphylococcus species. Bacterial cultures isolated an organism in 3 of 11 patients (27%) without clinical infection. Organisms identified included Nocardia species, Alcaligenes xylosoxidans, and Mycobacterium chelonae. Scleral buckles appearing clinically infected may be associated with more virulent organisms and a greater chance of identifying an organism. Bacterial cultures may be of value for scleral buckles upon removal.

Successful management of epithelial ingrowth after sequential intracameral 5-fluorouracil and Descemet-stripping automated endothelial keratoplasty.

To describe the successful treatment of epithelial ingrowth using combined surgical excision with intracameral adjuvant 5-fluorouracil (5-FU) followed by Descemet-stripping automated endothelial keratoplasty (DSAEK). A 71-year-old man presented with epithelial ingrowth after clear corneal phacoemulsification. He underwent surgical excision of the membrane together with pars plana vitrectomy, air fluid exchange, and intracameral 5-FU. This treatment resulted in corneal decompensation for which DSAEK was performed 6 months later. Despite interface haze, the postoperative corrected distance visual acuity returned to 20/40 three months after DSAEK. There was no clinical evidence of recurrence of the epithelial ingrowth 9 months after the surgical removal. Intracameral 5-FU can be used in conjunction with surgical excision and subsequent DSAEK to successfully treat epithelial ingrowth.

Assessing Retinal Structure in Patients with Parkinson's Disease.

OBJECTIVE: The retina is an extension of the central nervous system (CNS), and ocular symptoms can precede manifestations of CNS disorders. Given that several neurodegenerative conditions that affect the brain exhibit ocular symptoms, the retina may be an accessible biomarker to monitor disease progression. Dopamine, the key neurotransmitter related to Parkinson's disease (PD), is contained in amacrine and interplexiform cells, which reside in specific retinal layers. Understanding how loss of dopaminergic cells affects retinal anatomy could be relevant for monitoring disease progression. Here, our objective is to evaluate retinal structure (foveal pit morphology and thickness) in patients with PD. METHODS: Thirty-three Caucasian subjects diagnosed with PD and 40 age-matched Caucasian control subjects underwent retinal imaging with spectral-domain optical coherence tomography (SD-OCT). Axial length measurements were used to correct the lateral scale of each macular volume scan. From these corrected volumes, foveal morphology was quantified with previously described algorithms, and Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and incorporated into a logistic regression model to predict PD. RESULTS: Interocular foveal morphology measurements were highly symmetrical in PD patients and control subjects. There were no significant differences in foveal pit morphology between PD patients and control subjects. Using a model incorporating sex and axial length corrected ETDRS regions, we generated a receiver operating characteristic curve with a C-statistic of 0.80. CONCLUSION: Our study, which to our knowledge is the first to properly scale OCT measurements when quantifying retinal thickness, demonstrates that PD patients retain foveal symmetry between eyes. When constructing a model to predict PD, sex, along with the center 1 mm and temporal outer ETDRS regions, were significant predictors of PD. In addition to proper scaling of OCT measures, gender and racial differences in retinal anatomy should be considered in building future predictive PD models when using OCT.

Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors.

Delivery of foreign opsin genes to cone photoreceptors using recombinant adeno-associated virus (rAAV) is a potential tool for studying the basic mechanisms underlying cone based vision and for treating vision disorders. We used an in vivo retinal imaging system to monitor, over time, expression of virally-delivered genes targeted to cone photoreceptors in the Mongolian gerbil (Meriones unguiculatus). Gerbils have a well-developed photopic visual system, with 11-14% of their photoreceptors being cones. We used replication deficient serotype 5 rAAV to deliver a gene for green fluorescent protein (GFP). In an effort to direct expression of the gene specifically to either S or M cones, the transgene was under the control of either the human X-chromosome opsin gene regulatory elements, i.e., an enhancer termed the locus control region (LCR) and L promoter, or the human S-opsin promoter. Longitudinal fluorescence images reveal that gene expression is first detectable about 14 days post-injection, reaches a peak after about 3 months, and is observed more than a year post-injection if the initial viral concentration is sufficiently high. The regulatory elements are able to direct expression to a subpopulation of cones while excluding expression in rods and non-photoreceptor retinal cells. When the same viral constructs are used to deliver a human long-wavelength opsin gene to gerbil cones, stimulation of the introduced human photopigment with long-wavelength light produces robust cone responses.

Risk factors for scleral buckle removal: a matched, case-control study.

PURPOSE: To identify preoperative, perioperative, and postoperative risk factors for scleral buckle (SB) removal. DESIGN: Retrospective, consecutive, matched, case-control study. METHODS: Cases included all patients undergoing SB removal between August 1988 and December 2007 at a single academic center. Cases were matched against four randomly selected control patients who underwent SB implantation during the same year as the case. Odds ratios (OR) were calculated for each factor investigated. RESULTS: Forty cases of SB removal and 148 matched control cases were identified. Three cases of SB removal were omitted from analysis because of incomplete records. Factors associated with SB removal for any reason, using univariate analysis, included concurrent globe-penetrating injury at time of SB placement (OR, 24; 95% confidence interval [CI], 2.9 to 200), concurrent pars plana vitrectomy (PPV) (OR, 17.3; 95% CI, 4.9 to 61), diabetes mellitus (DM) (OR, 7.3; 95% CI, 1.8 to 30), prior chronic topical ocular therapy (OR, 4.3; 95% CI, 1.7 to 11), and subsequent ocular procedures (OR, 3.4; 95% CI, 1.5 to 7.5). Factors independently associated with SB removal using multivariate analysis included concurrent globe-penetrating injury (OR, 27.3; 95% CI, 1.7 to 426), concurrent PPV (OR, 11.3; 95% CI, 2.9 to 45), DM (OR, 8.9; 95% CI, 1.3 to 58), and subsequent ocular procedures (OR, 3.9; 95% CI, 1.4 to 11). Factors that did not alter SB removal risk included patient age; gender; and type, size, or location of buckling elements used. CONCLUSIONS: Awareness of these risk factors may be valuable for the surgical planning of retinal detachment repair in patients at higher risk for subsequent SB removal and for risk stratification subsequent to SB implantation.

Development of an inducible anti-VEGF rAAV gene therapy strategy for the treatment of wet AMD.

Vascular endothelial growth factor (VEGF) is a key mediator in the development and progression of choroidal neovascularization (CNV) in patients with wet age-related macular degeneration (AMD). As a consequence, current treatment strategies typically focus on the administration of anti-VEGF agents, such as Aflibercept (Eylea), that inhibit VEGF function. While this approach is largely successful at counteracting CNV progression, the treatment can require repetitive (i.e. monthly) intravitreal injections of the anti-VEGF agent throughout the patient's lifetime, imposing a substantial financial and medical burden on the patient. Moreover, repetitive injection of anti-VEGF agents over a period of years may encourage progression of retinal and choroidal atrophy in patients with AMD, leading to a decrease in visual acuity. Herein, we have developed a single-injection recombinant adeno-associated virus (rAAV)-based gene therapy treatment for wet AMD that prevents CNV formation through inducible over-expression of Eylea. First, we demonstrate that by incorporating riboswitch elements into the rAAV expression cassette allows protein expression levels to be modulated in vivo through oral supplementation on an activating ligand (e.g. tetracycline). We subsequently utilized this technology to modulate the intraocular concentration of Eylea following rAAV delivery, leading to nearly complete (p = 0.0008) inhibition of clinically significant CNV lesions in an established mouse model of wet AMD. The results shown in this study pave the way for the development of a personalized gene therapy strategy for the treatment of wet AMD that is substantially less invasive and more clinically adaptable than the current treatment paradigm of repetitive bolus injections of anti-VEGF agents.