Pharmaceutics. 2019 Oct 29;11(11). pii: E561.
Preclinical evaluation of UDCA-containing oral formulation in mice for the treatment of wet age-related macular degeneration.
Maharjan P, Kim D, Jin M, Ko HJ, Song YH, Lee Y, Ahn BN, Kim SK, Lee Y, Shin MC, Min KA, Yang J.
Abstract: As a posterior ocular disease, wet age-related macular degeneration (WAMD) has been known to be related to vision loss, accompanying ocular complications. The intravitreous injection of VEGF antibodies has been reported to be an effective treatment to relieve symptoms of WAMD. However, the limitations of this treatment are high costs and invasiveness. For this reason, oral delivery route can be considered as a cost-effective way and the safest method to deliver drug molecules to the eyes. Accordingly, ursodeoxycholic acid (UDCA) was included in the oral formulation as the potential substance for the cure of WAMD in the animal model. Various pharmacological activities, such as antioxidant or anti-inflammatory effects, have been reported for UDCA and recent reports support the effects of UDCA in ocular treatment. However, due to poor water solubility and low pKa (around 5.0), it has been challenging to formulate aqueous solution of UDCA in the neutral pH range. In the present study, we confirmed the aqueous solubility of the oral UDCA formulation and performed a preclinical study, including pharmacokinetic profiling and WAMD model efficacy study in mice after oral administration of the drug solution. The results demonstrated that the formulation improved bioavailability of UDCA and efficiently delivered UDCA to the eye tissues after oral absorption. UDCA formulation was found to have inhibitory effects of choroidal neovascularization with a functional recovery in mice retinas. Taken together, our results suggest that the oral UDCA formulation could be used as a potent supplement for the cure of WAMD and related retinal diseases.
PMID: 31671869 DOI: 10.3390/pharmaceutics11110561
Sci Rep. 2019 Oct 30;9(1):15633.
Femtosecond laser pulse ablation of sub-cellular drusen-like deposits.
Smith KN, Katchinskiy N, Elezzabi AY.
Abstract: Age-related macular degeneration (AMD) is a condition affecting the retina and is the leading cause of vision loss. Dry AMD is caused by the accumulation of lipid deposits called drusen, which form under the retina. This work demonstrates, for the first time, the removal of drusen-like deposits underneath ARPE-19 cell layers using femtosecond laser pulses. A novel cell culture model was created in response to the limited access to primary cell lines and the absence of animal models that recapitulate all aspects of AMD. In the cell culture model, deposits were identified with fluorescent stains specific to known deposit constituents. Trains of sub-10 femtosecond laser pulses from a Ti:Sapphire laser were used to successfully ablate the deposits without causing damage to surrounding cells. This drusen removal method can be used as a potential treatment for dry-stage AMD.
PMID: 31666658 DOI: 10.1038/s41598-019-52137-1
Ophthalmol Retina. 2019 Aug 28. pii: S2468-6530(19)30536-6.
Spectral-Domain OCT predictors of visual outcomes after ranibizumab treatment for macular edema resulting from retinal vein occlusion.
Yiu G, Welch RJ, Wang Y, Wang Z, Wang PW, Haskova Z.
Purpose: To evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE).
Design: Post hoc analysis of prospective clinical trial data.
Participants: Two hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema.
Methods: Baseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections.
Main Outcome Measures: Association of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections.
Results: Before therapy, worse baseline BCVA was associated with ERM presence (P = 0.0045), thicker SRF (P = 0.0006), larger intraretinal cysts (P = 0.0015), and higher percentage of DRIL (P < 0.0001), percentage of ELM disruption (P < 0.0001), percentage of EZ disruption (P = 0.0003), and percentage of IZ disruption (P = 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P < 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P < 0.0001) and worse baseline BCVA (P < 0.0001).
Conclusions: Although SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements.
PMID: 31669329 DOI: 10.1016/j.oret.2019.08.009
Ophthalmologica. 2019 Oct 30:1-9.
Assessment of exudative activity of choroidal neovascularization in age-related macular degeneration by OCT angiography.
von der Emde L, Thiele S, Pfau M, Nadal J, Meyer J, Möller PT, Schmid M, Fleckenstein M, Holz FG, Schmitz-Valckenberg S.
Purpose: Based on exudative activity, choroidal neovascularization (CNV) in age-related macular degeneration (AMD) can be classified as "active" aCNV, pretherapied "silent" sCNV (i.e., a treatment-free interval >12 weeks), or treatment-naïve "quiescent" qCNV. We evaluated the qualitative and quantitative optical coherence tomography angiography (OCTA) features of these CNV subgroups.
Methods: The presence of small-caliber vessels, peripheral arcades, and a -perilesional OCTA signal attenuation as well as values for vessel length, density, and branching index were evaluated for each CNV network in a 6 × 6 mm OCTA scan pattern.
Results: Fifty-one eyes of 51 patients with AMD (age 75.9 ± 7.5 years; 20 males [39.2%]) were included. The qCNV subgroup (n = 8) showed the highest prevalence of qualitative and quantitative values for OCTA activity criteria, reaching significance with regard to small-caliber vessels (p = 0.003), peripheral arcades (p = 0.039), vessel length (p = 0.020), and branching index (p < 0.001) when compared to the aCNV (n = 32) and sCNV (n = 11) subgroups. Qualitative criteria were inversely associated with the number of previous anti-VEGF injections (each p < 0.03), while quantitative metrics also suggested lower values.
Conclusions: These findings suggest that OCTA may be supportive in the phenotypical differentiation of CNV lesions secondary to AMD, while the assessed structural changes appeared to be more indicative of previously administered anti-VEGF therapy than current exudative activity.
PMID: 31665719 DOI: 10.1159/000503609
Ophthalmic Res. 2019 Oct 30:1-13.
Evaluation of retinal pigment epithelium and choroidal neovascularization in rats using laser-scanning optical-resolution photoacoustic microscopy.
Xiao M, Dai C, Li L, Zhou C, Wang F.
Purpose: To demonstrate the value of the laser-scanning optical-resolution (LSOR)-photoacoustic (PA) microscopy (PAM) system and the conventional multimodal imaging techniques in the evaluation of laser-induced retinal injury and choroidal neovascularization (CNV) in rats.
Methods: Different degrees of retinal injury were induced using laser photocoagulation. We compared the LSOR-PAM system with conventional imaging techniques in evaluating retinal injury with or without CNV. Six additional rats, treated with an anti-VEGF antibody or immunoglobulin G immediately after photocoagulation, were imaged 7 and 14 days after injection, and CNV lesion areas were compared.
Results: In the retinal injury model, fundus autofluorescence showed well-defined hyperreflection, while the lesion displayed abundant PA signals demonstrating nonuniform melanin distribution in retinal pigment epithelium (RPE). RPE was detected with higher contrast in the PAM B-scan image than optical coherence tomography (OCT). Additionally, the CNV lesion was present with multiple PA signal intensities which distinctly characterized the location and area of CNV as found in fundus fluorescein angiography. Furthermore, the decreased PA signals extending from the CNV lesion were similar to those of the vascular bud in ex vivo imaging, which was invisible in other in vivo images. When treated with anti-VEGF agents, statistically significant differences can be demonstrated by PAM similar to other modalities.
Conclusion: LSOR-PAM can detect the melanin distribution of RPE in laser-induced retinal injury and CNV in rats. PAM imaging provides a potential new tool to evaluate the vitality and functionality of RPE in vivo as well as to monitor the development and treatment of CNV.
PMID: 31665740 DOI: 10.1159/000502800
Eur J Ophthalmol. 2019 Oct 29:1120672119885047.
Near-infrared fundus autofluorescence in early age-related macular degeneration.
Battaglia Parodi M, Iacono P, Papayannis A, Alto G, Buzzotta A, Arrigo A, Cicinelli MV, Bandello F.
Purpose: To describe the patterns on near-infrared fundus autofluorescence in eyes affected by early age-related macular degeneration.
Design: Cross-sectional observational case series.
Participants: A total of 84 eyes of 84 patients suffering from early age-related macular degeneration (>63 μm but <125 μm drusen and no-to-mild retinal pigment epithelium abnormalities) were enrolled.
Methods: Patients underwent best-corrected visual acuity, biomicroscopy, infrared reflectance, short-wavelength fundus autofluorescence, and near-infrared fundus autofluorescence. Eyes were classified according to different patterns of near-infrared fundus autofluorescence. Main outcome was definition of relative prevalence and features of each near-infrared fundus autofluorescence pattern; secondary outcomes were correlation between near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence and between near-infrared fundus autofluorescence patterns and best-corrected visual acuity.
Results: Four different patterns of near-infrared fundus autofluorescence identified: normal foveal signal (Pattern A, 7%); normal foveal signal with hyperautofluorescent/hypoautofluorescent spots not involving the fovea (Pattern B, 65.5%); hyperautofluorescent/hypoautofluorescent spots involving the fovea (Pattern C, 15.5%); patchy pattern (Pattern D, 12%). best-corrected visual acuity was lower in eyes with foveal signal alteration (Patterns C and D).
Conclusion: Near-infrared fundus autofluorescence pattern in early age-related macular degeneration might be suggestive of visual function deterioration when the fovea is involved. Longitudinal studies are warranted to confirm our preliminary results.
PMID: 31661979 DOI: 10.1177/1120672119885047
Ophthalmol Retina. 2019 Aug 20. pii: S2468-6530(19)30520-2.
Prognostic value of retinal layers in comparison with other risk factors for conversion of intermediate age-related macular degeneration.
Thiele S, Nadal J, Pfau M, Saßmannshausen M, Emde LV, Fleckenstein M, Holz FG, Schmid M, Schmitz-Valckenberg S; Molecular Diagnostic of Age-related Macular Degeneration Study Group.
Purpose: To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages.
Design: Prospective, longitudinal natural history study.
Participants: Ninety-one eyes of 91 patients with AMD (73.3±7.3 years; 62 female patients [50.4%]) of the Molecular Diagnostic of Age-related Macular Degeneration (MODIAMD) study without exudative or nonexudative late-stage AMD in the study eye at baseline.
Methods: At each annual follow-up visit, all subjects underwent ophthalmic examination with assessment of best-corrected visual acuity (BCVA) and retinal imaging, including spectral-domain OCT (SD-OCT), over a study period of 6 years.
Purpose: To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages.
Main Outcome Measures: Qualitative structural AMD features and SD-OCT-based quantitative thickness changes of different retinal layers, such as the retinal pigment epithelium-drusen complex (RPEDC), were assessed by multimodal imaging. Their prognostic relevance regarding disease conversion was determined using Cox regression (cloglog link function).
Results: In the multivariable analysis, the presence of focal hyperpigmentation, almost reaching statistical significance, showed the strongest effect regarding the development of nonexudative late-stage AMD (hazard ratio [HR], 5.88; 95% confidence interval [CI], 0.69-50.2; P = 0.052) followed by the presence of refractile drusen (HR, 4.82; 95% CI, 1.33-17.44; P = 0.0164). A thickening of the RPEDC was the only assessed retinal layer that exhibited a significant effect on the development of nonexudative advanced AMD (HR, 1.03; 95% CI, 1.0-1.07; P = 0.0393), whereas no association was observable for the other retinal layers. Neither qualitative nor quantitative markers were significant predictors for the development of exudative late-stage AMD (P > 0.05).
Conclusions: The results indicate that the development of both exudative and nonexudative AMD is associated with distinct prognostic features. However, compared with the assessment of qualitative AMD features, the quantification of retinal layers on average across the central retina had less prognostic impact. Further studies are needed to identify and validate robust biomarkers in early AMD stages.
PMID: 31649003 DOI: 10.1016/j.oret.2019.08.003
Curr Eye Res. 2019 Oct 31.
A meta-analysis of cardiovascular events associated with intravitreal anti-VEGF treatment in patients with retinal vein occlusion.
Zhong P, He M, Yu H, Wu Q, Peng Q, Huang M, Xue Y, Yang X.
Purpose: Retinal vein occlusion is associated with an increased risk of cardiovascular diseases. Anti-vascular endothelial growth factor has been widely used as a treatment option. However, the systemic safety of intravitreal anti-vascular endothelial growth factor for retinal vein occlusion patients is still unclear.
Materials and Methods: A meta-analysis was conducted to investigate all randomized controlled trials published up to February 2019 of retinal vein occlusion patients who received intravitreal anti-vascular endothelial growth factor vs. control treatments. Fixed effect models were used and results were reported as odds ratios and 95% confidence intervals.
Results: Eight trials that evaluated 2320 patients were retrieved. Anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events (odds ratio,1.54; 95% confidence interval, 0.66-3.57), hypertension (odds ratio, 0.92; 95% confidence interval, 0.63-1.33), or heart rate disorders (odds ratio,1.53; 95% confidence interval, 0.37-6.28) when compared with control treatment. Subgroup analyses did not show a significant increase of cardiovascular events in aflibercept (odds ratio,1.96; 95% confidence interval, 0.44-8.81) vs. ranibizumab trials (odds ratio, 1.47; 95% confidence interval, 0.54-4.02); 0.5mg ranibizumab trials (odds ratio, 1.73; 95% confidence interval, 0.61-4.96) vs. 0.3mg ranibizumab trials (odds ratio, 0.70; 95% confidence interval, 0.14-3.59); nor branch retinal vein occlusion (odds ratio, 1.32; 95% confidence interval, 0.40-4.33) vs. central retinal vein occlusion trials (odds ratio, 1.93; 95% confidence interval, 0.59-6.29).
Conclusions: Intravitreal administration of anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events, hypertension or heart rate disorders in retinal vein occlusion patients.
PMID: 31670978 DOI: 10.1080/02713683.2019.1687727
Acta Ophthalmol. 2019 Oct 26.
Prevalence of Charles Bonnet syndrome in patients with age-related macular degeneration: systematic review and meta-analysis.
Niazi S, Krogh Nielsen M, Singh A, Sørensen TL, Subhi Y.
Abstract: Age-related macular degeneration (AMD) is the most common cause of visual impairment in the developed world. A number of patients experience complex lifelike visual experiences-Charles Bonnet syndrome (CBS). In this systematic review, our aim was to provide an overview of the CBS literature in relation to AMD, to determine the prevalence of CBS in patients with AMD and to provide an overview of associated demographical and clinical aspects. We searched the literature databases PubMed/MEDLINE, EMBASE, Web of Science, the Cochrane Central, and PsycINFO on 22 March 2019 for studies evaluating the prevalence of CBS in patients with AMD. Two independent authors extracted the data and evaluated risk of bias. Studies were reviewed qualitatively in the text and quantitatively in a meta-analysis including subgroup analyses for differences between demographic and clinical factors. We identified 18 studies with data on >4303 patients with AMD. We found an overall prevalence of CBS of 15.8% (95% confidence interval: 11.0%-21.2%). When looking at consecutively recruited patients with neovascular AMD from the clinic, prevalence of CBS was 7.2% (95% confidence interval: 4.3%-10.6%). Among visitors to visual rehabilitation centres, prevalence of CBS was 31.6% (95% confidence interval: 21.7%-42.3%). Taken together, we find that CBS is rather common in patients with AMD.
PMID: 31654492 DOI: 10.1111/aos.14287
Stem Cells. 2019 Oct 31.
Developing a simple method to enhance the generation of cone and rod photoreceptors in pluripotent stem cell-derived retinal organoids.
Zerti D, Dorgau B, Felemban M, Ghareeb AE, Yu M, Ding Y, Krasnogor N, Lako M.
Abstract: Cell replacement therapy is a promising treatment for irreversible retinal cell death in diverse diseases such as Stargardt's disease, age-related macular degeneration, and retinitis pigmentosa. The final impact of all retinal dystrophies is the loss of photoreceptors; hence, there is a pressing need for research into replacement. Seminal work has shown that a simple three-dimensional culture system enables differentiation of human pluripotent stem cells to retinal organoids containing large numbers of photoreceptors developing alongside retinal neurons and Müller glia cells in a laminated structure that resembles the native retina. Despite these promising developments, current protocols show different efficiencies across pluripotent stem cells and result in retinal organoids with a mixture of photoreceptor cells at varying maturation states, along with nonphotoreceptor cell types. In this study, we investigated the impact of stage-specific addition of retinoic acid (RA), 9-cis-retinal, 11-cis-retinal, levodopa (l-DOPA), triiodothyronine (T3), and γ-secretase inhibitor ((2S)-N-[(3,5-Difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine1,1-dimethylethyl ester2L [DAPT]) in the generation of cone and rod photoreceptors. Our results indicate that addition of RA + T3 during days 90 to 120 of differentiation enhanced the generation of rod and S-cone photoreceptor formation, while the combined addition of DAPT from days 28 to 42 with RA during days 30 to 120 of differentiation led to enhanced generation of L/M-cones at the expense of rods. l-DOPA when added together with RA during days 90 to 120 of differentiation also promoted the emergence of S-cones at the expense of rod photoreceptors. Collectively, these data represent an advance in our ability to direct generation of rod and cone photoreceptors in vitro. Stem Cells 2019.
PMID: 31670434 DOI: 10.1002/stem.3082
Adv Exp Med Biol. 2019;1186:1-31.
Pluripotent stem cells to model degenerative retinal diseases: The RPE perspective.
Dalvi S, Galloway CA, Singh R.
Abstract: Pluripotent stem cell technology, including human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), has provided a suitable platform to investigate molecular and pathological alterations in an individual cell type using patient's own cells. Importantly, hiPSCs/hESCs are amenable to genome editing providing unique access to isogenic controls. Specifically, the ability to introduce disease-causing mutations in control (unaffected) and conversely correct disease-causing mutations in patient-derived hiPSCs has provided a powerful approach to clearly link the disease phenotype with a specific gene mutation. In fact, utilizing hiPSC/hESC and CRISPR technology has provided significant insight into the pathomechanism of several diseases. With regard to the eye, the use of hiPSCs/hESCs to study human retinal diseases is especially relevant to retinal pigment epithelium (RPE)-based disorders. This is because several studies have now consistently shown that hiPSC-RPE in culture displays key physical, gene expression and functional attributes of human RPE in vivo. In this book chapter, we will discuss the current utility, limitations, and plausible future approaches of pluripotent stem cell technology for the study of retinal degenerative diseases. Of note, although we will broadly summarize the significant advances made in modeling and studying several retinal diseases utilizing hiPSCs/hESCs, our specific focus will be on the utility of patient-derived hiPSCs for (1) establishment of human cell models and (2) molecular and pharmacological studies on patient-derived cell models of retinal degenerative diseases where RPE cellular defects play a major pathogenic role in disease development and progression.
PMID: 31654384 DOI: 10.1007/978-3-030-28471-8_1
Retin Cases Brief Rep. 2019 Oct 24.
Optical coherence tomography angiography imaging of choroidal neovascularization secondary to choroidal rupture treated by intravitreal ranibizumab.
Benillouche J, Astroz P, Ohayon A, Srour M, Amoroso F, Pedinielli A, Mouallem A, Souied EH.
Purpose: To describe optical coherence tomography angiography findings at baseline and during the follow-up of choroidal neovascularization secondary to choroidal rupture (CR) in a patient with kidney transplant treated by a single intravitreal injection of ranibizumab.
Methods: The clinical course, conventional multimodal imaging findings including ultra-widefield fundus color photography and fundus autofluorescence (Optos California, Marlborough, MA), spectral-domain optical coherence tomography (SD-OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography (FA; Heidelberg Engineering, Heidelberg, Germany), indocyanine green angiography ,and optical coherence tomography angiography (Plex-Elite, Carl Zeiss Meditec, Inc, Dublin, CA) findings at baseline and during the follow-up of a patient with choroidal neovascularization secondary to CR.
Results: A 19-year-old young man with a history of blunt trauma presented with acute visual decline of the right eye. He had a systemic history of kidney transplant. His best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye at baseline. Funduscopic examination and ultra-widefield fundus autofluorescence imaging revealed a double vertical macular lesion corresponding to a CR in the right eye. Spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography revealed active Type 2 choroidal neovascularization secondary to the CR. Optical coherence tomography angiography showed a high-flow neovascular network consistent with conventional multimodal imaging. One month after intravitreal injection of ranibizumab, best-corrected visual acuity was 20/100, optical coherence tomography angiography showed a contraction and remodeling of the neovascular flow, and exudative signs disappeared on multimodal imaging. No side effect was detected.
Conclusion: Optical coherence tomography angiography is able to detect choroidal neovascularization secondary to CR at baseline and during the follow-up after a single intravitreal injection of ranibizumab. Ranibizumab was effective in the treatment of this sight-threatening lesion in a patient with a history of kidney transplant.
PMID: 31652192 DOI: 10.1097/ICB.0000000000000932