Developing novel anti-fibrotic therapeutics to modulate post-surgical wound healing in Glaucoma: big potential for small molecules

Ocular fibrosis leads to significant visual impairment and blindness in millions of people worldwide, and is one of the largest areas of unmet need in clinical ophthalmology. The antimetabolites, mitomycin C and 5-fluorouracil, are the current gold standards used primarily to prevent fibrosis after glaucoma surgery, but have potentially blinding complications like tissue damage, breakdown, and infection. This review thus focuses on the development of new classes of small molecule therapeutics to prevent post-surgical fibrosis in the eye, especially in the context of glaucoma filtration surgery. We discuss recent advances and innovations in ophthalmic wound healing research, including antibodies, RNA interference, gene therapy, nanoparticles, liposomes, dendrimers, proteoglycans, and small molecule inhibitors. We also review the challenges involved in terms of drug delivery, duration of action, and potential toxicity of new anti-fibrotic agents in the eye

Personalized Medicine in Ocular Fibrosis: Myth or Future Biomarkers

SIGNIFICANCE: Fibrosis-related events play a part in the pathogenesis or failure of treatment of virtually all the blinding diseases around the world, and also account for over 40% of all deaths. It is well established that the eye and other tissues of some group of patients, for example Afro-Caribbean people, scar worse than others. However, there is a current lack of reliable biomarkers to stratify the risk of scarring and postsurgical fibrosis in the eye. RECENT ADVANCES: Recent studies using genomics, proteomics, metabolomics, clinical phenotyping, and high-resolution in vivo imaging techniques have revealed potential novel biomarkers to identify and stratify patients at risk of scarring in different fibrotic eye diseases. CRITICAL ISSUES: Most of the studies, to date, have been done in animals or small cohorts of patients and future research is needed to validate these results in large longitudinal human studies. Detailed clinical phenotyping and effective biobanking of patient tissues will also be critical for future biomarker research in ocular fibrosis. FUTURE DIRECTIONS: The ability to predict the risk of scarring and to tailor the antifibrotic treatment regimen to each individual patient will be an extremely useful tool clinically to prevent undertreating, or exposing patients to unnecessary treatments with potential side effects. An exciting future prospect will be to use new advances in genotyping, namely next-generation whole genome sequencing like RNA-Seq, to develop a customized gene chip in ocular fibrosis. Successful translation of future biomarkers to benefit patient care will also ultimately require a strong collaboration between academics, pharmaceutical, and biotech companies

Motives for online gaming questionnaire: Its psychometric properties and correlation with Internet gaming disorder symptoms among Chinese people

Internet gaming disorder (IGD) imposes a potential public health threat worldwide. Gaming motives are potentially salient factors of IGD, but research on Chinese gaming motives is scarce. This study empirically evaluated the psychometric properties of the Chinese version of the Motives for Online Gaming Questionnaire (C-MOGQ), the first inventory that measures seven different gaming motives applicable to all type of online games. We also investigated the associations between various gaming motives and IGD symptoms among Chinese gamers. Methods Three hundred and eighty-three Chinese adult online gamers (Mean age = 23.7 years) voluntarily completed our online, anonymous survey in December 2015. Results The confirmatory factor analysis results supported a bi-factor model with a general factor subsuming all C-MOGQ items (General Motivation) and seven uncorrelated domain-specific factors (Escape, Coping, Fantasy, Skill Development, Recreation, Competition, and Social). High internal consistencies of the overall scale and subscales were observed. The criterion-related validity of this Chinese version was also supported by the positive correlations of C-MOGQ scale scores with psychological need satisfaction and time spent gaming. Furthermore, we found that high General Motivation (coupled with high Escape motive and low Skill Development motive) was associated with more IGD symptoms reported by our Chinese participants. Discussion and conclusions Our findings demonstrated the utility of C-MOGQ in measuring gaming motives of Chinese online gamers, and we recommend the consideration of both its total score and subscale scores in future studies

In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

Abstract Background Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.https://deepblue.lib.umich.edu/bitstream/2027.42/146540/1/12951_2018_Article_425.pd

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

PURPOSE. Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. METHODS. We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. RESULTS. Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log(10) unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. CONCLUSIONS. Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.Peer reviewe

Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues