Corticosteroids remain the mainstay of the management of patients with uveitis. Topical corticosteroids are effective in the control of anterior uveitis, but vary in strength, ocular penetration and side effect profile. Systemic corticosteroids are widely used for the management of posterior segment inflammation which requires treatment, particularly when it is associated with systemic disease or when bilateral ocular disease is present. However, when ocular inflammation is unilateral, or is active in one eye only, local therapy has considerable advantages, and periocular injections of corticosteroid are a useful alternative to systemic medication and are very effective in controlling mild or moderate intraocular inflammation. More recently, the injection of intraocular corticosteroids such as triamcinolone have been found to be effective in reducing macular oedema and improving vision in uveitic eyes which have proved refractory to systemic or periocular corticosteroids. The effect is usually transient, lasting around 3 months, but can be repeated although the side effects of cataract and raised intraocular pressure are increased in frequency with intraocular versus periocular corticosteroid injections. This has led to the development of new intraocular corticosteroid devices which are designed to deliver sustained-release drugs and obviate the need for systemic immunosuppressive treatment. The first such implant was Retisert, which is surgically implanted (in the operating theatre) and is designed to release fluocinolone over a period of about 30 months. More recently, Ozurdex, a ‘bioerodible’ dexamethasone implant which can be inserted in an office setting, has completed phase III clinical trials in patients with intermediate and posterior uveitis. This implant lasts approximately 6 months, and has been found to be effective with a much better side effect profile than Retisert or intravitreal triamcinolone injection, at least for one injection.
Background
The association of
HTRA1
rs11200638 and
ARMS2
rs10490924 gene polymorphisms with response to intravitreal ranibizumab therapy among neovascular AMD (nAMD) subjects in Malaysia was determined in this study, followed by the expression of
HTRA1
and
ARMS2
genes.
Results
Both single nucleotide polymorphisms (SNPs) recorded a significant association between nAMD and controls with
HTRA1
rs11200638 at
P
= 0.018 (OR = 1.52, 95% CI = 1.07–215) and
ARMS2
rs10490924 at
P
< 0.001 (OR = 2.44, 95% CI = 1.75–3.42). An association was also observed in response to ranibizumab for both SNPs in a logistic regression analysis (
P
< 0.001). The mRNA levels in the
HTRA1
variant between responder and non-responder groups were significantly different for the homozygous non-risk GG genotype (
P
= 0.032).
Conclusions
The
HTRA1
rs11200638 and
ARMS2
rs10490924 gene polymorphisms are associated with nAMD among Malaysians. Both gene polymorphisms were also correlated with response to intravitreal ranibizumab therapy based on visual and anatomical outcomes especially the
HTRA1
rs11200638 variant.
Retinal disorders account for a large proportion of ocular disorders that can lead to visual impairment or blindness, and yet our limited knowledge in the pathogenesis and choice of appropriate animal models for new treatment modalities may contribute to ineffective therapies. Although genetic in vivo models are favored, the variable expressivity and penetrance of these heterogeneous disorders can cause difficulties in assessing potential treatments against retinal degeneration. Hence, an attractive alternative is to develop a chemically-induced model that is both cost-friendly and standardizable. Sodium iodate is an oxidative chemical that is used to simulate late stage retinitis pigmentosa and age-related macular degeneration. In this study, retinal degeneration was induced through systemic administration of sodium iodate (NaIO3) at varying doses up to 80 mg/kg in Sprague-Dawley rats. An analysis on the visual response of the rats by electroretinography (ERG) showed a decrease in photoreceptor function with NaIO3 administration at a dose of 40 mg/kg or greater. The results correlated with the TUNEL assay, which revealed signs of DNA damage throughout the retina. Histomorphological analysis also revealed extensive structural lesions throughout the outer retina and parts of the inner retina. Our results provided a detailed view of NaIO3-induced retinal degeneration, and showed that the administration of 40 mg/kg NaIO3 was sufficient to generate disturbances in retinal function. The pathological findings in this model reveal a degenerating retina, and can be further utilized to develop effective therapies for RPE, photoreceptor, and bipolar cell regeneration.
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