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Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

ABSTRACT: Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.

SUBMITTER: Semkova I

PROVIDER: S-EPMC130591 | biostudies-literature | 2002 Oct

REPOSITORIES: biostudies-literature

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Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

Semkova Irina I Kreppel Florian F Welsandt Gerhard G Luther Thomas T Kozlowski Jolanta J Janicki Hanna H Kochanek Stefan S Schraermeyer Ulrich U

Proceedings of the National Academy of Sciences of the United States of America 20020918 20

Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of geneticall ...[more]

PMID: 12239351

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Project description:PurposeConflicting findings exist in the literature with regard to the relationship between iris color, ethnicity, macular pigment optical density (MPOD), and hue discrimination. This study re-examined these relationships, accounting for factors that may have confounded prior studies. Clinically, the relationship between MPOD and hue discrimination may impact the utility of macular pigment supplementation as a treatment for conditions such as macular degeneration.MethodsSubjects (n = 30, mean/SD age = 25.1/2.5 yrs.) with normal color vision completed MPOD testing and Farnsworth-Munsell 100 hue (FM100) testing. MPOD data was derived from the average of three measurements using the QuantifEYE II device and FM100 testing included training runs. The total error score of the FM100 test was used for analysis. Iris color was determined subjectively, while iris reflectance was derived using calibrated iris images. Spearman correlations were used to determine the relationship between MPOD and FM100 test scores. Kruskal-Wallis testing was used to investigate MPOD differences among different ethnicities and iris colors.ResultsMPODs were normally distributed with a mean/SD = 0.38/0.13. Total error scores had a mean/SD of 10.7/9.7, but were not normally distributed. Iris reflectances had a mean/SD = 11.0/8.7. MPODs were not correlated to total error scores (p = 0.93). MPODs were also not correlated with iris reflectances (p = 0.28) even though MPODs differed significantly by iris color (brown = 0.44, hazel = 0.31, blue = 0.33, p = 0.04). Iris reflectances were not correlated with total error scores (p = 0.68). MPODs differed significantly (p = 0.003) between Asian and Caucasian subjects, 0.44 and 0.33, respectively.ConclusionsThis study did not find a correlation between MPOD and hue discrimination as in some previous studies. While MPOD was associated with iris color and ethnicity as found in prior studies, it was not associated with iris reflectance, which may be a better indicator of ocular pigmentation compared to either iris color or ethnicity.

Project description:Age-related macular degeneration (AMD) is a common disease with a multifactorial aetiology, still lacking effective and curative therapies. Among the early events triggering AMD is the deterioration of the retinal pigment epithelium (RPE), whose fundamental functions assure good health of the retina. RPE is physiologically exposed to high levels of oxidative stress during its lifespan; thus, the integrity and well-functioning of its antioxidant systems are crucial to maintain RPE homeostasis. Among these defensive systems, the Nrf2-pathway plays a primary role. Literature evidence suggests that, in aged and especially in AMD RPE, there is an imbalance between the increased pro-oxidant stress, and the impaired endogenous detoxifying systems, finally reverberating on RPE functions and survival. In this in vitro study on wild type (WT) and Nrf2-silenced (siNrf2) ARPE-19 cells exposed to various AMD-related noxae (H2O2, 4-HNE, MG132 + Bafilomycin), we show that the Nrf2-pathway activation is a physiological protective stress response, leading downstream to an up-regulation of the Nrf2-targets HO1 and p62, and that a Nrf2 impairment predisposes the cells to a higher vulnerability to stress. In search of new pharmacologically active compounds potentially useful for AMD, four nature-inspired hybrids (NIH) were individually characterized as Nrf2 activators, and their pharmacological activity was investigated in ARPE-19 cells. The Nrf2 activator dimethyl-fumarate (DMF; 10 μM) was used as a positive control. Three out of the four tested NIH (5 μM) display both direct and indirect antioxidant properties, in addition to cytoprotective effects in ARPE-19 cells under pro-oxidant stimuli. The observed pro-survival effects require the presence of Nrf2, with the exception of the lead compound NIH1, able to exert a still significant, albeit lower, protection even in siNrf2 cells, supporting the concept of the existence of both Nrf2-dependent and independent pathways mediating pro-survival effects. In conclusion, by using some pharmacological tools as well as a reference compound, we dissected the role of the Nrf2-pathway in ARPE-19 stress response, suggesting that the Nrf2 induction represents an efficient defensive strategy to prevent the stress-induced damage.

Project description:PurposeTo investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD).DesignRetrospective analysis of a prospective cohort study.ParticipantsOf the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED.MethodsBaseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan-Meier analyses and multivariable proportional hazard regressions were performed.Main outcome measuresProgression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype.ResultsMean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98-2.82; P < 0.001); 67% of eyes progressed to late AMD 5 years after DPED detection. Drusenoid pigment epithelial detachment was associated with increased risk of ≥3 lines of VA loss (HR, 3.08; CI, 2.41-3.93; P < 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58-4.70; 2 vs. 0: HR, 3.16, CI, 1.60-6.21, P < 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66-40.45, P < 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2.ConclusionsThis study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Dataset Information

Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

Publications

Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

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