Atrophic Macular Degeneration Research Articles

Atrophic Macular Degeneration and Stem Cell Therapy: A Clinical Review.

Age-related macular degeneration (AMD) is one of the leading causes of visual loss in older patients. No effective drug is available for this pathology, but studies about therapy with stem cells replacing the damaged retinal cells with retinal pigment epithelium (RPE) were described. The documentation of AMD progression and the response to stem cell therapy have been performed by optical coherence tomography, microperimetry, and other diagnostic technologies.This chapter reports a clinical review of the most important clinical trials and protocols regarding the use of stem cells in AMD.

Extensive macular atrophy with pseudodrusen-like appearance: comprehensive review of the literature.

This review focuses on extensive macular atrophy with pseudodrusen-like appearance (EMAP), a recently described maculopathy presenting with pseudodrusen-like lesions and chorioretinal atrophy more pronounced in the vertical axis. Narrative review of the literature published until May 2024. The early onset age of EMAP (50-55 years) and its distinctive natural history, which includes night blindness followed by severe vision loss, differentiate it from atrophic age-related macular degeneration (AMD). A clear pathogenesis has not been determined, but risk factors include female gender and complement system abnormalities (altered levels of C3 and CH50). Moreover, lifelong exposure to pesticides has been suggested as risk factor for direct neuronal degeneration involving rods and cones. In the early phase of the disease, reticular pseudodrusen-like lesions appear in the superior perifovea and tend to coalescence horizontally into a flat, continuous, reflective material localized between the retinal pigmented epithelium and Bruch's membrane. Over time, EMAP causes profound RPE and outer retinal atrophy in the macular area, with a recent classification reporting a 3-stages evolution pattern. Blue autofluorescence showed rapidly evolving atrophy with either hyperautofluorescent or isoautofluorescent borders. Significant similarities between the diffuse-trickling phenotype of geographic atrophy and EMAP have been reported. Macular neovascularization is a possible complication. EMAP is specific form of early-onset atrophic macular degeneration with rapid evolution and no treatment. Further studies are needed to assess the best management.

Experience of use of the extended complex of ophthalmononeurostimulation in patients with non-exudative atrophic (geographic) form of age-of-aged macular degeneration

BACKGROUND: Non-exudative atrophic (geographic) macular degeneration of the retina is one of the causes of irreversible loss of central vision in the elderly. Its frequency of occurrence increases with age.
 AIM: to evaluate the effectiveness of the extended complex of ophthalmoneurostimulation in patients with non-exudative atrophic (geographical) form of age-related macular degeneration.
 MATERIAL AND METHODS: The study included 49 people (98 eyes) with geographic retinal atrophy, whose average age was 741.7 years, who were divided into 2 groups: group 1 ― 24 patients (48 eyes) aged 71.01.8 years, who underwent an extended complex of ophthalmoneurostimulation, including a course of endonasal electrophoresis of vitamin B12 (for a course of 10 daily procedures), transocular infrared stimulation (for a course of 10 daily procedures), oxygen therapy with Heliox-21 breathing mixture (for a course of 10 daily procedures), and acupuncture (for a course of 10 daily procedures), and group 2 ― 25 patients (50 eyes) aged 751.1 years, who underwent a course of conservative treatment with vitamins according to existing ophthalmological standards, which served as a background in group 1. Visual acuity was assessed (visual acuity), indicators of optical coherence tomography and optical coherence tomography with angiography function of the retina, local photosensitivity, autofluorescence of the retina and bioelectric potential in pattern-electroretinography. Studies were performed before therapy, after 2 weeks, 3 months, 6 months, and 12 months, after a course of treatment.
 RESULTS: Visual acuity and anatomical parameters of the retina in high resolution (thickness of the central zone and the thickness of the choroid) did not change during the entire observation period. Analysis of light sensitivity showed a significant normalization of the average threshold of retinal photosensitivity when prescribing an extended complex of ophthalmoneurostimulation.
 CONCLUSION: Conducted extended course of physiotherapy significantly reduced the functional depression of the central visual field, coordinating with foci of retinal pigment epithelium atrophy. Most likely, this positive effect was achieved due to the activation of the level of the ganglionic and bipolar layers of the retina.

Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 μm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 μm pixels matches the pixel pitch, while with 20 μm pixels, it reaches the 28 μm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.

Clinical characteristics of peripheral exudative hemorrhagic chorioretinopathy in a referral center in Spain

ObjectiveTo publish the clinical characteristics of peripheral exudative hemorrhagic chorioretinopathy (PHEC) in the Spanish population. MethodsRetrospective study and analysis of results in patients diagnosed with PHEC. The clinical characteristics, by OCT, the treatment used and the evolution after treatment were collected. Results39 eyes of 23 patients with PHEC were evaluated. The average age at diagnosis was 79 years (66–94 years). The main ocular symptom was low vision in 26 eyes (66.6%); only 11 eyes (28.2%) were asymptomatic. The most frequent referred diagnosis was bleeding/exudation in 24 eyes (61.5%), followed by choroidal melanoma in 9 (23.1%). Intra or subretinal hemorrhages were the type of peripheral lesion most frequently found, in 24 eyes (61.5%). Twenty-five eyes (58.9%) received some type of treatment: 15 eyes (60%) underwent intravitreal injection (IIV) of antiangiogenic agents (anti-VEGF); Laser photocoagulation was performed in 2 cases (8%), Photodynamic therapy in 2 cases (8%) and 6 cases (18.2%) required pars plana vitrectomy (PPV) due to vitreous hemorrhage. There were no changes in visual acuity (VA) in patients followed with observation between baseline 0.66±0.80 (0.04–2.82) and end of follow-up 0.75±0.96 (0.00–2.82) (P=.352), nor for those who received some type of treatment between the beginning 0.78±0.79 (0.04–2.30) and the end 1.22±1.01 (0.04–2.82) (P=.157), possibly due to the large component of atrophic or exudative age-related macular degeneration (AMD) presented in both groups. (29 eyes presented atrophic or exudative AMD) ConclusionsPHEC is a rare pathology, frequently associated with AMD, which typically presents as a peripheral mass that is frequently confused with choroidal melanoma and other intraocular tumors and hence the importance of learning to identify it, making the correct differential diagnosis and avoid unnecessary treatments. Antiangiogenic therapy is effective in most patients with an active phase (exudative/hemorrhagic) into leading to fibrosis of peripheral hemorrhagic areas.

Características clínicas de la coriorretinopatía exudativa hemorrágica periférica en un centro de referencia en España

ObjectiveTo publish the clinical characteristics of peripheral exudative hemorrhagic chorioretinopathy (PHEC) in the Spanish population. MethodsRetrospective study and analysis of results in patients diagnosed with PHEC. The clinical characteristics, by OCT, the treatment used and the evolution after treatment were collected. Results39 eyes of 23 patients with PHEC were evaluated. The average age at diagnosis was 79 years (66-94 years). The main ocular symptom was low vision in 26 eyes (66.6%); only 11 eyes (28.2%) were asymptomatic. The most frequent referred diagnosis was bleeding/exudation in 24 eyes (61.5%), followed by choroidal melanoma in 9 (23.1%). Intra or subretinal hemorrhages were the type of peripheral lesion most frequently found, in 24 eyes (61.5%). Twenty-five eyes (58.9%) received some type of treatment: 15 eyes (60%) underwent intravitreal injection (IIV) of antiangiogenic agents (anti-VEGF); Laser photocoagulation was performed in 2 cases (8%), Photodynamic therapy in 2 cases (8%) and 6 cases (18.2%) required pars plana vitrectomy (PPV) due to vitreous hemorrhage. There were no changes in visual acuity (VA) in patients followed with observation between baseline 0.66±0.80 (0.04-2.82) and end of follow-up 0.75±0.96 (0.00-2.82) (P=.352), nor for those who received some type of treatment between the beginning 0.78±0.79 (0.04-2.30) and the end 1.22±1.01 (0.04-2.82) (P=.157), possibly due to the large component of atrophic or exudative age-related macular degeneration (AMD) presented in both groups. (29 eyes presented atrophic or exudative AMD). ConclusionsPHEC is a rare pathology, frequently associated with AMD, which typically presents as a peripheral mass that is frequently confused with choroidal melanoma and other intraocular tumors and hence the importance of learning to identify it, making the correct differential diagnosis and avoid unnecessary treatments. Antiangiogenic therapy is effective in most patients with an active phase (exudative/hemorrhagic) into leading to fibrosis of peripheral hemorrhagic areas.

Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration.

The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on 21 human choroids, 11 of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.

Dual Sensory Impairment: The Correlation between Age Related Macular Degeneration and Sensorineural Hearing Loss.

The pathogeneses of age-related macular degeneration (AMD) and age-related hearing impairment are not yet fully understood. If AMD and age-related hearing impairment are correlated, the cause of both may be a result of a common vulnerability. The aim of this study was to assess the interrelation between age-related macular degeneration and age-related hearing loss. Material and methods: In our case-control analysis, the hearing conditions of 40 subjects with AMD were compared with 40 age-matched healthy controls. In all patients, retinal changes were certified by clinical examinations, optical coherence tomography (OCT), and fluorescein angiography (FA). All subjects were inspected with pure tone audiometry (PTA), impedance audiometry, and speech audiometry. Results: A significant correlation (p < 0.001) was identified between age-related macular degeneration and age-related hearing impairment. The predominant hearing impairment in this case was sensorineural (SNHL). Of the patients diagnosed with AMD, SNHL was found in 88.89% of those with exudative macular degeneration and in 67.74% of those with atrophic macular degeneration. In contrast, we found that a significant proportion of the control group had normal hearing. Conclusion: One possible explanation for the association between retinal and cochlear impairment may be due to a melanin disorder.

DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.

Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic noninfectious diseases, remain unknown. Here, we report that endogenous short interspersed nuclear element (SINE) RNAs, which promote atrophic macular degeneration (AMD) and systemic lupus erythematosus (SLE), induce NLRC4 inflammasome activation independent of NAIPs. We identify DDX17, a DExD/H box RNA helicase, as the sensor of SINE RNAs that licenses assembly of an inflammasome comprising NLRC4, NLR pyrin domain–containing protein 3, and apoptosis-associated speck-like protein–containing CARD and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 release in peripheral blood mononuclear cells of patients with SLE and prevented retinal degeneration in an animal model of AMD. Our findings uncover a previously unrecognized noncanonical NLRC4 inflammasome activated by endogenous retrotransposons and provide potential therapeutic targets for SINE RNA–driven diseases.

Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

Long interspersed nuclear element-1 (L1)–mediated reverse transcription (RT) of Alu RNA into cytoplasmic Alu complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of Alu cDNA–induced cytotoxicity and its relevance to human disease are unknown. Here we report that Alu cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages Alu cDNA to induce cytosolic mitochondrial DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to Alu RNA–induced Alu cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block Alu cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

Longevinex ® Improves Human Atrophic Aged-related Macular Degeneration (AMD) Photoreceptor / Retinal Pigment Epithelium Mediated Dark Adaptation*

Longevinex ® Improves Human Atrophic Aged-related Macular Degeneration (AMD) Photoreceptor / Retinal Pigment Epithelium Mediated Dark Adaptation*

Prognostic implications of imaging in atrophic macular degeneration and its use in clinical practice and clinical trial design.

Clinical prognostic markers in atrophic age-related macular degeneration include the extent of existing atrophy, fundus autofluorescence (FAF) patterns and optical coherence tomography changes in the outer retina/retinal pigment epithelium interface. The prognostic implications of these findings may be used to determine not just the rate of disease progression but also influence the likelihood, magnitude and clinical relevance of therapy responses. FAF phenotypes have been extensively investigated; however, the pathophysiological mechanisms behind their appearance have not been fully elucidated. Optical coherence tomography imaging is additive to FAF imaging in atrophic age-related macular degeneration, allowing the visualization of detail not available through FAF imaging whilst also displaying subtle changes correlating with the FAF phenotypes themselves, thereby giving clues to their histological determinates. The developing understanding of these imaging modalities and consequent development of prognostically useful classification systems have widespread implication in clinical care and clinical trial design.

The improvement of Spoke‐Wheel pattern foveoschisis in a patient with X‐linked retinoschisis treated with topical dorzolamide observed by high‐resolution adaptive optics camera

PurposeThe purpose of the study is to report the improvement of foveomacular cavities and spoke‐wheel pattern retinoschisis observed by spectral‐domain optical coherence topmography (SD‐OCT) and high‐resolution adaptive optics fundus camera in a patient with XLRS treated with topical dorzolamide.MethodsA 42 y.o. man with XLRS underwent detailed ophthalmic examinations. A mutation of RS1 gene was detected earlier. The ophthalmological examinations included SD‐OCT, fundus autofluorescence imaging, and full‐field and multifocal ERGs. Fundus images with microscopic resolution were obtained using the AO retinal camera (rtx1, Imagine Eyes, France). He was treated with topical dorzolamide three times a day. Transverse foveomacular cavities was observed by SD‐OCT and the en‐face images of spoke‐wheel pattern foveoschisis was observed by AO fundus camera during a follow‐up period.ResultsHis BCVA was 0.15 in the right eye and 0.3 in the left eye. The right eye showed atrophic macular degeneration and left eye showed spoke‐wheel pattern foveoschisis. SD‐OCT showed the thinning of retinal thickness in the right eye and cystoid foveoschisis in the left eye. AO images showed spoke‐wheel pattern retinal fold in the left eye. The spoke‐wheel pattern in AO was sharper compared to the images obtained by fundus photography and autofluorescence imaging. After 14 month of treatment with topical dorzolamid, improvement of foveomacular cavities in SD‐OCT was observed. The spoke‐wheel pattern retinal fold in AO become obscure after treatment, however still detectable even after foveomacular cavities in SD‐OCT was almost disappeared.ConclusionsAO imaging showed detailed microstructure of spoke‐wheel pattern foveoschisis and their improvement during a follow‐up period. AO imaging may be helpful in clarifying the pathology of the foveoschisis in XLRS.

Preliminary study on electrophysiological changes after cellular autograft in age-related macular degeneration.

Evolving atrophic macular degeneration represents at least 80% of all macular degenerations and is currently without a standardized care. Autologous fat transplantation efficacy was demonstrated by several studies, as these cells are able to produce growth factors. The aim of the work was to demonstrate possible therapeutic effect of the joined suprachoroidal graft of adipocytes, adipose-derived stem cells (ADSCs) in stromal vascular fractions (SVFs) of adipose tissue, and platelet-rich plasma (PRP).Twelve eyes in 12 dry age-related macular degeneration (AMD) patients, aged 71.25 (SD ± 6.8) between 62 and 80 years, were analyzed. A complete ocular evaluation was performed using best corrected visual acuity (BCVA), retinographic analysis, spectral-domain optical coherence tomography, microperimetry, computerized visual field, and standard electroretinogram (ERG). Each eye received a cell in graft between choroid and sclera of mature fat cells and ADSCs in SVF enriched with PRP by means of the variant second Limoli (Limoli retinal restoration technique [LRRT]). In order to test if the differences pre- and post-treatment were significant, the Wilcoxon signed-rank test has been performed.Adverse effects were not reported in the patients. After surgery with LRRT, the most significant increase in the ERG values was recorded by scotopic rod-ERG (answer coming from the rods), from 41.26 to 60.83 μV with an average increase of 47.44% highly significant (P < 0.05). Moderately significant was the one recorded by scotopic maximal ERG (answer coming from the rods and cones), from 112.22 to 129.68 μV with an average increase of 15.56% (P < 0.1).Cell-mediated therapy based on growth factors used appears interesting because it can improve the retinal functionality responses in the short term. The ERG could, therefore, be used to monitor the effect of cell-mediated regenerative therapies.

Retained Descemet&amp;rsquo;s membrane following penetrating keratoplasty for Fuchs&amp;rsquo; endothelial dystrophy: a case report of a post-operative complication

PurposeTo report a case of retained Descemet’s membrane following penetrating keratoplasty in a patient suffering from Fuchs’ endothelial corneal dystrophy. The use of confocal microscopy, histopathological tissue analysis, and treatment options are discussed.MethodsCase report of an 85-year-old man with a past ophthalmic history of atrophic macular degeneration, underwent a penetrating keratoplasty for Fuchs’ endothelial corneal dystrophy. Postoperative review revealed a retained retrocorneal membrane within the anterior chamber. Further surgery was performed to excise the membrane, with a subjective and objective postoperative improvement in visual acuity and without subsequent complications of the corneal graft.ResultsHistopathological assessment confirmed the clinical suspicion of a retained Descemet’s membrane, marrying with the initial histology from the corneal button excised during the penetrating keratoplasty, which showed only a very thin Descemet’s layer.ConclusionRetention of the Descemet’s membrane following penetrating keratoplasty is a rare but potential complication of this surgery, particularly in cases of Fuchs’ endothelial corneal dystrophy due to the thickened and abnormal histological nature of the endothelium and high index of suspicion is required.

Randomized, double-blind, placebo-controlled study of zeaxanthin and visual function in patients with atrophic age-related macular degeneration: The Zeaxanthin and Visual Function Study (ZVF) FDA IND #78, 973

Background The purpose of this study is to evaluate whether dietary supplementation with the carotenoid zeaxanthin (Zx) raises macula pigment optical density (MPOD) and has unique visual benefits for patients with early atrophic macular degeneration having visual symptoms but lower-risk National Institute of Health/National Eye Institute/Age-Related Eye Disease Study characteristics. Methods This was a 1-year, n = 60 (57 men, 3 women), 4-visit, intention-to-treat, prospective, randomized controlled clinical trial of patients (74.9 years, standard deviation [SD] 10) with mild-to-moderate age-related macular degeneration (AMD) randomly assigned to 1 of 2 dietary supplement carotenoid pigment intervention groups: 8 mg Zx (n = 25) and 8 mg Zx plus 9 mg lutein (L) (n = 25) or 9 mg L (“Faux Placebo,” control group, n = 10). Analysis was by Bartlett’s test for equal variance, 3-way repeated factors analysis of variance, independent t test ( P < 0.05) for variance and between/within group differences, and post-hoc Scheffé's tests. Estimated foveal heterochromic flicker photometry, 1° macular pigment optical density (MPOD QuantifEye ®), low- and high-contrast visual acuity, foveal shape discrimination (Retina Foundation of the Southwest), 10° yellow kinetic visual fields (KVF), glare recovery, contrast sensitivity function (CSF), and 6° blue cone ChromaTest ® color thresholds were obtained serially at 4, 8, and 12 months. Results Ninety percent of subjects completed ≥ 2 visits with an initial Age-Related Eye Disease Study report #18 retinopathy score of 1.4 (1.0 SD)/4.0 and pill intake compliance of 96% with no adverse effects. There were no intergroup differences in 3 major AMD risk factors: age, smoking, and body mass index as well as disease duration and Visual Function Questionnaire 25 composite score differences. Randomization resulted in equal MPOD variance and MPOD increasing in each of the 3 groups from 0.33 density units (du) (0.17 SD) baseline to 0.51 du (0.18 SD) at 12 m, ( P = 0.03), but no between-group differences (Analysis of Variance; P = 0.47). In the Zx group, detailed high-contrast visual acuity improved by 1.5 lines, Retina Foundation of the Southwest shape discrimination sharpened from 0.97 to 0.57 ( P = 0.06, 1-tail), and a larger percentage of Zx patients experienced clearing of their KVF central scotomas ( P = 0.057). The “Faux Placebo” L group was superior in terms of low-contrast visual acuity, CSF, and glare recovery, whereas Zx showed a trend toward significance. Conclusion In older male patients with AMD, Zx-induced foveal MPOD elevation mirrored that of L and provided complementary distinct visual benefits by improving foveal cone-based visual parameters, whereas L enhanced those parameters associated with gross detailed rod-based vision, with considerable overlap between the 2 carotenoids. The equally dosed (atypical dietary ratio) Zx plus L group fared worse in terms of raising MPOD, presumably because of duodenal, hepatic-lipoprotein or retinal carotenoid competition. These results make biological sense based on retinal distribution and Zx foveal predominance.

174delG Mutation in Mouse MFRP Causes Photoreceptor Degeneration and RPE Atrophy

The authors have identified a recessive mutation causing progressive retinal degeneration, white fundus flecks, and eventual retinal pigment epithelium (RPE) atrophy. The goal of these studies was to characterize the retinal phenotype, to identify the causative locus, and to examine possible functions of the affected gene. SNP mapping, DNA sequencing, and genetic complementation were used to identify the affected locus. Histology, electroretinography, immunohistochemistry, Western blot analysis, fundus photography, electron microscopy, and in vitro phagocytosis assays were used to characterize the phenotype of the mouse. Gene mapping identified a single base pair deletion in membrane-type frizzled related protein (MFRP), designated Mfrp(174delG). MFRP is normally expressed in the RPE and ciliary body but was undetectable by Western blot in mutants. CTRP5, a binding partner of MFRP, was upregulated at the mRNA level and at the protein level in most patients. Assays designed to test the integrity of retinoid cycling and phagocytic pathways showed no deficits in Mfrp(174delG) or rd6 animals. However, the RPE of both Mfrp(174delG) and rd6 mice exhibited a dramatic increase in the number of apical microvilli. Furthermore, evidence of RPE atrophy was evident in Mfrp(174delG) mice by 21 months. The authors have identified a novel null mutation in mouse Mfrp. This mutation causes photoreceptor degeneration and eventual RPE atrophy, which may be related to alterations in the number of RPE microvilli. These mice will be useful to identify a function of MFRP and to study the pathogenesis of atrophic macular degeneration.

Treatment for atrophic macular degeneration

To summarize ongoing and recently completed trials on geographic atrophy associated with age-related macular degeneration. A large number of investigational agents are under development for treatment of geographic atrophy in both pre and early-phase clinical testing. Therapies targeting all putative phases of pathogenesis in geographic atrophy are under development. Thus far, no therapies have been demonstrated to be effective.