Abstract Age-related Macular Degeneration Research Articles

How do research participants with age-related vision loss talk about their experiences? A secondary discourse analysis of published qualitative extracts

Abstract Age-related macular degeneration (AMD) is a chronic, progressive eye condition that can affect individuals in later life and lead to loss of central visual function. In this analysis, we aimed to explore the discursive landscape of talk about AMD, drawing on extracts published in peer-reviewed qualitative studies on AMD. Drawing on procedures of qualitative meta-synthesis, we compiled a corpus of raw data extracts from 25 qualitative studies on AMD published in English, largely carried out in high-income countries. Extracts were analysed to identify dominant discourses and key interpretative repertoires (such as recurring metaphors, tropes and figures of speech). We adopted a Foucauldian discourse analytic approach, to consider the implications of dominant discourses, and their associated subject positions, for the subjective experience of living with AMD. Our analysis identified five distinct ways in which AMD was constructed in research participants' talk about experiences of AMD. They included: AMD as a mysterious affliction, linked to biological ageing; AMD as a total loss of independence; AMD as grievous loss; AMD as a condition to be stoically accepted; and – to a more limited extent – AMD as an opportunity for discovery. Drawing on theory from critical disability studies and gerontology, we suggest that the constructions identified are underpinned by broader societal discourses which construct ageing and disability in largely negative, medicalised and individualistic terms. Taking up subject positions within such discourses may compound feelings of isolation, hopelessness and powerlessness. We suggest there may be value in exploring talk about experiences of living with AMD within a broader range of everyday social, relational and environmental contexts.

Advancements in the treatment of age-related macular degeneration: a comprehensive review

Abstract Age-related macular degeneration (AMD) stands as a leading cause of irreversible blindness, particularly affecting central vision and impeding daily tasks. This paper provides a thorough exploration of AMD, distinguishing between its two main subtypes—Wet and Dry AMD—while shedding light on the prevalence and risk factors, including age, genetics, and smoking. The focus shifts to the current and future treatment landscape, examining both Dry and Wet AMD. Regarding Dry AMD, interventions such as antioxidant supplementation and ongoing clinical trials offer hope. Notable among these is Pegcetacoplan which is the only Food and Drug Administration (FDA)-approved medication, displaying promising results in reducing geographic atrophy lesions. For Wet AMD, anti-Vascular Endothelial Growth Factor therapies like Ranibizumab (Lucentis®) have been instrumental, and newer drugs like Faricimab and OPT-302 show comparable efficacy with extended dosing intervals. Additionally, gene therapies such as RGX-314 present a potential paradigm shift, reducing or eliminating the need for frequent injections. Biosimilars offer cost-effective alternatives. The paper also delves into the integration of technology and artificial intelligence in AMD management, highlighting the role of smartphone apps for patient monitoring and artificial intelligence algorithms for diagnosis and surveillance. Furthermore, patient perspectives on artificial intelligence demonstrate a positive correlation between understanding and trust. The narrative concludes with a glimpse into ground-breaking technologies, including retinal implants and bionic chips, offering hope for vision restoration. Overall, this paper underscores the multifaceted approach in addressing AMD, combining traditional and innovative strategies, paving the way for a more promising future in AMD treatment.

Single-cell RNA sequencing reveals transcriptional changes of human choroidal and retinal pigment epithelium cells during fetal development, in healthy adult and intermediate age-related macular degeneration.

Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the developed world. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlying retinal pigment epithelium (RPE) and choroidal endothelial cells. The molecular events that underline the development of these cell types from in utero to adult as well as the progression to intermediate and advanced stages AMD are not yet fully understood. We performed single-cell RNA-sequencing (RNA-Seq) of human fetal and adult RPE-choroidal tissues, profiling in detail all the cell types and elucidating cell type-specific proliferation, differentiation and immunomodulation events that occur up to midgestation. Our data demonstrate that progression from the fetal to adult state is characterized by an increase in expression of genes involved in the oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE-choroid tissue. Single-cell comparative transcriptional analysis between a patient with intermediate AMD and an unaffected subject revealed a reduction in the number of RPE cells and melanocytes in the macular region of the AMD patient. Together these findings may suggest a macular loss of RPE cells and melanocytes in the AMD patients, but given the complex processing of tissues required for single-cell RNA-Seq that is prone to technical artefacts, these findings need to be validated by additional techniques in a larger number of AMD patients and controls.

Inflammasome Activation in Retinal Pigment Epithelium from Human Donors with Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. One of the risk factors associated with developing AMD is the single nucleotide polymorphism (SNP) found within the gene encoding complement factor H (CFH). Part of the innate immune system, CFH inhibits alternative complement pathway activation. Multi-protein complexes called inflammasomes also play a role in the innate immune response. Previous studies reported that inflammasome activation may contribute to AMD pathology. In this study, we used primary human adult RPE cell cultures from multiple donors, with and without AMD, that were genotyped for the Y402H CFH risk allele. We found complement and inflammasome-related genes and proteins at basal levels in RPE tissue and cell cultures. Additionally, treatment with rotenone, bafilomycin A, and ATP led to inflammasome activation. Overall, the response to priming and activation was similar, irrespective of disease state or CFH genotype. While these data show that the inflammasome is present and active in RPE, our results suggest that inflammasome activation may not contribute to early AMD pathology.

The Association Between Consumption of 100% Fruit Juice and Risk of Age-Related Macular Degeneration: Data From the National Health and Nutrition Examination Survey Database.

Age-related macular degeneration (AMD) is the main irreversible blindness disease worldwide. The current study aimed to investigate whether the consumption of 100% fruit juice increases the risk of age-related macular degeneration and find approaches to prevent and reduce the development of age-related macular degeneration from the aspect of dietary habits. A cross-sectional clinical study design was adopted. We screened participants from the 2005 to 2006 NHANES database. The logistic regression model was used to evaluate the relationship between 100% fruit juice consumption and advanced AMD and to adjust variables such as demographics, general health status, body mass index (BMI), health-related behaviors, systemic complications, and ophthalmic complications. The results show that 100% fruit juice consumption did not affect early AMD and any AMD. High consumers of 100% fruit juice are more likely to develop advanced age-related macular degeneration than those who never drink 100% fruit juice.

Nutraceuticals for Age-Related Macular Degeneration: Formulation Optimization Focused on Safety

Age-related macular degeneration (AMD) is a multifactorial disease, with oxidative stress as a main pathogenetic factor in the development and progression. Large clinical trials have shown that the additional intake of vitamins and minerals in high doses reduce the risk progression to advanced wet AMD by 25 %. Some of these powerful antioxidants are not synthesized in the human body and can only be obtained with food as part of dietary supplements. However, patients with AMD, belonging to the older age group, often have comorbid conditions, for which they are used to take appropriate drug and vitamin therapy for a long time, as well as they have malnutrition of varying severity. Additional intake of high doses of ophthalmic vitamin-mineral complexes can lead to side effects due to overdose and possible disorders of drug absorption due to concomitant pathology. The article presents the results of the AREDS 2 study and a number of other clinical trials that studied long-term intake of vitamins and minerals in dosages similar to the AREDS 1 formula, containing vitamin C (500 mg), vitamin E (400 international units), beta-carotene (15 mg), zinc (80 mg as zinc oxide) and copper (2 mg as copper oxide). The cited works show that long-term intake of high dosages of some vitamins in elderly patients with severe concomitant diseases and a history of smoking can lead to undesirable consequences for the eye and other body systems. Potential side effects include an increased risk of glaucoma and cataract, an increased risk of prostate cancer in healthy men, an increased risk of lung cancer in former smokers, and an increased risk of cardiovascular disease in postmenopausal women with diabetes. Thus, high dosages of vitamins and minerals in nutraceuticals should be administered with great caution, and a reduction in dosages to the recommended intake rates when switching to long-term intake may be considered. One of the possibilities for increasing the bioavailability of active substances in the composition of dietary supplements can be a microencapsulation.

Stem cell therapy to treat macular degeneration

Age-related macular degeneration (AMD) is a progressive disease characterized by deterioration of the macula and central vision loss. Stem cell therapy is at the forefront for upcoming AMD treatments, and while there is general consensus that it represents a promising approach, debate is ongoing over the best way to render treatment. Questions over whether to use human embryonic or induced pluripotent stem cells, and whether to inject cell suspensions or implant a patch of cells into the eye remain unresolved. Here, we compare and contrast all options and discuss recent clinical progress in treating AMD with stem cell therapy.

LONGL-Net: temporal correlation structure guided deep learning model to predict longitudinal age-related macular degeneration severity.

Age-related macular degeneration (AMD) is the principal cause of blindness in developed countries, and its prevalence will increase to 288 million people in 2040. Therefore, automated grading and prediction methods can be highly beneficial for recognizing susceptible subjects to late-AMD and enabling clinicians to start preventive actions for them. Clinically, AMD severity is quantified by Color Fundus Photographs (CFP) of the retina, and many machine-learning-based methods are proposed for grading AMD severity. However, few models were developed to predict the longitudinal progression status, i.e. predicting future late-AMD risk based on the current CFP, which is more clinically interesting. In this paper, we propose a new deep-learning-based classification model (LONGL-Net) that can simultaneously grade the current CFP and predict the longitudinal outcome, i.e. whether the subject will be in late-AMD in the future time-point. We design a new temporal-correlation-structure-guided Generative Adversarial Network model that learns the interrelations of temporal changes in CFPs in consecutive time-points and provides interpretability for the classifier's decisions by forecasting AMD symptoms in the future CFPs. We used about 30,000 CFP images from 4,628 participants in the Age-Related Eye Disease Study. Our classifier showed average 0.905 (95% CI: 0.886–0.922) AUC and 0.762 (95% CI: 0.733–0.792) accuracy on the 3-class classification problem of simultaneously grading current time-point's AMD condition and predicting late AMD progression of subjects in the future time-point. We further validated our model on the UK Biobank dataset, where our model showed average 0.905 accuracy and 0.797 sensitivity in grading 300 CFP images.

Evaluation of vascular endothelial growth factor (VEGF) level in the tears and serum of age-related macular degeneration patients

Age-related macular degeneration (AMD) is an important cause of irreversible central blindness worldwide. Clinical manifestations range from asymptomatic in early and intermediate AMD to significant vision loss in late AMD. Approximately 10% of cases of early AMD eventually progress to the late advanced stage, influenced by the upregulation of vascular endothelial growth factor (VEGF). In this study, we evaluated VEGF concentration in the tears and serum of AMD patients. Our study revealed a significantly higher level of VEGF in the tears of patients with AMD compared with controls. The tear VEGF level has high sensitivity and specificity, and is significantly related to the severity of AMD, whilst serum VEGF level is non-specific and non-predictive of AMD severity. Thus, VEGF level in the tears may be used as a non-invasive biomarker for AMD progression. A large cohort study is needed for further verification.

Diagnostic Markers and Molecular Dysregulation Mechanisms in the Retinal Pigmented Epithelium and Retina of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a chronic and progressive macular degeneration disease, which can also lead to serious visual loss. In our research, we aim to efficiently identify biomarkers relevant for AMD diagnosis. We collected the gene expression data of retinal segmented epithelium (RPE) and retina tissues of GSE29801 and GSE135092 and performed differential expression analysis. The differentially expressed genes (DEGs) related to the RPE and retina in the two sets of data were identified and enriched by intersection analysis. A PPI network was constructed for intersection genes, and the top 20 genes with the largest connectivity in the network were selected as candidate genes. The LASSO model was used to identify key genes from candidate genes, and the nomogram and ROC curve were used to evaluate the diagnostic ability of key genes. We identified 464 intersection genes associated with RPE and 509 intersection genes associated with retina. The TGF-beta signaling pathway was enriched by RPE-related DEGs, while oxidative phosphorylation was enriched by retina-related DEGs. Among the candidate genes of RPE, the LASSO model identified 7 key genes. MAPK1 and LUM can predict the clinical diagnosis of AMD. Among the candidate genes of retina, the LASSO model identified four key genes. PTPN11 has the highest predictive diagnostic value. The results suggest that the imbalance mechanism of RPE in AMD may be related to the TGF-beta signaling pathway, and the imbalance mechanism of the retina may be related to oxidative phosphorylation. MAPK1 and LUM are potential diagnostic markers of RPE, and PTPN11 is a potential diagnostic marker of the retina. Also, our results provide a theoretical basis for better understanding the molecular mechanisms of AMD onset and treatment in the future.

Modulated anti-VEGF therapy under the influence of lipid metabolizing proteins in Age related macular degeneration: a pilot study

Age-related macular degeneration (AMD) is a devastating retinal disease that results in irreversible vision loss in the aged population. The complex genetic nature and degree of genetic penetrance require a redefinition of the current therapeutic strategy for AMD. We aimed to investigate the role of modifiers for current anti-VEGF therapy especially for non-responder AMD patients. We recruited 78 wet AMD cases (out of 278 AMD patients) with their socio-demographic and treatment regimen. Serum protein levels were estimated by ELISA in AMD patients. Data pertaining to the number of anti-VEGF injections given (in 1 year) along with clinical images (FFA and OCT) of AMD patients were also included. Visual acuity data (logMAR) for 46 wet AMD cases out of a total of 78 patients were also retrieved to examine the response of anti-VEGF injections in wet AMD cases. Lipid metabolizing genes (LIPC and APOE) have been identified as chief biomarkers for anti-VEGF response in AMD patients. Both genotypes ‘CC’ and ‘GC’ of LIPC have found to be associated with a number of anti-VEGF injections in AMD patients which could influence the expression of B3GALTL,HTRA1, IER3, LIPC and SLC16A8 proteins in patients bearing both genotypes as compared to reference genotype. Elevated levels of APOE were also observed in group 2 wet AMD patients as compared to group 1 suggesting the significance of APOE levels in anti-VEGF response. The genotype of B3GALTL has also been shown to have a significant association with the number of anti-VEGF injections. Moreover, visual acuity of group 1 (≤ 4 anti-VEGF injections/year) AMD patients was found significantly improved after 3 doses of anti-VEGF injections and maintained longitudinally as compared to groups 2 and 3. Lipid metabolising genes may impact the outcome of anti-VEGF AMD treatment.

Progress of autophagy in the pathogenesis of dry age-related macular degeneration

Age-related macular degeneration (AMD) is a major clinical blind-inducing eye disease, and its pathogenesis is closely related to the autophagy of RPE cells and the signaling pathway of nuclear factor erythroid-2 related factor 2 (Nrf2). Autophagy is one of the common and important physiological phenomena in human body, which is of vital significance for maintaining the stability and metabolism of cells. Nrf2 is a key transcription factor regulating cells to fight against foreign bodies and oxidative damage, and Nrf2 signaling pathway plays a wide range of cell protective functions in anti-tumor, anti-stress and other aspects. With the development of research, it is found that there are extensive interaction mechanisms between autophagy and Nrf2 signaling pathway. Inhibition of autophagy leads to accumulation of p62, which activates the Nrf2 signaling pathway by binding with Keap1 (kelch-like ech-associated protein1). At the same time, studies have also found that reactive oxygen species (ROS) and other factors also participate in the mutual regulation between autophagy and Nrf2.This paper will review the recent research progress on the interaction between Nrf2 signaling pathway and autophagy in the development of AMD. Hope to provide a new perspective for the treatment of AMD.

Benefits of Implementing Eye-Movement Training in the Rehabilitation of Patients with Age-Related Macular Degeneration: A Review.

Age-related macular degeneration (ARMD) is one of the most debilitating eye-related illnesses worldwide. Eye-movement training is evolving to be a non-invasive, rapid, and effective method that is positively impacting vision and QoL (quality of life) in patients suffering from ARMD. This review aims to highlight why a greater adoption of eye-movement training in the clinical and research setting is of importance. A PubMed and ResearchGate search was performed for articles published between 1982 and 2020. Patients with advanced ARMD tend to experience a diminished QoL. Studies regarding eye-movement training for patients with central vision loss revealed overall significant improvements in reading speeds, fixation, and saccade performance. They also experienced less fatigue. In select studies, eye-movement training revealed an improvement in binocular vision, fixation, reading speed, and diminished reading exhaustion. The process of eye-movement training used in some of the studies was rather empirical. The latter requires standardization so that a uniform and applicable methodology can be adopted overall.

A novel deep learning technique for analysis and detection of ARMD using OCT scan images

Age-Related Macular Degeneration (ARMD) is a medical situation resulting in blurred or no vision in the middle of the eye view. Though this disease doesn’t make the person completely blind, it makes it very difficult for the person to perform day to day activities like reading, driving, recognizing people etc. This paper aims to detect ARMD though Optical Coherence Tomography (OCT) scans where the drusen in the macula is detected and identify the infected. The images are first passed though Directional Total Variation (DTV) Denoising followed by Active contour algorithm to mark the boundaries of the layers in macula. In deep learning, a convolutional neural network is a class of deep neural networks, most commonly applied to analyzing visual imagery. Then these images categorized as healthy and infected using Convolution Neural Network. Different CNN variant algorithms like Alexnet, VggNet and GoogleNet have been compared in the experiments and the results obtained are better compared to traditional methods.

Fully-automated atrophy segmentation in dry age-related macular degeneration in optical coherence tomography

Age-related macular degeneration (AMD) is a progressive retinal disease, causing vision loss. A more detailed characterization of its atrophic form became possible thanks to the introduction of Optical Coherence Tomography (OCT). However, manual atrophy quantification in 3D retinal scans is a tedious task and prevents taking full advantage of the accurate retina depiction. In this study we developed a fully automated algorithm segmenting Retinal Pigment Epithelial and Outer Retinal Atrophy (RORA) in dry AMD on macular OCT. 62 SD-OCT scans from eyes with atrophic AMD (57 patients) were collected and split into train and test sets. The training set was used to develop a Convolutional Neural Network (CNN). The performance of the algorithm was established by cross validation and comparison to the test set with ground-truth annotated by two graders. Additionally, the effect of using retinal layer segmentation during training was investigated. The algorithm achieved mean Dice scores of 0.881 and 0.844, sensitivity of 0.850 and 0.915 and precision of 0.928 and 0.799 in comparison with Expert 1 and Expert 2, respectively. Using retinal layer segmentation improved the model performance. The proposed model identified RORA with performance matching human experts. It has a potential to rapidly identify atrophy with high consistency.

Optimized Prediction Models from Fundus Imaging and Genetics for Late Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. In this study, we compare the performance of retinal fundus images and genetic-information-based machine learning models for the prediction of late AMD. Using data from the Age-related Eye Disease Study, we built machine learning models with various combinations of genetic, socio-demographic/clinical, and retinal image data to predict late AMD using its severity and category in a single visit, in 2, 5, and 10 years. We compared their performance in sensitivity, specificity, accuracy, and unweighted kappa. The 2-year model based on retinal image and socio-demographic (S-D) parameters achieved a sensitivity of 91.34%, specificity of 84.49% while the same for genetic and S-D-parameters-based model was 79.79% and 66.84%. For the 5-year model, the retinal image and S-D-parameters-based model also outperformed the genetic and S-D parameters-based model. The two 10-year models achieved similar sensitivities of 74.24% and 75.79%, respectively, but the retinal image and S-D-parameters-based model was otherwise superior. The retinal-image-based models were not further improved by adding genetic data. Retinal imaging and S-D data can build an excellent machine learning predictor of developing late AMD over 2–5 years; the retinal imaging model appears to be the preferred prognostic tool for efficient patient management.

Systemic complement levels in patients with age-related macular degeneration carrying rare or low-frequency variants in the CFH gene.

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. Genetic variants in the complement factor H (CFH) gene are associated with AMD, but the functional consequences of many of these variants are currently unknown. In this study, we aimed to determine the effect of 64 rare and low-frequency variants in the CFH gene on systemic levels of factor H (FH) and complement activation marker C3bBbP using plasma samples of 252 carriers and 159 non-carriers. Individuals carrying a heterozygous nonsense, frameshift or missense variant in CFH presented with significantly decreased FH levels and significantly increased C3bBbP levels in plasma compared to non-carrier controls. FH and C3bBbP plasma levels were relatively stable over time in samples collected during follow-up visits. Decreased FH and increased C3bBbP concentrations were observed in carriers compared to non-carriers of CFH variants among different AMD stages, with the exception of C3bBbP levels in advanced AMD stages, which were equally high in carriers and non-carriers. In AMD families, FH levels were decreased in carriers compared to non-carriers, but C3bBbP levels did not differ. Rare variants in the CFH gene can lead to reduced FH levels or reduced FH function as measured by increased C3bBbP levels. The effects of individual variants in the CFH gene reported in this study will improve the interpretation of rare and low-frequency variants observed in AMD patients in clinical practice.

Implication of N-Methyl-d-Aspartate Receptor in Homocysteine-Induced Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated homocysteine (Hcy) (Hyperhomocysteinemia) (HHcy) has been reported in AMD. We previously reported that HHcy induces AMD-like features. This study suggests that N-Methyl-d-aspartate receptor (NMDAR) activation in the retinal pigment epithelium (RPE) is a mechanism for HHcy-induced AMD. Serum Hcy and cystathionine-β-synthase (CBS) were assessed by ELISA. The involvement of NMDAR in Hcy-induced AMD features was evaluated (1) in vitro using ARPE-19 cells, primary RPE isolated from HHcy mice (CBS), and mouse choroidal endothelial cells (MCEC); (2) in vivo using wild-type mice and mice deficient in RPE NMDAR (NMDARR−/−) with/without Hcy injection. Isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1, and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage, and choroidal neovascularization (CNV). A neovascular AMD patient’s serum showed a significant increase in Hcy and a decrease in CBS. Hcy significantly increased HIF-1α, VEGF, and NMDAR in RPE cells, and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retina and CNV. Knocking down RPE NMDAR improved retinal structure and CNV. Our findings underscore the role of RPE NMDAR in Hcy-induced AMD features; thus, NMDAR inhibition could serve as a promising therapeutic target for AMD.

Genetic Mechanism Revealed of Age-Related Macular Degeneration Based on Fusion of Statistics and Machine Learning Method.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world which affects the quality of life for millions of elderly individuals worldwide. Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to AMD. To better understand the disease pathogenesis and identify causal genes for AMD, we applied random walk (RW) and support vector machine (SVM) to identify AMD-related genes based on gene interaction relationship and significance of genes. Our model achieved 0.927 of area under the curve (AUC), and 65 novel genes have been identified as AMD-related genes. To verify our results, a statistics method called summary data-based Mendelian randomization (SMR) has been implemented to integrate GWAS data and transcriptome data to verify AMD susceptibility-related genes. We found 45 genes are related to AMD by SMR. Among these genes, 37 genes overlap with those found by SVM-RW. Finally, we revealed the biological process of genetic mutations leading to changes in gene expression leading to AMD. Our results reveal the genetic pathogenic factors and related mechanisms of AMD.

CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.