Therapy For Macular Degeneration Research Articles

SA106 Efficacy and Safety of Anti-VEGF Drugs for Neovascular Age-Related Macular Degeneration Therapy: Systematic Review and Meta-Analysis

SA106 Efficacy and Safety of Anti-VEGF Drugs for Neovascular Age-Related Macular Degeneration Therapy: Systematic Review and Meta-Analysis

Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 μm increase in central sub-field thickness (CST)are considered, 90% will be eligible for interval extension. Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

Full thickness macular hole after intravitreal brolucizumab injection in neovascular age-related macular degeneration.

To describe a case of full thickness macular hole after intravitreal brolucizumab injection in neovascular age-related macular degeneration, which has not been reported to date. A 65-year-old male patient received brolucizumab intravitreal injection therapy for neovascular macular degeneration of the right eye. He received multiple intravitreal anti-VEGF injections on a pro re nata regimen and developed a full thickness macular hole. Surgical treatment was performed with pars plana vitrectomy of the right eye. Full thickness macular hole was successfully treated. Although a full thickness macular hole following intravitreal brolucizumab injection is an uncommon complication, it requires caution.

Novel fabrication of anti-VEGF drug ranibizumab loaded PLGA/PLA co-polymeric nanomicelles for long-acting intraocular delivery in the treatment of age-related macular degeneration therapy

Age associated macular degeneration is the 3rd primary cause of blind fundus diseases globally. A reliable and long-lasting method of intraocular drug delivery is still needed. Herein, this study was aim to develop the novel fabrication of ranibizumab loaded co-polymeric nanomicelles (Rabz-CP-NMs) for AMD. The CMC of co-polymeric nanomicelles was determined to be low, at 6.2μg/ml. The ring copolymerization method was employed to fabricate the NMs and characterize via FTIR, XRD, TEM, DLS and Zeta potential. Rabz-CP-NMs was spherical shape with 10-50nm in size. Stable and prolonged drug release was achieved with the Rabz from CP-NMs at 48h. D407 and ARPE19 ocular cell lines showed dose-dependent cell viability with Rabz-CP-NMs. The Rabz-CP-NMs also had less toxicity, higher uptake, lower cell death and prolonged VEGF-A inhibition, as shown by cytoviability assay. Thus, Rabz-CP-NMs were safe for ocular use, suggesting that could be used to improve intraocular AMD treatment.

Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

Investigating bevacizumab and its fragments sustained release from intravitreal administrated PLGA Microspheres: A modeling approach

Intravitreal administrated bevacizumab has emerged as an effective antibody for suppressing VEGF expression in age-related macular degeneration (AMD) therapy. This study discusses certain issues related to the sustained release of bevacizumab from intravitreal poly(lactic-co-glycolic acid) (PLGA) microspheres. A computational model elucidating the ocular kinetics of bevacizumab is demonstrated, wherein the release of the drug from PLGA microspheres is modeled using the Koizumi approach, complemented by an empirical model that links the kinetics of bevacizumab release to a size-dependent hydrolytic degradation of the drug-loaded polymeric microparticles. The results of the simulation were then rigorously validated against experimental data. The as-developed model proved remarkably accurate in predicting the time-concentration profiles obtained following the intravitreal injection of PLGA microspheres of significantly different sizes. Notably, the time-concentration profiles of bevacizumab in distinct ocular tissues were almost unaffected by the size of the intravitreally administered PLGA microparticles. Furthermore, the model successfully predicted the retinal concentration of bevacizumab and its fragments (e.g., ranibizumab) administrated in the form of a solution. As such, this model for drug sustained release and ocular transport holds tremendous potential for facilitating the reliable evaluation of planned anti-VEGF therapies.

Rethinking the potential and necessity of drug delivery systems in neovascular age-related macular degeneration therapy.

Age-related macular degeneration (AMD) is the predominant threat to human vision and ultimately results in blindness. With the increase in the aging population, it has become a more crucial issue to human health. AMD is a multifactorial disease with the unique feature of uncontrollable angiogenesis during initiation and progression. Although increasing evidence indicates that AMD is largely hereditary, the predominant efficient treatment is antiangiogenesis, which mainly involves VEGF and HIF-α as therapeutic targets. The repeated administration of this treatment over the long term, generally through intravitreal injection, has called for the introduction of long-term drug delivery systems, which are expected to be achieved by biomaterials. However, the clinical results of the port delivery system indicate that the optimization of medical devices toward prolonging the activities of therapeutic biologics in AMD therapy seems more promising. These results indicate that we should rethink the possibility and potential of biomaterials as drug delivery systems in achieving long-term, sustained inhibition of angiogenesis in AMD therapy. In this review, the etiology, categorization, risk factors, pathogenesis, and current clinical treatments of AMD are briefly introduced. Next, the development status of long-term drug delivery systems is discussed, and the drawbacks and shortages of these systems are emphasized. By comprehensively considering the pathological aspect and the recent application of drug delivery systems in AMD therapy, we hope to find a better solution for the further development of long-term therapeutic strategies for AMD.

Time and Distance Cost of Longer Acting Anti-VEGF Therapies for Macular Degeneration: Contributions to Drug Cost Comparisons.

To evaluate the holistic cost of longer acting anti-VEGF therapy for macular degeneration when considering the associated costs of travel to the retina clinic. Theoretical evaluation of cost using publicly available pricing data and reimbursements at the Veterans Affairs (VA) Medical Center. Setting: VA Medical Center. Study population: Patients with age related macular degeneration. Main outcome measures: Three-year cost of therapy when considering medication as well as travel costs and time spent in transit. Based on cost data derived purely from wholesale acquisition cost and projected injection frequency over the first three years of treatment, faricimab is less expensive than ranibizumab and aflibercept by $37,709 and $6359, respectively. Aflibercept is less expensive ranibizumab by $31,350 over the first 3 years of treatment. When considering even small distances traveled by patients, these cost differences grow, amplified at even larger distances: at 25 miles, ranibizumab becomes $38,814 and $32,133 more expensive than faricimab and aflibercept, respectively. Aflibercept becomes $6681 more expensive than faricimab. At 100 miles, ranibizumab becomes $41,502 and $34,038 more expensive than faricimab and aflibercept, respectively. Aflibercept becomes $7464 more expensive than faricimab. Longer acting anti-VEGF therapies may differ not only in their wholesale acquisition cost, but also in the frequency of per label injections and associated clinic visits. Taking into account distance and time cost of travel may contribute to a more holistic view of cost differences among these therapies.

Developing autologous cell therapy for macular degeneration: From bench‐to‐bedside

AbstractInduced pluripotent stem cells (iPSCs) can provide autologous and allogeneic replacement tissues, potentially for all degenerative diseases. Autologous tissues have the advantage of not requiring immune‐suppressive drugs that have deleterious side‐effects. The safety and feasibility of autologous iPSC‐based therapies has not been established. Here, we developed an autologous iPSC‐based therapy for age‐related macular degeneration (AMD), a blinding eye disease that affects over 30 million people world‐wide. AMD is caused by the progressive degeneration of retinal pigment epithelium (RPE), a monolayer tissue that maintains photoreceptor function and survival. We tissue engineered a clinical‐grade iPSC‐RPE‐patch on a biodegradable scaffold using autologous cells from AMD patients. Preclinical investigational new drug (IND)‐enabling studies performed on iRPE‐patch derived from multiple AMD patients demonstrated reproducible manufacturing, validating our manufacturing process – a key requirement for an autologous phase I trial. Functional validation of clinical‐grade iRPE‐patches allowed determination of tissue barrier resistance, purity of RPE cells, and RPE cell shape metrics as key critical quality attributes now used as clinical product release criteria. Preclinical animal studies performed in immune‐compromised rats confirmed safety of the auto‐iRPE‐patch and efficacy studies performed in a porcine laser‐induced RPE injury model that mimics AMD‐like eye conditions demonstrated integration and functionality of RPE patches. A phase I/IIa IND‐application for an auto‐iRPE‐patch to treat AMD was recently cleared by the FDA. This Phase I/IIa clinical trial will test safety, feasibility, and integration of an auto‐iRPE‐patch in twelve advanced AMD patients. The trial is currently being run as a single site study at the NIH and targets patient enrollment in two cohorts – with visual acuity between 20/100 to 20/500 and between 20/80 to 20/500.

Long-Term Outcomes of Nonadherence to Anti-VEGF Therapy in Advanced Neovascular Age-Related Macular Degeneration

Purpose: To study long-term outcomes in neovascular age-related macular degeneration (nAMD) patients with low visual acuity and nonadherence to a treatment regimen of anti-vascular endothelial growth factor (VEGF) therapy.Patients and methods. In this study we included nAMD patients with best corrected visual acuity lower than 0.1 decimal equivalent, nonadherent to anti-VEGF therapy (13 eyes, group I), treatment-naïve (15 eyes, group II) or nonadherence to anti-VEGF therapy followed by termination of anti-VEGF treatment (18 eyes, group III). All participants received comprehensive ophthalmic examination and optical coherence tomography baseline and at the end of the follow-up period.Results: In group I, 7.6 ± 4.3 intravitreal anti-VEGF injections were performed over a mean period of 38.9 ± 27.5 months. In group II, a mean follow-up was 31.7 ± 28.6 months. In group III 4.8 ± 2.2 intravitreal anti-VEGF injections were performed over a mean period of 26.9 ± 26.4 months followed by treatment discontinuation for a mean period of 24.6 ± 18.6 months. None of study groups showed statistically significant changes in BCVA or an increase of central retinal thickness (p > 0.05). At baseline all study eyes frequently demonstrated severe morphological changes in the macula including atrophy of retinal pigment epithelium (RPE), subretinal fibrosis, RPE tear, or giant intraretinal cysts.Conclusion: In nAMD patients with low BCVA and severe anatomical changes in the macula nonadherence to a treatment regimen of anti-VEGF therapy results in non-superior long-term outcomes compared to natural course of the disease.

Research Trends and Hotspots of Retinal Optical Coherence Tomography: A 31-Year Bibliometric Analysis.

The emergence of optical coherence tomography (OCT) over the past three decades has sparked great interest in retinal research. However, a comprehensive analysis of the trends and hotspots in retinal OCT research is currently lacking. We searched the publications on retinal OCT in the Web of Science database from 1991 to 2021 and performed the co-occurrence keyword analysis and co-cited reference network using bibliometric tools. A total of 25,175 publications were included. There has been a progressive increase in the number of publications. The keyword co-occurrence network revealed five clusters of hotspots: (1) thickness measurements; (2) therapies for macular degeneration and macular edema; (3) degenerative retinal diseases; (4) OCT angiography (OCTA); and (5) vitrectomy for macular hole and epiretinal membrane. The co-citation analysis displayed 26 highly credible clusters (S = 0.9387) with a well-structured network (Q = 0.879). The major trends of research were: (1) thickness measurements; (2) therapies for macular degeneration and macular edema; and (3) OCTA. Recent emerging frontiers showed a growing interest in OCTA, vessel density, choriocapillaris, central serous chorioretinopathy, Alzheimer’s disease, and deep learning. This review summarized 31 years of retinal OCT research, shedding light on the hotspots, main themes, and emerging frontiers to assist in future research.

Novel approach to antiangiogenic factors in age-related macular degeneration therapy.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the population above 85 worldwide. There are two main types of AMD: neovascular and dry AMD. Neovascular AMD leads to macular changes resulting from abnormal choroidal neovascularization. Untreated neovascular AMD leads to scar formation and irreversible sight deterioration. Dry AMD in consequence leads to atrophic changes of the macula.The last decades brought a breakthrough in the therapy of neovascular age-related macular degeneration by introduction of, firstly, photodynamic therapy and, later, anti-VEGF agents administered intravitreally in order to stop neoangiogenesis. However, the treatment of dry AMD is still challenging. Among the directions in dry AMD treatment, the most promising are complement cascade inhibitors and complement cascade targeted gene therapy.In the article we outline the main directions in up-to-date experimental and practical approaches to wet and dry AMD therapy with the emphasis on antiangiogenic factors and gene therapy focused on the inhibition of pathological angiogenesis.

Preclinical Efficacy of Pro- and Anti-Angiogenic Peptide Hydrogels to Treat Age-Related Macular Degeneration.

Pro-angiogenic and anti-angiogenic peptide hydrogels were evaluated against the standard of care wet age-related macular degeneration (AMD) therapy, Aflibercept (Eylea®). AMD was modeled in rats (laser-induced choroidal neovascularization (CNV) model), where the contralateral eye served as the control. After administration of therapeutics, vasculature was monitored for 14 days to evaluate leakiness. Rats were treated with either a low or high concentration of anti-angiogenic peptide hydrogel (0.02 wt% 8 rats, 0.2 wt% 6 rats), or a pro-angiogenic peptide hydrogel (1.0 wt% 7 rats). As controls, six rats were treated with commercially available Aflibercept and six with sucrose solution (vehicle control). Post lasering, efficacy was determined over 14 days via fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT). Before and after treatment, the average areas of vascular leak per lesion were evaluated as well as the overall vessel leakiness. Unexpectedly, treatment with pro-angiogenic peptide hydrogel showed significant, immediate improvement in reducing vascular leak; in the short term, the pro-angiogenic peptide performed better than anti-angiogenic peptide hydrogel and was comparable to Aflibercept. After 14 days, both the pro-angiogenic and anti-angiogenic peptide hydrogels show a trend of improvement, comparable to Aflibercept. Based on our results, both anti-angiogenic and pro-angiogenic peptide hydrogels may prove good therapeutics in the future to treat wet AMD over a longer-term treatment period.

EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS

Abstract Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.

ITVT-02. Elucidating the pleiotropic effects of verteporfin photodynamic therapy in preclinical glioblastoma models

Abstract Glioblastoma (GBM) ranks the highest in mortality rate, incidence, and aggressiveness of primary brain tumor types. The highly malignant nature of GBM makes it difficult for mainstay treatments to have an effect beyond stabilizing the disease. Deregulation of receptor tyrosine kinase (RTKs), such as EGFR and PI3K, have been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), an FDA-approved macular degeneration therapy, has antitumor effects in in vitro and in vivo GBM preclinical models and phase I/II clinical trials for patients with EGFR mutated/amplified GBM by abrogating YAP/TAZ-TEAD interactions. As a porphyrin derivative, VP can exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate that VP-PDT reduces cell viability to a greater extent than solitary VP treatment (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.

In silico model of bevacizumab sustained release from intravitreal administrated PLGA drug-loaded microspheres

This paper demonstrates a computational model of the bevacizumab release from intravitreal administrated microspheres made of biodegradable poly(lactic-co-glycolic acid) PLGA. Intravitreal administrated bevacizumab is known to be an efficient antibody directed against VEGF expression supplied in the age-related macular degeneration (AMD) therapy. The developed diffusion-convection model of the ocular drug transport considering bevacizumab controlled release from intravitreal injected degradable PLGA microspheres and the drug clearance caused by the aqueous humor drainage. The applied model of the drug release from biodegradable microspheres was based on the Koizumi empirical approach. The aqueous humor drainage was predicted by computer fluid dynamics (CFD). The developed model enables for prediction of the time-drug concentration profiles separately for the vitreous and the aqueous body. It was validated against the experimental rabbit models data on the bevacizumab controlled release from intravitreal injected PLGA nano- and microspheres. One can see that the numerical results are in good agreement with the experimental results obtained for PLGA drug-loaded spheres having micrometer size. It is expected that the developed model of drug sustained release and ocular transport will allow for reliable evaluation of planned anti-VEGF therapies.

Gene Therapy for Neovascular Macular Degeneration, Diabetic Retinopathy, and Diabetic Macular Edema.

J.S.H.: Consultant (4DMT, Adverum, Aerie, Aerpio, Aldeyra, Allegro, Alzheon, Annexon, Apellis, Aprea, Asclepix, Aviceda, Beaver-Visitec, Bionic Vision Technologies, DTx, Eloxx, Galimedix, Genentech, Greybug, Gyroscope, Horizon Therapeutics, iRenix, Iveric, jCyte, Kanghong, LensGen, NGM,Notal Vision, Novartis, Ocular therapeutics, OcuTerra, Oxurion, Palatin, Regeneron, Regenxbio, Stealth, Thea, Verseon, Vinci, Voyant); Research Grants (Aerpio, Aldeyra, Apellis, asclepix, Bayer, Genentech, Graybug, Gyroscope, Hemera, Iveric, Janssen R&D, jCyte, Kanghong, Kodiak, Novartis, Regeneron, Regenxbio, Stealth). P.L.M. declares that there is no conflicts of interest to disclose.

Comment on: Safety and efficacy of a nepafenac punctal plug delivery system in controlling postoperative ocular pain and inflammation after cataract surgery

We have read the article by Donnenfeld et al. regarding nepafenac sustained-delivery punctal plugs with great interest.1 The authors present promising results and significant efficacy of the alternative drug delivery system, to be used after cataract surgery instead of topical treatment. Because the outcomes in contemporary cataract surgery partially depend on patient compliance, new therapeutic approaches, such as the one presented in this study, represent an appealing alternative. In the study, patients were randomized after cataract surgery to receive a nepafenac intracanalicular insert or a placebo. Other anti-inflammatory treatment was not permitted preoperatively, intraoperatively, or postoperatively, as stated by the authors. This part of the study design raises some concerns. Routine anti-inflammatory management after cataract surgery, including corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), was not administered in the placebo arm; therefore, the patients in this group were exposed to a higher risk for adverse events.3 Such concerns were confirmed by the results of the study. More patients in the placebo group experienced pain at both day 3 (62% in the placebo group vs 31% in the treatment group) and day 7 (69% in the placebo group vs 33% in the treatment group), and worse visual acuity at day 7.1 The rescue medication protocol appears to provide a safety net for alarming levels of inflammation or pain. However, the same therapeutic hypothesis could be tested in a different research model. We believe that using a noninferiority study design could be beneficial. Since the 1990s, placebo-controlled trials have become ethically controversial if a standard treatment exists.2 A noninferiority trial aims to show that an experimental treatment is not worse than the accepted one.3 The new treatment might be safer, have better secondary endpoints, be easier to administer, or simply be less expensive. In ophthalmology, noninferiority trials are commonly applied for analyzing outcomes of age-related macular degeneration therapy and glaucoma treatment with prostaglandins. We believe that comparing the efficacy of the nepafenac insert with the accepted topical anti-inflammatory treatment is a good alternative in studies such as this one. Patients in the placebo group had worse outcomes, at least short term, and this could have been prevented with a noninferiority study design, while still offering the possibility of robust scientific scrutiny of the proposed treatment.

Abstract 1111: Verteporfin inhibits GBM growth and migration and confers survival benefit in xenograft models

Abstract The diffusely infiltrative growth and spread, complex molecular and oncogenic signaling aberrations, and inter-and intra-tumoral heterogeneity in glioblastoma (GBM) impedes gross-total resection and chemoradiation and highlight the need for improved tumor-specific brain-penetrant therapies that inhibit cell migration in addition to proliferation. Invasive GBM cells undergo an epithelial-mesenchymal transition (EMT) phenotypic switch, expressing higher levels of genes involved in EMT remodeling, survival, and immune response compared to non-invasive GBM tumor cells. Recently, our lab defined a regulatory chromatin accessibility signature centered around the TEAD transcriptional family, which relates specifically to tumor migration in uncultured, patient-derived GBM stem cell populations, and we functionally validated TEAD1 as a driver of GBM migration and EMT, both in vitro and in vivo. The TEAD family of transcription factors, along with their co-activators YAP/TAZ, are the main downstream effectors of the Hippo pathway, a regulator of tissue growth and cell fate whose dysregulation has been implicated in tumor invasion, metastasis, and chemoresistance in other solid tumors. Here we explored the therapeutic efficacy of Verteporfin (VP), an FDA-approved macular degeneration therapy, and a small-molecule inhibitor of the YAP/TEAD complex, in patient-derived GBM cells and orthotopic xenotransplant mouse models (PDX), assessing VP's impact on GBM proliferation and migration both in vitro and in vivo. VP treatment across three different cell lines inhibited not only glioma growth but also significantly impaired tumor migration in three different in vitro assays (live cell tracking, transwell invasion, and spheroid dispersion) in a dose-dependent manner. At the protein and whole transcriptomic levels, VP-treated cells showed dose-dependent downregulation of TEAD-target activity and significant downregulation of EMT and cell migration functional gene sets, compared to vehicle. In several independent in vivo experiments, intraperitoneal administration of VP in mice with aggressive PDX glioblastoma showed consistent drug penetration into the brain parenchyma without systemic toxicity, resulted in lower tumor burden both at the tumor core and the leading infiltrative edge (n=22 VP, n=21 VEH, p=0.02, each), showed decreased number of individual distal migratory tumor cells (n=6 VP, n=5 VEH, p=0.0001 / n=6 VP, n=5 VEH, p=0.04), and, notably, conferred a survival benefit in combination with TMZ and radiation (n=10 per condition, p=0.02). Furthermore, in PDX mice transplanted with a more typical GBM, daily administration of VP for up to 280 days conferred survival benefit even as monotherapy (n=8 per condition, p=0.02), in the absence of systemic toxicity. The inhibitory effect of Verteporfin on downstream YAP/TEAD signaling and GBM migration, and its brain penetrance at non-toxic levels, underscore potential future therapeutic value and repurposing of this drug in GBM patients. Citation Format: Anne Marie Barrette, Alexandros Bouras, German Nudelman, Dominique Bozec, Noshin Shakawat, Elena Zaslavsky, Constantinos Hadjipanayis, Marc R. Birtwistle, Nadejda M. Tsankova. Verteporfin inhibits GBM growth and migration and confers survival benefit in xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1111.

Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities.

PurposeAccumulation of the long noncoding Alu element RNA activates the NLRP3 inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the NLRP3 inflammasome. Currently, the intracellular response of the senescence marker p16Ink4a to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against Alu RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1β and of p16INK4a in RPE cells.MethodsCultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed Alu RNA, and changes in IL-18, IL-1β, and p16Ink4a expression measured in the presences of 3TC or 3,4-(M)CA as a negative control.ResultsTreatment with 3TC markedly reduced Alu RNA-induced expression of IL-18 and IL-1β in human and mouse RPE cells compared with the negative control. Further, Alu RNA-induced p16INK4a expression was suppressed by 3TC in human RPE cells.ConclusionsOur data suggest that Alu RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC.Translational RelevanceFurther verifying this study leads to potential targets for age-related macular degeneration therapy.