Kir4.1 is specifically expressed and active in non-myelinating Schwann cells.

Non-myelinating Schwann cells (NMSC) play important roles in peripheral nervous system formation and function. However, the molecular identity of these cells remains poorly defined. We provide evidence that Kir4.1, an inward-rectifying K+ channel encoded by the KCNJ10 gene, is specifically expressed and active in NMSC. Immunostaining revealed that Kir4.1 is present in terminal/perisynaptic SCs (TPSC), synaptic glia at neuromuscular junctions (NMJ), but not in myelinating SCs (MSC) of adult mice. To further examine the expression pattern of Kir4.1, we generated BAC transgenic Kir4.1-CreERT2 mice and crossed them to the tdTomato reporter line. Activation of CreERT2 with tamoxifen after the completion of myelination onset led to robust expression of tdTomato in NMSC, including Remak Schwann cells (RSC) along peripheral nerves and TPSC, but not in MSC. In contrast, activating CreERT2 before and during the onset of myelination led to tdTomato expression in NMSC and MSC. These observations suggest that immature SC express Kir4.1, and its expression is then downregulated selectively in myelin-forming SC. In support, we found that while activating CreERT2 induces tdTomato expression in immature SC, it fails to induce tdTomato in MSC associated with sensory axons in culture. NMSC derived from neonatal sciatic nerve were shown to express Kir4.1 and exhibit barium-sensitive inwardly rectifying macroscopic K+ currents. Thus, this study identified Kir4.1 as a potential modulator of immature SC and NMSC function. Additionally, it established a novel transgenic mouse line to introduce or delete genes in NMSC.

Approved treatments for neovascular age-related macular degeneration: current safety and future directions.

INTRODUCTION: Age-related macular degeneration (AMD) is a progressive retinal degenerative disease that is implicated as one of the leading causes of visual impairment in the elderly population. Vascular endothelial growth factor (VEGF) has been identified as the main driver of AMD, and various therapeutics have revolutionized the treatment and management of neovascular AMD (nAMD) with favorable visual and anatomical outcomes. AREAS COVERED: Physicians have a variety of approved therapeutics in their arsenal for patients with varying disease progression and patient-specific needs, with the ultimate goal of achieving optimal visual and anatomic outcomes. The literature search was conducted using PubMed, Google Scholar, and sources from companies' websites, allowing us to locate findings recently presented at conferences. EXPERT OPINION: Scientific advancements in the field have led to newly approved therapeutics and devices, such as the port-delivery system with ranibizumab (PDS), and further investigation is ongoing in the realm of gene therapy for retinal diseases. In addition to efficacy and durability, newer agents must have comparable safety profiles to older agents in order to be used broadly. These options introduce a level of complexity in nAMD treatment; however, physicians to personalize treatment to improve vision in nAMD patients and reduce treatment burden overall.

Cooling Anesthesia for Intravitreal Injections - A Review.

Intravitreal (IVT) injections are the most common procedure performed in retinal clinics today. It has revolutionized the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular edema, macular edema due to veinous occlusive disease and other forms of exudative maculopathy. Though IVT injections prevent vision loss, the discomfort at the time of the injection has been troublesome to patients. This has led to patients missing their regular and routine dosage of treatment. Various modes of pre-injection anesthetic methods have been tried but in vain. Lidocaine-based topical anesthesia, in the form of pledgets, topical gel or subconjunctival lidocaine injection, has been the standard of care (SOC) for IVT injections worldwide. This article highlights the role of cooling anesthesia in reducing pain, anxiety and discomfort associated with needle penetration at the time of injection. PubMed and MedLine search were related to anesthesia for intravitreal injections, cooling anesthesia, mechanism of cooling anesthesia, COOL-1 trial, COOL-2 trial, results of COOL-1 trial and ultrarapid cooling anesthesia.

Emerging Treatment Options for Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is characterized as a chronic, multifactorial disease and is the leading cause of irreversible blindness. Advanced AMD is classified as neovascular (wet) AMD and non-neovascular (dry) AMD. Dry AMD can progress to a more advanced form that manifests as geographic atrophy (GA), which significantly threatens vision, leading to progressive and irreversible loss of visual function. There are currently no approved therapeutics commercially available for GA patients. However, data from various clinical trials have demonstrated favorable results with significant reduction in GA lesion growth. This review furthers the understanding of the pathophysiology of GA, as well as current clinical trial data on investigational therapeutics.

The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study - 6 month results.

BACKGROUND/OBJECTIVE: Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD). SUBJECTS/METHODS: Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid. RESULTS: After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 µM (p < 0.001), a - 25.3 µM (p < 0.001) and a - 84.5 µM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 µM (p < 0.001), a - 38.1 µM (p < 0.001) and a - 80.1 µM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved. CONCLUSIONS: Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.

Review of gene therapies for age-related macular degeneration.

Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider.

A Phase I, Single Ascending Dose Study of GEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy.

Purpose: To establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA). Design: Phase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866). Participants: Twelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye. Methods: Participants were assigned to the increasing dose cohorts and received 1 50-µl intravitreal injection of GEM103 at doses of 50 µg/eye, 100 µg/eye, 250 µg/eye, or 500 µg/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities. Main Outcome Measures: Safety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a. Results: No dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 µg or more. Complement activation biomarkers were reduced 7 days after dose administration. Conclusions: A single intravitreal administration of GEM103 (up to 500 µg/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD.

Quantifying burden of intravitreal injections: questionnaire assessment of life impact of treatment by intravitreal injections (QUALITII).

AIM: To quantify the areas of burden experienced by patients requiring repeated intravitreal injections (IVI) in the management of exudative retinal diseases. METHODS: The validated Questionnaire to Assess Life Impact of Treatment by Intravitreal Injections survey was administered to patients at four retina clinical practices across four US states. The primary outcome measure was Treatment Burden Score (TBS), a single score assessing overall burden. RESULTS: Of 1416 (n=657 age-related macular degeneration; n=360 diabetic macular oedema/diabetic retinopathy; n=221 retinal vein occlusion; n=178 other/uncertain) patients, 55% were women with an average age of 70 years. Patients most frequently reported receiving IVI every 4-5 weeks (40%). The mean TBS was 16.1±9.2 (range 1-48; scale of 1-54), and the TBS was higher in patients with diabetic macular oedema and/or diabetic retinopathy (DMO/DR) (17.1) compared with those with age-related macular degeneration (15.5) or retinal venous occlusive (15.3) (p=0.028). Though the mean level of discomfort was quite low (1.86) (scale 0-6), 50% of patients reported experiencing side effects more than half of the visits. Patients having received fewer than 5 IVI reported higher mean anxiety levels before (p=0.026), during (p=0.050) and after (p=0.016) treatment compared with patients having received more than 50 IVI. After the procedure, 42% of patients reported restrictions from usual activities due to discomfort. Patients reported a high mean satisfaction rating of 5.46 (scale 0-6) with the care of their diseases. CONCLUSIONS: The mean TBS was moderate and highest among patients with DMO/DR. Patients with more total injections reported lower levels of discomfort and anxiety but higher disruption to daily life. Despite the challenges related to IVI, the overall satisfaction with treatment remained high.

Emerging Therapies in Nonexudative Age-Related Macular Degeneration in 2020.

ABSTRACT: Age-related macular degeneration (AMD) is one of the most common causes of severe vision loss in the developed world. Advanced forms of AMD are seen in primarily 2 types, exudative AMD involving the presence of choroidal neovascularization and nonexudative or dry AMD with geographic atrophy. For the latter, the combination of vitamins and minerals known as the Age-Related Eye Disease Study-2 formulation has been shown to decrease the rate of progression of nonexudative to exudative AMD, as no other treatments are currently approved for nonexudative AMD. This review will highlight upcoming treatments for nonexudative AMD. Six upcoming agents have shown results at least in the 2A phase. This includes intravitreal agents that are inhibitors of integrin (Risuteganib), intravitreal agents that disrupt the complement pathway (Zimura, APL-2), neuroprotective implants (Brimonidine DDS), a subcutaneous injectable (Elamipretide), and photobiomodulation (Valeda Light Delivery System).

Port delivery system: a novel drug delivery platform to treat retinal diseases.

INTRODUCTION: Retinal disease treatment delivery is mostly limited to intravitreal injections and slow-release injectable implants due to structural barriers in the eye, and carry associated adverse effects and relatively high treatment burden. The Port Delivery System with ranibizumab (PDS) is a novel drug delivery device that is surgically implanted into the vitreous cavity and allows for continuous release of the anti-vascular endothelial growth factor (anti-VEGF) ranibizumab, eliminating the need for frequent intravitreal injections while maintaining therapeutic intraocular drug levels to control disease activity. Investigations of PDS are summarized in this review. AREAS COVERED: The most recent reported findings from preliminary studies and phase I-III trials are reviewed. We discuss the ramifications of these studies and the future potential for PDS in the treatment of retinal diseases. EXPERT OPINION: PDS is a novel drug delivery platform for the treatment of retinal diseases. Currently, the data from the PDS has shown promising efficacy and ability to substantially mitigate treatment burden while effectively generating visual and anatomic outcomes similar to those in patients receiving the standard monthly ranibizumab for neovascular age-related macular degeneration. Further studies are ongoing to investigate this novel drug delivery system in other disease states.

Angiopoietins as Potential Targets in Management of Retinal Disease.

The Ang/Tie2 pathway complements VEGF-mediated activity in retinal vascular diseases such as DME, AMD, and RVO by decreasing vascular integrity, increasing neovascularization, and increasing inflammatory signaling. Faricimab is a bispecific antibody that has been developed as an inhibitor of both VEGF and Ang2 that has shown positive results in phase I, II and III trials. Recent Year 1 data from phase III clinical trials YOSEMITE, RHINE, TENAYA, and LUCERNE have confirmed the efficacy, safety, durability, and superiority of faricimab in patients with DME and nAMD. Faricimab, if approved, may significantly decrease treatment burden in patients with retinal vascular diseases to a greater extent than would current standard of care anti-VEGF injections.

Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab.

This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.

Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020.

Age-related macular degeneration (AMD) is one of the most common causes of vision loss. Advanced forms of AMD are seen in primarily 2 types-neovascular AMD (nAMD) with the presence of choroid neovascularization and nonneovascular AMD (nnAMD) with geographic atrophy. Although there are 4 anti-vascular endothelial growth factor drugs either widely used or approved for the former, there are no current treatments for the latter. This review will highlight upcoming treatments for AMD currently in clinical trials. For nAMD: Abicipar pegol, an intravitreal anti-vascular endothelial growth factor based on designed ankyrin repeat proteins (DARP) in protein, is currently pending approval. Conbercept and Faricimab, 2 intravitreal anti-growth factors, are currently in phase 3. Nine other upcoming agents have at least produced results in the 2A phase including intravitreal injections (KSI-301, OPT-302, RGX-314, ICON-1, and DE-122), depot (GB-102), drug reservoir (PDS), topical drops (PAN-90806), and oral formulations (AKST4290). We summarize all the newer molecules.