Elamipretide: First Approval.

Barth Syndrome (BTHS) is an X-linked recessive disorder that results in abnormal metabolism of the mitochondrial phospholipid cardiolipin (CL). CLs are decreased and monolysocardiolipins (MLCLs), intermediates in CL metabolism, are increased in a variety of tissues. Measurement of decreased CL levels in skin fibroblasts has previously been proposed as a diagnostic test for BTHS. We investigated whether elevated MLCL is specific for BTHS and whether the MLCL-to-CL ratio is a more sensitive and specific marker for BTHS. We measured CLs and MLCLs in skin fibroblasts from 5 BTHS patients, 8 controls, and 14 patients with biochemical and clinical findings similar to those in BTHS (group D), using high performance liquid chromatography-mass spectrometry. Our results showed a clear decrease of CL in combination with a marked increase of MLCL in fibroblasts from BTHS patients when compared with controls. MLCL/CL ratios ranged from 0.03-0.12 in control fibroblasts and from 5.41-13.83 in BTHS fibroblasts. In group D, the MLCL/CL ratio range was 0.02-0.06. We therefore conclude that elevations of MLCLs are specific for BTHS and that the MLCL/CL ratio in fibroblasts is a better diagnostic marker than CL alone. We also report the finding of two novel mutations in the TAZ gene that cause BTHS.

Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O(2) extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O(2) extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O(2) extraction. Adjusting for age, peak O(2) consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg(-1)·min(-1), P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O(2) saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: -5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.

Age-related macular degeneration is one of the most common irreversible causes of visual loss. It has been well established from both animal and human studies that vascular endothelial growth factor plays an important role in the pathogenesis of this process. Ranibizumab is a monoclonal antibody fragment directed towards human vascular endothelial growth factor that was developed to halt the progression of wet age-related macular degeneration. The antibody fragment has a molecular weight of 48 kDa and is produced by an Escherichia coli expression system. Ranibizumab received approval in the USA in July 2006 and the European Union in January 2007. It is introduced into the eye by injection into the vitreous cavity. Conjunctival hemorrhage, vitreous floaters, intraocular inflammation, increased intraocular pressure and eye pain were the most common ocular complaints of patients receiving ranibizumab injections over sham treatments. The rates of retinal detachment, cataract and endophthalmitis do not exceed that of other intravitreal injections and patients should be treated under strict aseptic conditions to reduce this risk. No unanticipated systemic adverse events were found during any phase of the studies of ranibizumab thus far and the risk of thromboembolic events was less than 4% and not different to sham. Combined data from the Minimally classic/occult trial of the Anti-vascular endothelial growth factor antibody Ranibizumab In the treatment of Neovascular Age-related macular degeneration (MARINA), ANti-vascular endothelial growth factor antibody for the treatment of predominantly classic CHORoidal neovascularization in age-related macular degeneration (ANCHOR), and Phase IIIb, multicenter, randomized, double-masked, sham Injection-controlled study of the Efficacy and safety of Ranibizumab in subjects with subfoveal choroidal neovasularization with or without classic choroidal neovascularization secondary to age-related macular degeneration (PIER) studies have validated the safety and efficacy of ranibizumab amongst a large population compared with sham and standard treatment (photodynamic therapy). Intravitreal administration is recommended monthly for patients. However, an alternative dosing of every 3 months is better than no treatment but probably less effective than sham treatment.

Comment on: Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study

Aging is the major cause of age-related macular degeneration, but its mechanism of action is still unclear. Research has indicated that aging, macrophages and age-related macular degeneration are closely correlated. Owing to the heterogeneity of ocular macrophages and their diverse/plastic phenotypes, recognition of the role of macrophages in age-related macular degeneration is relatively rare, which hinders the development of precision treatments for age-related macular degeneration. In this narrative review, we discuss the classification of retinal macrophages and their diverse polarization states in age-related macular degeneration. To better understand the causal relationship between senescent macrophages and age-related macular degeneration, a novel model for manipulating the macrophage senile state in age-related macular degeneration was proposed. By transplanting senescent macrophages into an age-related macular degeneration model, we can test the ability of senescent macrophages to increase the age-related macular degeneration phenotype; moreover, by replacing senescent macrophages in an age-related macular degeneration model with young macrophages, we can test the necessity of senescent macrophages to cause an age-related macular degeneration phenotype and validate the effectiveness of transplantation of therapeutic macrophages as a treatment for advanced age-related macular degeneration based on the modulation of the inflammatory environment. This proposal is expected to solve the controversy regarding the role of macrophages in age-related macular degeneration and inspire future research on macrophage therapy for senescent diseases.

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.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. There are two types of AMD: dry and wet. The exact cause of the disease is unknown, but is thought to result from interplay of genetic and environmental factors. Smoking, hypertension and low intake and/or low levels of serum antioxidants are known risk factors for both forms. As yet there are no treatments available for the dry form of AMD. Smoking cessation and healthy lifestyles are important in the prevention of progression of AMD. Progression of early stages of AMD to advanced forms is slowed by regular intake of ocular nutritional supplements as found in the Age-Related Eye Disease Study (AREDS) Study. Recently, there have been significant breakthroughs in the treatment of wet or neovascular AMD, including photodynamic therapy (PDT), intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs, including pegaptanib, ranibizumab and bevacizumab. Newer agents including aflibercept and anti-platelet-derived growth factor (anti-PDGF) compounds are under investigation. The current gold standard for treatment of wet AMD is intravitreal injections of ranibizumab. Combination therapy with PDT and anti-VEGF agents is useful especially in idiopathic polypoidal choroidopathy (IPCV) or when anti-VEGF monotherapy has failed. Rapid referral of patients with neovascular AMD is important as the visual outcome is dependent on the visual acuity at treatment. Diagnostic confirmation with retinal imaging, particularly fundus fluorescein angiography and optical coherent tomography, are required before treatment commencement. The new treatments for wet AMD are repetitive, and have significant service implications. These implications occur irrespective of which anti- VEGF agent is adopted. Visual rehabilitation is still important in the management of AMD.

Introduction: Treatment of exudative age-related macular degeneration (ARMD) has shifted to pro re nata and treat-extend-stop strategies. However, a rational discontinuation strategy is lacking. To develop such a strategy, it is important to determine choroidal neovascularization (CNV) recurrence rates after anti-VEGF treatment is discontinued. Here we report prospective data on persistent and recurrent CNV activity after discontinuation of bevacizumab treatment. Methods: This prospective, single-center clinical trial enrolled 191 patients with exudative ARMD. Patients were randomly assigned to receiving intravitreal bevacizumab injections every 4, 6, or 8 weeks for 1 year. CNV activity was determined in the 157 patients who completed the 1-year treatment regimen. Patients with inactive CNV were then followed for signs of CNV reactivation. Results: After 1 year of treatment, 66 (42%) of the 157 patients still had signs of persistent active CNV. Of the remaining 91 (58%) patients, 61 (67%) needed retreatment for active CNV within the first year after discontinuation of treatment (mean 4.28 ± 0.29 months). CNV was reactivated in 50 (80%) of the 61 patients within 6 months after their final treatment for CNV. Conclusion: Based on quiescent disease, anti-VEGF therapy was discontinued in 58% of the patients after they received bevacizu­mab injections every 4, 6, or 8 weeks for 1 year; 67% showed reactivated CNV within a year after discontinuation. The high reactivation rate of CNV shown in this study should help clinicians to develop rational discontinuation protocols. Trial Registration: This study is registered as NTR1174 at http://www.trialregister.nl.

Antiangiogenic therapy is a new approach to the treatment of neovascular age-related macular degeneration. Interferon alfa is one antiangiogenic agent thought to function by inhibiting the migration and proliferation of vascular endothelial cells. It has been used in the treatment of hepatitis, solid tumors and hematologic malignancies. The aim of this review was to investigate interferon alfa as a treatment modality for neovascular age-related macular degeneration. We searched and identified trials from the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Group Trials Register, in The Cochrane Library (Issue 2, 2005), MEDLINE (1966 to 2005/06 week 1), EMBASE (1980 to 2005/week 23), LILACS (Latin American and Caribbean Health Science Literature Database) (June 2005) and the reference lists of included studies. This review included randomized controlled trials evaluating interferon alfa therapy in people with neovascular age-related macular degeneration who were followed for at least one year. Both review authors independently extracted data and assessed trial quality. No data synthesis was conducted as only one trial met the inclusion criteria. The one included trial enrolled and randomized 481 participants from 45 centers worldwide into four groups. The study allowed for analysis of the number of participants who had lost three or more lines of vision at 52 weeks in three interferon alfa-2a groups versus placebo. The results show an odds ratio of 1.60 (95% Confidence Interval 1.01 to 2.53) indicating that interferon is associated with a 60% increased odds of losing three or more lines at 52 weeks. This finding is marginally statistical with a P value of 0.04 and indicates that the treatment has the potential for harm rather than benefit. At present there is not enough evidence to recommend the use of interferon alfa-2a for the treatment of age-related macular degeneration.

Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the TAFAZZIN/Taz gene which encodes a transacylase required for cardiolipin remodeling. Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining mitochondrial membrane structure, respiration, mtDNA biogenesis, and mitophagy. Mutations in the TAFAZZIN gene deplete mature cardiolipin, leading to mitochondrial dysfunction, dilated cardiomyopathy, and premature death in BTHS patients. Currently, there is no effective treatment for this debilitating condition. In this study, we showed that TAFAZZIN deficiency caused hyperactivation of MTORC1 signaling and defective mitophagy, leading to accumulation of autophagic vacuoles and dysfunctional mitochondria in the heart of Tafazzin knockdown mice, a rodent model of BTHS. Consequently, treatment of TAFAZZIN knockdown mice with rapamycin, a potent inhibitor of MTORC1, not only restored mitophagy, but also mitigated mitochondrial dysfunction and dilated cardiomyopathy. Taken together, these findings identify MTORC1 as a novel therapeutic target for BTHS, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for BTHS. Abbreviations: BTHS: Barth syndrome; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CL: cardiolipin; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; KD: knockdown; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LV: left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; OCR: oxygen consumption rate; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB/S6K: ribosomal protein S6 kinase beta; SQSTM1/p62: sequestosome 1; TLCL: tetralinoleoyl cardiolipin; WT: wild-type.

Reply

ABSTRACTBackground: Lutein is the primary macular pigment with an favorable effect on the treatment of age-related macular degeneration (AMD). However, the poor water solubility of lutein hinders its absorption and delivery. In this study, a penetratin-modified lutein nanoemulsion in-situ gel (GEL) was prepared for the treatment of AMD.Methods: A nanoemulsion (NE) was prepared and modified with penetratin (P-NE) to improve the penetration. The effect of penetratin was evaluated by cell uptake and intraocular distribution assays. A dry AMD model was induced using NaIO3, and the therapeutic effect was evaluated by electroretinography, the number of apoptosis cells and the reactive oxygen species (ROS) level.Results: Lutein showed a good ability to protect ARPE-19 from the damage of H2O2 and the uptake rate of P-NE was significantly higher than NE. In the efficacy experiments, the structure of retina was significantly improved after treatment, the apoptosis rate decreased from 31.98% to 2.05%, and the level of ROS was significantly decreased (p < 0.0001).Conclusions: With the aid of penetratin, lutein could be delivered to the retina effectively. The P-NE GEL could evidently inhibit the apoptosis and ROS, demonstrating that the P-NE GEL has a good application prospect in the treatment of AMD.

Emerging treatments for dry age-related macular degeneration (AMD) and geographic atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

Age-related macular degeneration is a global disease with a significant societal impact. The advent of anti-vascular endothelial growth factor therapy (anti-VEGF) has revolutionised the treatment of neovascular age-related macular degeneration (nAMD). Dry age-related macular degeneration (dAMD) is being investigated for possible therapeutic options. The therapeutic categories undergoing clinical trials include complement pathway inhibitors, visual cycle modulators, reduction of toxic byproducts, antioxidative therapy, neuroprotective agents, laser therapy, surgical options, gene therapy, stem cell therapy, and miscellaneous treatments. Two intravitreal anti-complement factors (pegcetacoplan and avacincaptad pegol) have recently shown phase 3 clinical trial evidence of a reduction in the growth of geographic atrophy. In this review, we provide an update on treatment options currently undergoing clinical research trials for the management of dAMD and preventing the progression of Geographic Atrophy (GA).

Objective To compare the efficacy between intravitreal injection conbercept and ranibizumab in the treatment of wet age-related macular degeneration(AMD). Methods The clinical data of 40 eyes of 40 patients with wet AMD from Feb. 2017 to Aug. 2018 in this hospital were analyzed retrospectively. Group A, 20 eyes of 20 cases, received conbercept and group B, 20 eyes of 20 cases, received ranibizumab. All patients underwent intravitreal injection once a month for three consecutive times.The follow-up time was 3 months. Results The visual acuity at 1 week, 1 and 3 months after intravitreal injection was better than that before injection (P 0.05). There was no significant difference between the two groups at different time after injection (P=0.839, 0.402, 0.849). Central macular thickness were decreased in both groups after injection compared with that before injection (P<0.05), but the difference between the two groups was not statistically significant (P=0.885, 0.476, 0.634). Choroidal thickness of the two groups decreased after injection (P<0.05), but the difference between the two groups was not statistically significant (P=0.280, 0.831, 0.093). Conclusion Intravitreal injection of conbercept or ranibizumab can improve visual acuity, ameliorate macular structure, and decrease choroidal thickness for the treatment of wet age-related macular degeneration. There is no significant difference between the two drugs. Key words: Degeneration, macular, age-related, wet; Conbercept, Ranibizumab, intravitreal injection; Efficacy, clinical