Suprachoroidal delivery of viral and non-viral vectors for treatment of retinal and choroidal vascular diseases.

Current treatments for retinal and choroidal neovascular diseases suffer from insufficient durability, including anti-vascular endothelial growth factor-A (VEGF-A) agents. It is, therefore, of interest to explore alternative methods that could allow for robust improvement in visual acuity with fewer injections required. Amongst various pre-clinical and clinical studies in the literature, a promising approach is the use of suprachoroidal injection with viral and non-viral gene delivery vectors.

Improved protocol for histological and histopathological preparation of large eyes.

The development of new treatments for ocular diseases often requires investigating eyes similar in size and structure to human eyes. Such studies are challenging because analyzing the histopathology of large, human-sized eyes can be technically difficult. In particular, obtaining high-quality frozen sections is almost impossible due to the formation of ice crystals in the vitreous, which causes crush artifacts during the procedures of section and post sectioning manipulations.

Interim Results of the Phase III Portal Extension Trial of the Port Delivery System with Ranibizumab in Neovascular Age-Related Macular Degeneration.

Objective: The Port Delivery System with ranibizumab (PDS) is approved in the United States for neovascular age-related macular degeneration (nAMD). Portal (NCT03683251) is evaluating long-term safety and tolerability of the PDS in patients with nAMD who completed the phase II Ladder (NCT02510794) or phase III Archway (NCT03677934) trials.

Design: Multicenter, nonrandomized, open-label, extension clinical trial.

Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study.

Background: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection.

Suprachoroidal gene transfer with nonviral nanoparticles in large animal eyes.

Suprachoroidal nonviral gene therapy with biodegradable poly(β-amino ester) nanoparticles (NPs) provides widespread expression in photoreceptors and retinal pigmented epithelial (RPE) cells and therapeutic benefits in rodents. Here, we show in a human-sized minipig eye that suprachoroidal injection of 50 μl of NPs containing 19.2 μg of GFP expression plasmid caused GFP expression in photoreceptors and RPE throughout the entire eye with no toxicity.

Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab.

Background/aims: We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON.

Methods: Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7-15) of SHORE and through 12 months of HORIZON.

Exudation in Patients With Neovascular Age-Related Macular Degeneration Treated With the Port Delivery System or Monthly Injections.

Purpose: To evaluate for the presence, severity, and type of exudation at each study visit for a subgroup of patients with neovascular age-related macular degeneration from the Archway and Portal trials.

Design: Retrospective analysis of prospectively obtained data.

Methods: Spectral-domain optical coherence tomography scans from each study visit of 44 patients from the Port Delivery System (PDS) arm and 32 patients from the monthly injection arm of Archway were evaluated, and composites of horizontal scans through the fovea were created.

Anti-angiogenic collagen IV-derived peptide target engagement with αβ and αβ in ocular neovascularization models.

AXT107, a collagen-derived peptide that binds integrins αβ and αβ with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, and suppresses neovascularization (NV) and vascular leakage. Immunohistochemical staining for αβ and αβ was markedly increased in NV compared with normal retinal vessels. After intravitreous injection of AXT107, there was no staining with an anti-AXT107 antibody on normal vessels but robust staining of NV that co-localized with αβ and αβ.

Reduced inspired oxygen decreases retinal superoxide radicals and promotes cone function and survival in a model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by many different mutations that promote the degeneration of rod photoreceptors and have no direct effect on cones. After the majority of rods have died cone photoreceptors begin to slowly degenerate. Oxidative damage contributes to cone cell death and it has been hypothesized that tissue hyperoxia due to reduced oxygen consumption from the loss of rods is what initiates oxidative stress.

Pharmacokinetics of the Port Delivery System with Ranibizumab in the Ladder Phase 2 Trial for Neovascular Age-Related Macular Degeneration.

Introduction: Ladder was a phase 2 trial that evaluated the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration. Serum and aqueous humor samples were collected to characterize the pharmacokinetics (PK) of ranibizumab delivered through the PDS.

Methods: Ladder was a multicenter, randomized, active treatment-controlled, phase 2 clinical trial.

Viewpoints: Dual-blocking antibody against VEGF-A and angiopoietin-2 for treating vascular diseases of the eye.

Faricimab, a bispecific antibody that targets the endothelial cell growth factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Angpt2), was recently approved for treating neovascular age-related macular degeneration and diabetic macular edema. Here, Koh and Augustin review how mechanistic studies have translated into therapies, while Campochiaro evaluates their impact and value for clinical practice.

Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa.

Retinitis pigmentosa occurs due to mutations that cause rod photoreceptor degeneration. Once most rods are lost, gradual degeneration of cone photoreceptors occurs. Oxidative damage and abnormal glucose metabolism have been implicated as contributors to cone photoreceptor death.

Eye of the Needle.

A retired patient visits our author, who is professor of ophthalmology and neuroscience at Johns Hopkins University School of Medicine, to find out why he is suddenly struggling with his vision and learn why but a single treatment option exists for macular degeneration, a condition that affects 200-million people worldwide.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD).

Design: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial.

Participants: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy.

Using crowdsourcing to understand patients attitudes toward a clinical trial for retinitis pigmentosa requiring 4 years of participation.

Background: Clinical trials for retinitis pigmentosa (RP) likely require long follow-ups because of the slow progression of RP. Understanding patients' attitudes toward participation in a long trial and their acceptability of strategies aimed at promoting retention/compliance is important for assessing feasibility and resource needs and optimizing trial design.

Methods: A crowdsourcing survey to adult RP patients was administered on social media in 2020 July-November.

Proteosomal degradation impairs transcytosis of AAV vectors from suprachoroidal space to retina.

Suprachoroidal injection provides a new route of delivery for AAV vectors to retinal pigmented epithelial cells and photoreceptors that can be done in an outpatient setting and is less invasive and potentially safer than subretinal injection, the most common route of delivery for ocular gene therapy. After suprachoroidal injection of AAV8 or AAV9 vectors, there is strong transduction of photoreceptors, but it is unclear how vector traverses the retinal pigmented epithelium. In this study, we found that transduction of photoreceptors was significantly increased after suprachoroidal injection of AAV2tYF-CBA-GFP versus AAV2-CBA-GFP vector.

The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress.

Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The sulfhydryl-containing tripeptide glutathione (GSH), which is synthesized and maintained at high concentrations in all cells, is one of the mechanisms by which cells protect themselves from oxidative stress. N-acetylcysteine (NAC), a synthetic derivative of the endogenous amino acid L-cysteine and a precursor of GSH, has been used for several decades as a mucolytic and as an antidote to acetaminophen (paracetamol) poisoning.

Retinal vascular occlusions.

Acute retinal vascular occlusions are common causes of visual impairment. Although both retinal artery occlusions and retinal vein occlusions are associated with increased age and cardiovascular risk factors, their pathophysiology, systemic implications, and management differ substantially. Acute management of retinal artery occlusions involves a multidisciplinary approach including neurologists with stroke expertise, whereas treatment of retinal vein occlusions is provided by ophthalmologists.

Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases.

Neovascular age-related macular degeneration (NVAMD) is the most prevalent choroidal vascular disease, and diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the most prevalent retinal vascular diseases. In each of these, hypoxia plays a central role by stabilizing hypoxia-inducible factor-1 which increases production of vascular endothelial growth factor (VEGF) and other hypoxia-regulated gene products. High VEGF causes excessive vascular permeability, neovascularization, and in DR and RVO, promotes closure of retinal vessels exacerbating hypoxia and creating a positive feedback loop.

Structure-Guided Molecular Engineering of a Vascular Endothelial Growth Factor Antagonist to Treat Retinal Diseases.

Background: Ocular neovascularization is a hallmark of retinal diseases including neovascular age-related macular degeneration and diabetic retinopathy, two leading causes of blindness in adults. Neovascularization is driven by the interaction of soluble vascular endothelial growth factor (VEGF) ligands with transmembrane VEGF receptors (VEGFR), and inhibition of the VEGF pathway has shown tremendous clinical promise. However, anti-VEGF therapies require invasive intravitreal injections at frequent intervals and high doses, and many patients show incomplete responses to current drugs due to the lack of sustained VEGF signaling suppression.

Suprachoroidal gene transfer with nonviral nanoparticles.

Subretinal injections of viral vectors provide great benefits but have limited cargo capacity; they induce innate and adaptive immune responses, which may cause damage and preclude repeated injections; and they pose administration risks. As a new biotechnology, suprachoroidal injections of biodegradable nanoparticles (NPs) containing a reporter plasmid induce reporter expression in rat photoreceptors and RPE throughout the entire eye and maintain expression for at least 8 months. Multiple injections markedly increase expression.

Gelling hypotonic polymer solution for extended topical drug delivery to the eye.

Eye-drop formulations should hold as high a concentration of soluble drug in contact with ocular epithelium for as long as possible. However, eye tears and frequent blinking limit drug retention on the ocular surface, and gelling drops typically form clumps that blur vision. Here, we describe a gelling hypotonic solution containing a low concentration of a thermosensitive triblock copolymer for extended ocular drug delivery.

Locus-Level Changes in Macular Sensitivity in Patients with Retinitis Pigmentosa Treated with Oral N-acetylcysteine.

Purpose: To identify characteristics of loci associated with locus-level sensitivity loss or improvement during treatment with N-acetylcysteine (NAC) in retinitis pigmentosa (RP).

Design: Retrospective analysis of prospectively collected data in the FIGHT RP clinical trial.

Methods: Patients (n = 30) were treated with 600, 1,200, or 1,800 mg of NAC twice daily for 3 months and then 3 times/day for 3 months.