Exploring Superselective Intraarterial Thrombolysis for Autologous Fat Injection-Induced Vision Loss.

BACKGROUND: Intravascular injection represents the most severe complication in fat transplantation procedures. Currently, the prognosis for patients who suffer from blindness due to fat transplantation-induced ocular vascular occlusion is far from optimistic. OBJECTIVES: The aim of this study was to explore and evaluate the efficacy and safety of arterial thrombolysis in the treatment of ocular vascular occlusion caused by fat transplantation. METHODS: We analyzed the data of 12 patients who underwent intraarterial thrombolysis and conservative treatments for facial autologous fat grafting-associated ocular vascular occlusion. Among the cases, there were 6 instances of ophthalmic artery embolism and 6 cases of central retinal artery occlusion. All patients suffered with sudden blindness, sometimes accompanied by eye pain, ptosis, strabismus, skin necrosis at the injection site, or cerebral microinfarction. They received symptomatic conservative treatments and intraarterial thrombolysis, encompassing mechanical vessel recanalization, vessel dilation, and dissolution of thrombus constituents. RESULTS: Following intraarterial thrombolysis, a noteworthy improvement in the blood flow of both the main trunk and peripheral branches of the ophthalmic artery was observed in the majority of patients when contrasted with their pretreatment status. One patient experienced a headache intraoperatively, while no significant discomfort was reported by the remaining patients. After conservative treatments and intraarterial thrombolysis, all patients experienced improvement in ocular symptoms, skin necrosis, and cerebral infarction. Three patients demonstrated improvement in visual acuity. These patients had surpassed the recommended time window for treatment, yet the occlusion of the ophthalmic artery was not complete. CONCLUSIONS: Intraarterial thrombolysis combined with conservative treatments achieves early perfusion and is expected to promote visual recovery. Hospitals that possess the necessary treatment capabilities are encouraged to establish this therapeutic pathway.

Towards biologically plausible phosphene simulation for the differentiable optimization of visual cortical prostheses.

Blindness affects millions of people around the world. A promising solution to restoring a form of vision for some individuals are cortical visual prostheses, which bypass part of the impaired visual pathway by converting camera input to electrical stimulation of the visual system. The artificially induced visual percept (a pattern of localized light flashes, or 'phosphenes') has limited resolution, and a great portion of the field's research is devoted to optimizing the efficacy, efficiency, and practical usefulness of the encoding of visual information. A commonly exploited method is non-invasive functional evaluation in sighted subjects or with computational models by using simulated prosthetic vision (SPV) pipelines. An important challenge in this approach is to balance enhanced perceptual realism, biologically plausibility, and real-time performance in the simulation of cortical prosthetic vision. We present a biologically plausible, PyTorch-based phosphene simulator that can run in real-time and uses differentiable operations to allow for gradient-based computational optimization of phosphene encoding models. The simulator integrates a wide range of clinical results with neurophysiological evidence in humans and non-human primates. The pipeline includes a model of the retinotopic organization and cortical magnification of the visual cortex. Moreover, the quantitative effects of stimulation parameters and temporal dynamics on phosphene characteristics are incorporated. Our results demonstrate the simulator's suitability for both computational applications such as end-to-end deep learning-based prosthetic vision optimization as well as behavioral experiments. The modular and open-source software provides a flexible simulation framework for computational, clinical, and behavioral neuroscientists working on visual neuroprosthetics.

Losing, preserving, and restoring vision from neurodegeneration in the eye.

The retina is a part of the brain that sits at the back of the eye, looking out onto the world. The first neurons of the retina are the rod and cone photoreceptors, which convert changes in photon flux into electrical signals that are the basis of vision. Rods and cones are frequent targets of heritable neurodegenerative diseases that cause visual impairment, including blindness, in millions of people worldwide. This review summarizes the diverse genetic causes of inherited retinal degenerations (IRDs) and their convergence onto common pathogenic mechanisms of vision loss. Currently, there are few effective treatments for IRDs, but recent advances in disparate areas of biology and technology (e.g., genome editing, viral engineering, 3D organoids, optogenetics, semiconductor arrays) discussed here enable promising efforts to preserve and restore vision in IRD patients with implications for neurodegeneration in less approachable brain areas.

Attitudes of potential recipients toward emerging visual prosthesis technologies.

With the advent of multiple visual prosthesis devices to treat blindness, the question of how potential patients view such interventions becomes important in order to understand the levels of expectation and acceptance, and the perceived risk-reward balance across the different device approaches. Building on previous work on single device approaches done with blind individuals in Chicago and Detroit, USA, Melbourne, Australia, and Bejing, China, we investigated attitudes in blind individuals in Athens, Greece with coverage expanded to three of the contemporary approaches, Retinal, Thalamic, and Cortical. We presented an informational lecture on the approaches, had potential participants fill out a preliminary Questionnaire 1, then organized selected subjects into focus groups for guided discussion on visual prostheses, and finally had these subjects fill out a more detailed Questionnaire 2. We report here the first quantitative data that compares multiple prosthesis approaches. Our primary findings are that for these potential patients, perceived risk continues to outweigh perceived benefits, with the Retinal approach having the least negative overall impression and the Cortical approach the most negative. Concerns about the quality of restored vision were primary. Factors that drove the choice of hypothetical participation in a clinical trial were age and years of blindness. Secondary factors focused on positive clinical outcomes. The focus groups served to swing the impressions of each approach from neutrality toward the extremes of a Likert scale, and shifted the overall willingness to participate in a clinical trial from neutral to negative. These results, coupled with informal assessment of audience questions after the informational lecture, suggest that a substantial improvement in performance over currently available devices will be necessary before visual prostheses gain wide acceptance.

Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering.

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons of the retina. Glaucoma is the most common cause of irreversible blindness and affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, and elevated intraocular pressure. Current strategies only target intraocular pressure management and do not directly target the neurodegenerative processes occurring at the level of the retinal ganglion cell. Despite strategies to manage intraocular pressure, as many as 40% of glaucoma patients progress to blindness in at least one eye during their lifetime. As such, neuroprotective strategies that target the retinal ganglion cell and these neurodegenerative processes directly are of great therapeutic need. This review will cover the recent advances from basic biology to on-going clinical trials for neuroprotection in glaucoma covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, and neuroinflammation. With an increased understanding of both the basic and clinical mechanisms of the disease, we are closer than ever to a neuroprotective strategy for glaucoma.

Corneal Regeneration Using Gene Therapy Approaches.

One of the most remarkable advancements in medical treatments of corneal diseases in recent decades has been corneal transplantation. However, corneal transplants, including lamellar strategies, have their own set of challenges, such as graft rejection, delayed graft failure, shortage of donor corneas, repeated treatments, and post-surgical complications. Corneal defects and diseases are one of the leading causes of blindness globally; therefore, there is a need for gene-based interventions that may mitigate some of these challenges and help reduce the burden of blindness. Corneas being immune-advantaged, uniquely avascular, and transparent is ideal for gene therapy approaches. Well-established corneal surgical techniques as well as their ease of accessibility for examination and manipulation makes corneas suitable for in vivo and ex vivo gene therapy. In this review, we focus on the most recent advances in the area of corneal regeneration using gene therapy and on the strategies involved in the development of such therapies. We also discuss the challenges and potential of gene therapy for the treatment of corneal diseases. Additionally, we discuss the translational aspects of gene therapy, including different types of vectors, particularly focusing on recombinant AAV that may help advance targeted therapeutics for corneal defects and diseases.

Applications of hydrogel materials in different types of corneal wounds.

Severe corneal injury can lead to a decrease in light transmission and even blindness. Currently, corneal transplantation has been applied as the primary treatment for corneal blindness; however, the worldwide shortage of suitable corneal donor tissue means that a large proportion of patients have no access to corneal transplants. This situation has contributed to the rapid development of various corneal substitutes. The development and optimization of novel hydrogels that aim to replace partial or full-thickness pathological corneas have advanced in the last decade. Meanwhile, with the help of 3D bioprinting technology, hydrogel materials can be molded to a refined and controllable shape, attracting many scientists to the field of corneal reconstruction research. Although hydrogels are not yet available as a substitute for traditional clinical methods of corneal diseases, their rapid development makes us confident that they will be in the near future. We summarize the application of hydrogel materials for various types of corneal injuries frequently encountered in clinical practice, especially focusing on animal experiments and preclinical studies. Finally, we discuss the development and achievements of 3D bioprinting in the treatment of corneal injury.

Ameliorating Hemianopia with Multisensory Training.

Hemianopia (unilateral blindness), a common consequence of stroke and trauma to visual cortex, is a debilitating disorder for which there are few treatments. Research in an animal model has suggested that visual-auditory stimulation therapy, which exploits the multisensory architecture of the brain, may be effective in restoring visual sensitivity in hemianopia. It was tested in two male human patients who were hemianopic for at least 8 months following a stroke. The patients were repeatedly exposed to congruent visual-auditory stimuli within their blinded hemifield during 2 h sessions over several weeks. The results were dramatic. Both recovered the ability to detect and describe visual stimuli throughout their formerly blind field within a few weeks. They could also localize these stimuli, identify some of their features, and perceive multiple visual stimuli simultaneously in both fields. These results indicate that the multisensory therapy is a rapid and effective method for restoring visual function in hemianopia.SIGNIFICANCE STATEMENT Hemianopia (blindness on one side of space) is widely considered to be a permanent disorder. Here, we show that a simple multisensory training paradigm can ameliorate this disorder in human patients.

Multidisciplinary speech and language therapy approach in a child with multiple disabilities including blindness due to retinopathy of prematurity: a case study with a one year follow-up.

Aim: This study aims to show speech and language, sensory-motor, and emotional progress after one year of therapy according to the needs of and resources for a child with multiple disabilities and blindness due to retinopathy of prematurity (ROP).Methods: A 45-month-old boy was examined by a multidisciplinary team and assessed using the Sensory Profile 2, The Vineland Adaptive Behavior Scale II, The Communication Matrix, and The Scale for Evaluation of Psychophysiological Abilities of Children Aged 0-7. After a year of daily individually adopted speech and language therapy followed by supplementary therapeutics method, based on a multidisciplinary approach, the child was reassessed using the same battery of tests.Results: The obtained results might indicate the importance of factors such as a multidisciplinary approach, individualization, communication pathways, therapist's characteristics, and trust when working with children with multiple disabilities.Conclusion: Taking into account all the features of multiple disabilities during the treatment course, continuous monitoring, modification, and adaptation of applied therapy method proved successful in this case.

Venous sinus stenting for the treatment of acute blindness in a patient with idiopathic intracranial hypertension.

We present a case of acute onset of blindness treated with venous sinus stenting in the hyperacute period (24-48 h). The patient had not been diagnosed previously with idiopathic intracranial hypertension and presented at an outside facility with a short history of headache, nausea, vomiting and visual deficits. Initial management included lumbar punctures for pressure relief. Unfortunately, the patient's condition deteriorated and she experienced the rapid onset of blindness. Within 24-48 h of blindness onset, she was transferred to our institution for emergent endovascular stenting of the venous sinuses. The intervention resulted in improvement of symptoms and recovery of visual acuity over a short-term follow-up period.

Towards aSmart Bionic Eye: AI-powered artificial vision for the treatment of incurable blindness.

Objective.How can we return a functional form of sight to people who are living with incurable blindness? Despite recent advances in the development of visual neuroprostheses, the quality of current prosthetic vision is still rudimentary and does not differ much across different device technologies.Approach.Rather than aiming to represent the visual scene as naturally as possible, aSmart Bionic Eyecould provide visual augmentations through the means of artificial intelligence-based scene understanding, tailored to specific real-world tasks that are known to affect the quality of life of people who are blind, such as face recognition, outdoor navigation, and self-care.Main results.Complementary to existing research aiming to restore natural vision, we propose a patient-centered approach to incorporate deep learning-based visual augmentations into the next generation of devices.Significance.The ability of a visual prosthesis to support everyday tasks might make the difference between abandoned technology and a widely adopted next-generation neuroprosthetic device.

Update on Viral Gene Therapy Clinical Trials for Retinal Diseases.

In 2001, the first large animal was successfully treated with a gene therapy that restored its vision. Lancelot, the Briard dog that was treated, suffered from a human childhood blindness called Leber's congenital amaurosis type 2. Sixteen years later, the gene therapy was approved by the U.S. Food and Drug Administration. The success of this gene therapy in dogs led to a fast expansion of the ocular gene therapy field. By now every class of inherited retinal dystrophy has been treated in at least one animal model and many clinical trials have been initiated in humans. In this study, we review the status of viral gene therapies for the retina, with a focus on ongoing human clinical trials. It is likely that in the next decade we will see several new viral gene therapies approved.

Flexible ultrasound-induced retinal stimulating piezo-arrays for biomimetic visual prostheses.

Electronic visual prostheses, or biomimetic eyes, have shown the feasibility of restoring functional vision in the blind through electrical pulses to initiate neural responses artificially. However, existing visual prostheses predominantly use wired connections or electromagnetic waves for powering and data telemetry, which raises safety concerns or couples inefficiently to miniaturized implant units. Here, we present a flexible ultrasound-induced retinal stimulating piezo-array that can offer an alternative wireless artificial retinal prosthesis approach for evoking visual percepts in blind individuals. The device integrates a two-dimensional piezo-array with 32-pixel stimulating electrodes in a flexible printed circuit board. Each piezo-element can be ultrasonically and individually activated, thus, spatially reconfigurable electronic patterns can be dynamically applied via programmable ultrasound beamlines. As a proof of concept, we demonstrate the ultrasound-induced pattern reconstruction in ex vivo murine retinal tissue, showing the potential of this approach to restore functional, life-enhancing vision in people living with blindness.

Regenerative and restorative medicine for eye disease.

Causes of blindness differ across the globe; in higher-income countries, most blindness results from the degeneration of specific classes of cells in the retina, including retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells. Advances over the past decade in retinal regenerative medicine have allowed each of these cell types to be produced ex vivo from progenitor stem cells. Here, we review progress in applying these technologies to cell replacement - with the goal of vision restoration in degenerative disease. We discuss the landscape of human clinical trials for RPE transplantation and advanced preclinical studies for other cell types. We also review progress toward in situ repair of retinal degeneration using endogenous progenitor cells. Finally, we provide a high-level overview of progress toward prosthetic ocular vision restoration, including advanced photovoltaic devices, opsin-based gene therapy, and small-molecule photoswitches. Progress in each of these domains is at or near the human clinical-trial stage, bringing the audacious goal of vision restoration within sight.

Innovative Technologies for Optimized Artificial Vision. / Innovative Technologien für optimiertes künstliches Sehen.

Despite significant advances in the treatment of severe eye diseases, certain forms of blindness cannot be cured or improved to this day. These include, for example, retinitis pigmentosa, a hereditary degeneration of photoreceptors. Technology approaches with implantable visual prostheses based on electrical stimulation of remaining neurons in the retina or cortex, have already been tested in a number of patients with limited results. New findings in the biology of these diseases as well as new technological developments give hope for better results in the future.

Gene-independent therapeutic interventions to maintain and restore light sensitivity in degenerating photoreceptors.

Neurodegenerative retinal diseases are a prime cause of blindness in industrialized countries. In many cases, there are no therapeutic treatments, although they are essential to improve patients' quality of life. A set of disease-causing genes, which primarily affect photoreceptors, has already been identified and is of major interest for developing gene therapies. Nevertheless, depending on the nature and the state of the disease, gene-independent strategies are needed. Various strategies to halt disease progression or maintain function of the retina are under research. These therapeutic interventions include neuroprotection, direct reprogramming of affected photoreceptors, the application of non-coding RNAs, the generation of artificial photoreceptors by optogenetics and cell replacement strategies. During recent years, major breakthroughs have been made such as the first optogenetic application to a blind patient whose visual function partially recovered by targeting retinal ganglion cells. Also, RPE cell transplantation therapies are under clinical investigation and show great promise to improve visual function in blind patients. These cells are generated from human stem cells. Similar therapies for replacing photoreceptors are extensively tested in pre-clinical models. This marks just the start of promising new cures taking advantage of developments in the areas of genetic engineering, optogenetics, and stem-cell research. In this review, we present the recent therapeutic advances of gene-independent approaches that are currently under clinical evaluation. Our main focus is on photoreceptors as these sensory cells are highly vulnerable to degenerative diseases, and are crucial for light detection.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Hypertonic packs to reverse blindness caused by facial lymphoedema in the setting of head and neck cancer - A case report.

BACKGROUND: Severe, cancer-related facial oedema can impair vision. It can result from lymphatic and/or venous obstruction due to disease and/or treatment related fibrosis. There is very limited data on the use of directly applied hypertonic packs for the relief of periorbital oedema. CASE: A 63 year old man with recurrent laryngeal squamous cell carcinoma developed functional blindness secondary to periorbital oedema in the setting of severe facial swelling. This was refractory to maximal facial lymphatic massage available in the community setting. POSSIBLE COURSES OF ACTION: Management dilemmas included what non-medical interventions may relieve his periorbital oedema and thereby restore his vision outside of daily lymphatic massage from a qualified physiotherapist. FORMULATION OF MANAGEMENT PLAN: The patient agreed to an initial dry hypertonic pack with a great functional improvement of his vision. He was taught how to do this so that he could repeat ad libitum. OUTCOME: The patient had previously expressed that his most distressing thought was the prospect of becoming functionally blind prior to dying. The provision of an easy additional therapy to relieve his visual obstruction provided him with much comfort. He passed away peacefully a few weeks later. LESSONS: The case demonstrates that application of a dry hypertonic pack can relieve periorbital oedema in the setting of facial oedema in cases which are refractory to the combination of self-massage, cold-compress application, and daily lymphatic massage by a certified physiotherapist. RESEARCH AVENUES: A case series to define incidence of adverse effects and duration of treatment effectiveness.

Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins.

Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.