Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

The Application of Clinical Genetics, Год журнала: 2023, Номер Volume 16, С. 111 - 130

Опубликована: Май 1, 2023

Abstract: Owing to their small size and safety profiles, adeno-associated viruses (AAVs) have become the vector of choice for gene therapy applications in retina. In addition naturally occurring AAVs, several engineered variants with enhanced properties are being developed experimental therapeutic applications. Nonetheless, there still some challenges impeding successful application AAVs a broader range retinal therapies. The AAV particles ensures efficient tissue transduction but also limits packaging capacity few kilobases. Further, AAV's ability cross barriers is an obstacle pan-retinal outer retina tolerable doses. Lastly, despite overall safety, been recent reports immune responses eye. Hence, evaluation prediction has come be considered integral part future clinical success. This review focuses on use trials diseases, discusses developments novel strategies overcome AAVs. Keywords: therapy, virus, AAV, trials, capsid variants,

Язык: Английский

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Gene-agnostic therapeutic approaches for inherited retinal degenerations

Frontiers in Molecular Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Янв. 9, 2023

Inherited retinal diseases (IRDs) are associated with mutations in over 250 genes and represent a major cause of irreversible blindness worldwide. While gene augmentation or editing therapies could address the underlying genetic small subset patients, their utility remains limited by great heterogeneity IRDs costs developing individualised therapies. Gene-agnostic therapeutic approaches target common pathogenic pathways that drive degeneration provide functional rescue vision independent cause, thus offering potential clinical benefits to all IRD patients. Here, we review key gene-agnostic approaches, including cell reprogramming replacement, neurotrophic support, immune modulation optogenetics. The relative limitations these strategies timing interventions discussed.

Язык: Английский

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ENHANCED RESTORATION OF VISUAL CODE AFTER TARGETING ON BIPOLAR CELLS COMPARED TO RETINAL GANGLION CELLS WITH OPTOGENETIC THERAPY

Molecular Therapy, Год журнала: 2025, Номер 33(3), С. 1264 - 1281

Опубликована: Янв. 18, 2025

Язык: Английский

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Evolution of Light-Sensitive Proteins in Optogenetic Approaches for Vision Restoration: A Comprehensive Review

Biomedicines, Год журнала: 2025, Номер 13(2), С. 429 - 429

Опубликована: Фев. 10, 2025

Retinal degenerations, such as age-related macular degeneration and retinitis pigmentosa, present significant challenges due to genetic heterogeneity, limited therapeutic options, the progressive loss of photoreceptors in advanced stages. These are compounded by difficulties precisely targeting residual retinal neurons ensuring sustained efficacy interventions. Optogenetics offers a novel approach vision restoration inducing light sensitivity through gene delivery light-sensitive opsins. This review traces evolution opsins optogenetic therapies, highlighting advancements from early research on channelrhodopsin-2 (ChR2) engineered variants addressing key limitations. Red-shifted opsins, including ReaChR ChrimsonR, reduced phototoxicity enabling activation under longer wavelengths, while Chronos introduced superior temporal kinetics for dynamic visual tracking. Further innovations, Multi-Characteristic Opsin 1 (MCO1), optimized opsin performance ambient light, bridging gap real-world applications. Key milestones include first partial human patient using ChrimsonR with light-amplifying goggles ongoing clinical trials exploring opsin-based therapies degeneration. While progress has been made, remain achieving sufficient functional normal lighting conditions manner that is both effective safe, eliminating need external light-enhancing devices. As progresses, positioned redefine management degenerative diseases, offering new hope millions affected loss.

Язык: Английский

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Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 27, 2024

Abstract Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients healthcare providers. Here, we introduce completely noninvasive ultrasonic prosthesis, featuring customized ultrasound two-dimensional array allows for simultaneous imaging stimulation. With synchronous three-dimensional guidance auto-alignment technology, prosthesis generate programmed waves dynamically precisely form arbitrary wave patterns on Neuron responses brain’s visual center mirrored these patterns, evidencing successful artificial creation, was further corroborated behavior experiments. Quantitative analysis spatial-temporal resolution field view demonstrated advanced performance elucidated biophysical mechanism retinal As could lead more effective, widely acceptable treatment blind patients. Its real-time imaging-guided stimulation strategy with single array, also benefit neurostimulation other diseases.

Язык: Английский

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A membrane-targeted photoswitch restores physiological ON/OFF responses to light in the degenerate retina

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 11, 2025

Язык: Английский

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Current approaches to vision restoration using optogenetic therapy

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Авг. 16, 2023

Inherited progressive degeneration of photoreceptors such as retinitis pigmentosa (RP) is the most common cause blindness leading to severe vision impairment affecting ~1 in 5,000 people worldwide. Although function and morphology get disrupted, there evidence that inner retinal neurons bipolar cells ganglion are left intact until later stages. Among several innovative therapeutic options aiming restore vision, optogenetic therapy can bestow light sensitivity remaining by ectopic expression light-sensitive proteins. Since advent this technique, a diverse class opsins (microbial mammalian opsins), chimeric proteins, ligand-gated ion channels, switchable have been used study their potential restoration. These proteins differ excitation spectra, response kinetics, signal amplification cascade. studies reported high fidelity responses retina, only handful them achieved functional visual cortex. This review summary visuocortical behavioral after treatment degenerated retina. clarifies what extent improved meaningful be obtained for efficacy continued clinical progress.

Язык: Английский

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Micromolded honeycomb scaffold design to support the generation of a bilayered RPE and photoreceptor cell construct

Bioactive Materials, Год журнала: 2023, Номер 30, С. 142 - 153

Опубликована: Июль 31, 2023

Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers retina. Given small size macula importance direct contact between RPE PRs, use scaffolds for targeted reconstruction outer retina in later stage AMD other dystrophies is particularly attractive. We developed microfabricated, honeycomb-patterned, biodegradable poly(glycerol sebacate) (PGS) deliver organized, adjacent PRs subretinal space. Furthermore, an optimized process was photocure PGS, shortening scaffold production time from days minutes. The resulting robustly supported seeding human pluripotent stem cell-derived either separately or as a dual cell-layered construct. These advanced, economical, versatile can accelerate cell transplantation efforts benefit patients with degenerative diseases.

Язык: Английский

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Theoretical prediction of broadband ambient light optogenetic vision restoration with ChRmine and its mutants

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 21, 2024

Vision restoration is one of the most promising applications optogenetics. However, it limited due to poor-sensitivity, slow-kinetics and narrow band absorption spectra opsins. Here, a detailed theoretical study retinal ganglion neurons (RGNs) expressed with ChRmine, ReaChR, CoChR, CatCh their mutants, near monochromatic LEDs, broadband sunlight, halogen lamp, RGB LED light, pure white light sources has been presented. All opsins exhibit improved sensitivity larger photocurrent on illuminating compared LEDs. ChRmine allows firing at ambient sunlight (1.5 nW/mm2) (1.2 nW/mm2), which lowest among considered. The activation spectrum its mutants also useful restore color sensitivity. Although exhibits slower turn-off kinetics high-fidelity spikes can be evoked upto 50 Hz. This limit extends 80 Hz hsChRmine mutant although requires double irradiance ChRmine. present shows that allow RGNs for goggle-free optogenetic prostheses quality restored vision.

Язык: Английский

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Correlations between the Michigan Retinal Degeneration Questionnaire and visual function parameters in patients with retinitis pigmentosa

Acta Ophthalmologica, Год журнала: 2023, Номер 102(5), С. 555 - 563

Опубликована: Дек. 29, 2023

Abstract Purpose To validate the use of best‐corrected visual acuity (BCVA), low‐luminance (LLVA), deficit (LLD; difference between BCVA and LLVA), mean macular sensitivity fixation stability as parameters vision‐related quality life based on novel Michigan Retinal Degeneration Questionnaire (MRDQ) in retinitis pigmentosa (RP) patients. Methods In this prospective cross sectional study, 30 patients with RP (47% female) were included a median age 41.0 years (interquartile range: 24.1–58.3 years). BCVA, LLVA LLD measured Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Mesopic microperimetry was performed to measure stability. Patients completed Dutch translation MRDQ which results an experienced disability (Θ‐)score seven domains. Spearman's rank correlation used. Results correlated significantly domain central vision ( r = 0.657; p < 0.001) colour 0.524; 0.003). Lower higher domains for (=0.550; 0.002) contrast 0.502; 0.005). scotopic function (r −0.484; 0.007) mesopic peripheral −0.533; 0.002). associated high all except photosensitivity . Conclusions The majority is strongly parameters. These findings show that measurements, especially LLVA, microperimetry, reflect can be used relevant outcome measures clinical trials RP.

Язык: Английский

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