Restoration Of Visual Function Research Articles

Outcomes of epiretinal proliferation embedding technique in the surgery for full-thickness macular hole

To compare visual and anatomical outcomes between peeling and embedding of epiretinal proliferation in patients with full-thickness macular holes (FTMH) with epiretinal proliferation (EP), this retrospective cohort study classified patients into two groups based on whether EP was completely peeled (peeling group, n = 25 eyes), or embedded into the hole (embedding group, n = 31 eyes) during surgery. Preoperative characteristics and postoperative outcomes, including best-corrected visual acuity and the length of the disrupted external limiting membrane and ellipsoid zone, were compared. Preoperative features including visual acuity and hole size did not differ between the two groups. All studied eyes achieved closure of the macular hole postoperatively. Visual acuity significantly improved at 3, 6, and 12 months postoperatively in both groups. The visual acuity 1-month after surgery was better in the embedding group than that in the peeling group (0.28 ± 0.29 vs. 0.50 ± 0.42 logarithm of the minimum angle of resolution, P = 0.016), although the difference was not noted after 3 months postoperatively. The embedding group showed shorter disruption of the external limiting membrane than the peeling group postoperatively (62.6 ± 40.2 μm vs. 326.2 ± 463.9 μm at postoperative 12 months, P = 0.045). In conclusion, the embedding technique during surgical repair of a FTMH with EP facilitates recovery of the outer foveal layers and promotes earlier restoration of visual function.

A typical case of miraculous relief from blindness

This article describes a case of hysterical amblyopia in a 10.5-year-old girl. She complained of decreased vision for 4 months. The decrease in vision was a result of infectious mononucleosis and conjunctivitis. During the initial examination, typical signs of hysterical amblyopia were observed: a bilateral decrease in visual acuity, loss of field to tubular, and a corresponding impaired orientation in the surrounding space. Reversible changes in visual evoked potentials (VEP) were noted, indicating functional changes in the visual system, impaired color perception. A complete ophthalmological examination was performed, including standard methods and electrophysiological studies. Upon repeated examination after 1 day, complete relief of signs of hysterical amblyopia was noted, namely, an increase in visual acuity to 1.2, expansion of the boundaries of the visual field to normal values, normal binocular and accommodation functions, and normal trichromasia. This case was unique because of the complete restoration of visual functions that occurred spontaneously within 1 day. For the first time, reversible changes in visual evoked potential that were not previously described in the literature were revealed, and an undifferentiated violation of color perception was described.

Низкоэнергетическая лентикулярная лазерная хирургия в коррекции миопии

Purpose. To improve the efficiency and safety of SMILE-type lenticular surgery procedure in correction of different degrees myopia based on the use of low-energy laser parameters. Material and methods. This study includes a comparative analysis of data from 193 patients (288 eyes) operated for different degrees myopia including a number of cases with myopic astigmatism using SMILE technology with different FSL energy levels from 130 to 150 nJ. The parameters were analyzed on the 1st day and after 1 week, 1 month, 3, 6 and 12 months after surgery with assessment of NCVA, quality of life (QIRC questionnaire), general corneal wavefront aberrations (RMS), densitometry and pachymetry. Results. According to visometry, quality of life assessment, RMS, densitometry and pachymetry, the best functional results were obtained in subgroups with mild and moderate myopia on the 1st day after SMILE using an energy level in the range of 130 nJ. And in subgroups with a high degree of myopia, when using an energy level in the range of 140 nJ, no direct effect of energy on other indicators was found. Conclusion. According to the results of the study, it was found that the correction of myopic refractive error using the SMILE technology with a FSL energy level in the range of 130–140 nJ in its effectiveness on the 1st day after surgery exceeds the previously used energy levels (150 nJ) in terms of the quality of restoration of visual functions and does not have a negative effect on other parameters of the cornea. Key words: myopia, lenticular surgery, femtosecond laser energy, SMILE

Prevention and control of myopia based on meridians and zang-fu organs theory for unblocking meridians and harmonizing zang-fu organs

The prevention and control of myopia has always been a global challenge, as high myopia can lead to visual field defects, distorted vision, blindness, and other serious risks. Traditional Chinese Medicine (TCM) believes that myopia is the external manifestation of the overall physical condition in the eyes, which is related to the function of the eyes and the overall body functions. Based on the meridians and zang-fu organs theory, this article explores the associations of meridians and the zang-fu organs with the eyes, as well as their influence on myopia. Obstruction of meridians and disharmony of the zang-fu organs were found to be the fundamental pathological mechanisms that lead to the inability of the eyes to see distant objects. As one of the myopia prevention and control techniques, tuina shows significant therapeutic efficacy and green safety. On the one hand, it helps transport essence and brighten the eyes by unblocking the meridians around the eyes, neck, shoulder, and back to promote the flow of qi and blood. On the other hand, it can generate essence and brighten the eyes by harmonizing cold, heat, deficiency, and excess in the zang-fu organs to tonify qi and blood. Under a combination of localized and holistic action, this ultimately promotes the generation of essence and qi, unobstructed the flow of the visual pathway, and restoration of visual function, effectively preventing the occurrence and progression of myopia.

BILATERAL SEROUS RETINAL DETACHMENT AS OCULAR MANIFESTATION IN ACUTE LYMPHOBLASTIC LEUKEMIA: A CASE REPORT

Introduction : Acute lymphoblastic leukemia (ALL) is known to cause several ocular involvements. However, retinal detachment is a rare complication. This report aims to present unusual ocular manifestations in the form of bilateral serous retinal detachment in a pediatric patient.
 Case Illustration : An 11-year-old girl with a diagnosis of relapsed ALL and thrombocytopenia was referred to the Ophthalmology Department due to sudden blurred vision. The patient was undergoing chemotherapy on the third cycle due to the relapse. Visual acuity was 1/300 in both eyes. Fundus examination showed bilateral serous retinal detachment. No treatment in ophthalmology was given due to the unstable condition of this patient.
 Discussion : Up to 90% of all leukemia patients have fundus changes during the disease. The presence of unilateral or bilateral serous retinal detachment as a sign of choroidal infiltration may be one of the manifestations of acute leukemia, both as a primary sign and a relapse. Literature has shown that chemotherapy, radiation, and systemic prednisone would improve the visual acuity in these patients. However, in this case, when the patient is unstable and experiencing a series of complications, we decided that life-saving treatment comes first.
 Conclusion : The incidence of ocular involvements in ALL could be due to the treatment and the disease itself. Prompt recognition of disease led to early systemic treatment and restoration of visual function. The goal of sight-saving comes second after life-saving treatments.

Glial cells as a promising therapeutic target of glaucoma: beyond the IOP

Glial cells, a type of non-neuronal cell found in the central nervous system (CNS), play a critical role in maintaining homeostasis and regulating CNS functions. Recent advancements in technology have paved the way for new therapeutic strategies in the fight against glaucoma. While intraocular pressure (IOP) is the most well-known modifiable risk factor, a significant number of glaucoma patients have normal IOP levels. Because glaucoma is a complex, multifactorial disease influenced by various factors that contribute to its onset and progression, it is imperative that we consider factors beyond IOP to effectively prevent or slow down the disease’s advancement. In the realm of CNS neurodegenerative diseases, glial cells have emerged as key players due to their pivotal roles in initiating and hastening disease progression. The inhibition of dysregulated glial function holds the potential to protect neurons and restore brain function. Consequently, glial cells represent an enticing therapeutic candidate for glaucoma, even though the majority of glaucoma research has historically concentrated solely on retinal ganglion cells (RGCs). In addition to the neuroprotection of RGCs, the proper regulation of glial cell function can also facilitate structural and functional recovery in the retina. In this review, we offer an overview of recent advancements in understanding the non-cell-autonomous mechanisms underlying the pathogenesis of glaucoma. Furthermore, state-of-the-art technologies have opened up possibilities for regenerating the optic nerve, which was previously believed to be incapable of regeneration. We will also delve into the potential roles of glial cells in the regeneration of the optic nerve and the restoration of visual function.

Fabrication of a 3D bioprinting model for posterior capsule opacification using GelMA and PLMA hydrogel-coated resin.

Posterior capsule opacification (PCO) remains the predominant complication following cataract surgery, significantly impairing visual function restoration. In this study, we developed a PCO model that closely mimics the anatomical structure of the crystalline lens capsule post-surgery. The model incorporated a threaded structure for accurate positioning and observation, allowing for opening and closing. Utilizing 3D printing technology, a stable external support system was created using resin material consisting of a rigid, hollow base and cover. To replicate the lens capsule structure, a thin hydrogel coating was applied to the resin scaffold. The biocompatibility and impact on cellular functionality of various hydrogel compositions were assessed through an array of staining techniques, including calcein-AM/PI staining, rhodamine staining, BODIPY-C11 staining and EdU staining in conjunction with transwell assays. Additionally, the PCO model was utilized to investigate the effects of eight drugs with anti-inflammatory and anti-proliferative properties, including 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), THZ1, sorbinil, 4-octyl itaconate (4-OI), xanthohumol, zebularine, rapamycin and caffeic acid phenethyl ester, on human lens epithelial cells (HLECs). Confocal microscopy facilitated comprehensive imaging of the PCO model. The results demonstrated that the GelMA 60 5% + PLMA 2% composite hydrogel exhibited superior biocompatibility and minimal lipid peroxidation levels among the tested hydrogels. Moreover, compared to using hydrogel as the material for 3D printing the entire model, applying surface hydrogel spin coating with parameters of 2000 rpm × 2 on the resin-based 3D printed base yielded a more uniform cell distribution and reduced apoptosis. Furthermore, rapamycin, 4-OI and AICAR demonstrated potent antiproliferative effects in the drug intervention study. Confocal microscopy imaging revealed a uniform distribution of HLECs along the anatomical structure of the crystalline lens capsule within the PCO model, showcasing robust cell viability and regular morphology. In conclusion, the PCO model provides a valuable experimental platform for studying PCO pathogenesis and exploring potential therapeutic interventions.

Restoration of vision by combined experimental antithymocyte therapy, and orbital radiation with high-dose steroids for severe, acute, steroid-refractory, congestive thyroid orbitopathy

PurposeWe report diagnostic and therapeutic dilemmas in the difficult case of compressive optic neuropathy with severe visual acuity and visual field loss with subsequent visual recovery in both eyes, in a patient with Graves’ orbitopathy (GO) by a combination of experimental antithymocyte therapy, orbital radiotherapy with high-dose steroids.MethodsA 72-year-old man presented with severe vision loss in both eyes. The visual symptoms had appeared over a year before the GO diagnosis. He was initially misdiagnosed with neuroborreliosis and optic neuritis based on brain and orbital magnetic resonance imaging. There was no exophthalmos. The ophthalmological examination included visual acuity, visual field, tonometry in primary and upgaze eye position, optical coherence tomography (OCT), pattern electroretinogram (PERG), pattern, and flash visual evoked potentials (PVEP and FVEP). The patient received experimental therapy with ATG, followed by high-dose of intravenous steroids and orbital radiotherapy.ResultsDelayed VEP peaks became shorter after treatment. After systemic and local therapy lowering of intraocular pressure was achieved. Abnormal PERG has been found three months before ganglion cells atrophy was detected in OCT. Visual acuity and visual field improvement occurred in both eyes after therapy, despite partial left optic nerve atrophy. The patient regained full decimal visual acuity (1.0 right from as poor as 0.3 to 1.0 in the right eye and from hand movements to 0.9 in the left. Severe visual field loss with advanced absolute scotomata has improved to slight relative scotomata. The duration of follow-up time after the treatment was 4 months.ConclusionsIntensive treatment of steroid-resistant Graves’ orbitopathy (GO) may prevent total optic nerve atrophy. Despite severely advanced optic neuropathy, this report emphasizes the necessity of therapy even with nearly complete visual function loss hence there is always a possibility to regain full visual acuity and visual field. Patients with tense orbital septum may not present with significant exophthalmos, thus delaying the correct diagnosis of orbitopathy. A supporting sign of GO was the difference in intraocular pressure in the primary and upgaze eye positions. Electrophysiological examinations are helpful in the diagnosis and monitoring of GO therapy. To our knowledge, this is the first report of this kind presenting visual function restoration and structural recovery in a patient with advanced optic neuropathy in GO.

OPTOGENETICS: FUNDAMENTAL AND APPLIED ASPECTS

The paper is devoted to optogenetics as a method that allows the cells of an organism to acquire light sensitivity. The history of the origin and development of optogenetics is briefly reviewed. The role of optogenetics in studying both the fundamental mechanisms of brain functions and in understanding the mechanisms of a number of neurological and psychiatric diseases, including those associated with memory loss, is discussed.
 The real field of clinical application of optogenetics methods to date, namely in ophthalmology, is discussed in detail. Clinical trials have shown the principal possibility of optogenetic prosthetics of “blind” retina and partial restoration of visual functions. Data on one of the four ongoing clinical trials, its success and limitations are presented. The conditions and prospects for further development of optogenetic prosthetic technologies for blind retina in the last stages of the neurodegenerative process are discussed in detail. The question of the type of nerve cells in the degenerating retina most promising for optogenetic prosthetics is discussed. The authors believe that genes of visual, G-protein-binding rhodopsins (most likely cones), which trigger the enzymatic cascade of light signal amplification, are the most promising for optogenetic prosthetics. The use of genes of genetically modified channel rhodopsins as “tools” for optogenetic prosthetics of degenerative retina is undoubtedly possible and, as clinical trials show, quite realistic.

Acute Vascular Pathology of the Eye as a Complication of the Past COVID-19 Infection. Clinical Observations

Ophthalmological manifestations in COVID-19 infection are diverse, manifesting themselves in all anatomical structures of organ of vision, they occur both in the acute period of the disease and in the post-COVID period. Currently, the literature describes changes in the anterior segment of the eye more often, and also there are publications describing pathological changes in the posterior segment, and acute vascular pathology of the retina after COVID-19 infection in particular. It has been established that the comorbid background of the patient is of great importance in the development and the course of the disease. These findings are also confirmed by our two clinical observations of acute ocular vascular pathology after COVID-19. In the first case, retinovasculitis of the right eye complicated by thrombosis of the inferior temporal branch of the central retinal vein was described. The development of vascular pathology of the eye in this case was observed 1.5 months after the onset of the first symptoms of COVID-19 infection. The patient promptly turned to an ophthalmologist and was hospitalized to an eye hospital, where she received anti-inflammatory, hemostatic, anticoagulant, antibacterial, angioprotective, antioxidant therapy. As a result of treatment — the improvement of condition, restoration of visual functions. In the second presented case, we observed the development of an acute ischemic circulatory disorder of the retina of the left eye (thrombosis of the central retinal vein) 2.5 months after the onset of the disease with a new coronavirus infection. The treatment in an ophthalmological hospital included: steroid and non-steroidal anti-inflammatory drugs, antibiotics, mydriatics, haemostatics, angioprotectors, antioxidants, anticoagulants, vitamins. On discharge from the hospital, there was a slight improvement, but after 2 months, the condition of the left eye worsened again. The pathology of the organ of vision proceeded with the development of complication — secondary neovascular glaucoma of a refractory nature with an outcome to subatrophy of the eyeball. It was facilitated by the comorbid background of the patient: hypertension, type 2 diabetes mellitus, dyslipidemia.Based on the results of the analysis of clinical observations, the specific features of ophthalmological changes, their severity and dynamics on the background of comorbidity and the received therapy were established. The relationship between COVID-19 infection and complications of the organ of vision has been shown.

Роль пигментного эпителия сетчатки в лечении субмакулярных кровоизлияний

Objective. To evaluate the structural and functional changes in the retina depending on the duration of the morphological structure disorder of the retinal pigment epithelium (RPE) after treatment of patients with submacular hemorrhage (SMH) against the background of age-related macular degeneration (AMD). Material and methods. Depending on the duration of AMD, the patients were divided into two groups: Group 1 (24 patients) – SMH with newly diagnosed AMD; group 2 (19 patients) – SMH with AMD with an established diagnosis for more than 12 months. All patients underwent two-port 27 G surgery with subretinal injection of a fibrinolytic agent with air tamponade of the vitreal cavity. Then all patients were prescribed antivasoproliferative therapy. Results. After 2 weeks, the indices of maximally corrected visual acuity in the 1st group increased to 0.18 ± 0.05 and in the 2nd group to 0.15 ± 0.03. At the end of the 12-month follow-up period, the 1st group demonstrated stable visual acuity at the same levels, and the 2nd group showed a significant decrease in visual functions to 0.1 ± 0.04. The central retinal thickness before therapy was 826.2 ± 168, 9 in the 1st and 778.7 ± 151.9 µm in the 2nd group. One year after the start of treatment, a decrease to 231.3 ± 22.4 and 305.2 ± 57.6 µm was demonstrated in the 1st and 2nd groups, respectively. Before vitreoretinal intervention, the average height of RPE detachment was 167.2 ± 79.9 µm in the 1st group and 184.4 ± 85.1 µm in the 2nd group. and after 12 months – up to 38.8 ± 6.2 and 63.9 ± 11.6 microns in the 1st and 2nd groups, respectively. Conclusion. Vitreoretinal intervention followed by antivasoproliferative therapy in patients with SMH associated with AMD can improve the morphological and functional prognosis of the course of the disease. However, the long-term prospects for the restoration of visual function largely depend on the initial state of RPE and the duration of AMD. Keywords: submacular hemorrhage, tissue plasminogen activator, pneumodislocation

Brain organoids restore cortical damage.

Cortical damage is irreparable and poses a challenge to regenerative medicine. Whether brain organoids can compensate for injured brain regions remains unclear. In this issue of Cell Stem Cell, Jgamadze etal. report that human forebrain organoids transplanted into the rat visual system show long-term structural connectivity and the restoration of visual function following lesions.

Visual function restoration in a mouse model of Leber congenital amaurosis via therapeutic base editing

Leber congenital amaurosis (LCA), an inherited retinal degeneration, causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants, such as RPE65, are evident in specific genes, related to the functions of retinal pigment epithelium and photoreceptors. In contrast to the original Cas9, base editing tools can correct pathogenic substitutions without generation of DNA double-stranded breaks (DSBs). In this study, dual adeno-associated virus (AAV) vectors containing split adenine base editors (ABEs) with trans-splicing intein were prepared for invivo base editing in retinal degeneration of 12 (rd12) mice, an animal model of LCA, possessing a nonsense mutation of C to T transition in the Rpe65 gene (p.R44X). Subretinal injection of AAV-ABE in retinal pigment epithelial cells of rd12 mice resulted in an A to G transition. The on-target editing was sufficient for recovery of wild-type mRNA, RPE65 protein, and light-induced electrical responses from the retina. Compared with our previous therapeutic editing strategies using Cas9 and prime editing, or with the gene transfer strategy shown in the current study, our results suggest that, considering the editing efficacy and functional recovery, ABEs could be a strong, reliable method for correction of pathogenic variants in the treatment of LCA.

Dynamic functional and structural remodeling during retinal regeneration in zebrafish.

Zebrafish regenerate their retinas following damage, resulting in restoration of visual function. Here we evaluate recovery of retinal function through qualitative and quantitative analysis of the electroretinogram (ERG) over time following retinal damage, in correlation to histological features of regenerated retinal tissue. Retinas of adult zebrafish were lesioned by intravitreal injection of 10 μM (extensive lesion; destroys all neurons) or 2 μM (selective lesion; spares photoreceptors) ouabain. Unlesioned contralateral retinas served as controls. Function of retinal circuitry was analyzed at selected timepoints using ERG recordings from live zebrafish, and whole eyes were processed for histological analyses immediately thereafter. Qualitative and quantitative assessment of waveforms during retinal regeneration revealed dynamic changes that were heterogeneous on an individual level within each sampling time, but still followed common waveform recovery patterns on a per-fish and population-level basis. Early in the regeneration period (13-30 days post injury; DPI), for both lesion types, b-waves were essentially not detected, and unmasked increased apparent amplitudes, implicit times, and half-widths of a-waves (vs. controls). In control recordings, d-waves were not obviously detected, but apparent d-waves (OFF-bipolar responses) from regenerating retinas of several fish became prominent by 30DPI and dominated the post-photoreceptor response (PPR). Beyond 45DPI, b-waves became detectable, and the ratio of apparent d- to b-wave contributions progressively shifted with most, but not all, fish displaying a b-wave dominated PPR. At the latest timepoints (extensive, 90DPI; selective, 80DPI), recordings with measurable b-waves approached a normal waveform (implicit times and half-widths), but amplitudes were not restored to control levels. Histological analyses of the retinas from which ERGs were recorded showed that as regeneration progressed, PKCa + ON-bipolar terminals and parvalbumin + amacrine cell processes became more stereotypically positioned within the deep sublaminae of the INL over recovery time after each lesion type, consistent with the shift in PPR seen in the ERG recordings. Taken together, these data suggest that photoreceptor-OFF-bipolar component/connectivity may functionally recover and mature earlier during regeneration compared to the photoreceptor-ON-bipolar component, though the timeframe in which such recovery happens is heterogeneous on a per-fish basis. Collectively our studies suggest gradual restoration of ON-bipolar functional circuitry during retinal regeneration.

Опыт применения глюкокортикоидов у пациентов с макулярным отеком, связанным с саркоидозом

Purpose. To evaluate the results of treatment of patients with sarcoidosis with chronic non-infectious uveitis complicated by macular edema by intravitreal injection of a glucocorticosteroid implant with previously used methods. Material and methods. The study performed a comparative analysis of data from patients with cystic macular edema against the background of chronic non-infectious uveitis associated with sarcoidosis, with corrected visual acuity of more than 0.05 (according to the Golovin-Sivtsev table). Group 1 (prospective analysis) included the results of treatment of patients with sarcoidosis with corticosteroid implants (4 eyes, 4 patients). In the 2nd group (retrospective analysis of the medical history), patients underwent peribulbar administration of betamethasone (9 eyes, 7 patients). The parameters were analyzed after 2.0±0.5, 4.0±0.5 and 6.0±0.5 months with assessment of maximally corrected visual acuity (BCVA), OCT, color photography, and IOP control. The risk of recurrence of macular edema when comparing groups was assessed over a 6-month follow-up period. Results. During the observed period in both groups, no complications were detected in any case. According to visometry and OCT, the best functional results were obtained in group 1. Average visual acuity after 6 months. was 0.7±0.1, the thickness of the retina in the central zone was 331±15µm. Conclusion. According to the results of the study, it was found that intravitreal injection of dexamethasone implant in its effectiveness surpasses the previously used peribulbar injections of betamethasone in terms of the quality of restoration of visual functions, the effectiveness of reducing macular edema and the duration of remission of the chronic inflammatory process. Key words: sarcoidosis, chronic uveitis, macular edema, dexamethasone implant, surgical treatment

Clinically relevant small-molecule promotes nerve repair and visual function recovery

Adult mammalian injured axons regenerate over short-distance in the peripheral nervous system (PNS) while the axons in the central nervous system (CNS) are unable to regrow after injury. Here, we demonstrated that Lycium barbarum polysaccharides (LBP), purified from Wolfberry, accelerated long-distance axon regeneration after severe peripheral nerve injury (PNI) and optic nerve crush (ONC). LBP not only promoted intrinsic growth capacity of injured neurons and function recovery after severe PNI, but also induced robust retinal ganglion cell (RGC) survival and axon regeneration after ONC. By using LBP gene expression profile signatures to query a Connectivity map database, we identified a Food and Drug Administration (FDA)-approved small-molecule glycopyrrolate, which promoted PNS axon regeneration, RGC survival and sustained CNS axon regeneration, increased neural firing in the superior colliculus, and enhanced visual target re-innervations by regenerating RGC axons leading to a partial restoration of visual function after ONC. Our study provides insights into repurposing of FDA-approved small molecule for nerve repair and function recovery.

Complement C3a receptor inactivation attenuates retinal degeneration induced by oxidative damage

Retinal degeneration causes vision loss and threatens the health of elderly individuals worldwide. Evidence indicates that the activation of the complement system is associated with retinal degeneration. However, the mechanism of complement signaling in retinal degeneration needs to be further studied. In this study, we show that the expression of C3 and C3a receptor (C3ar1) is positively associated with the inflammatory response and retinal degeneration. Genetic deletion of C3 and pharmacological inhibition of C3ar1 resulted in the alleviation of neuroinflammation, prevention of photoreceptor cell apoptosis and restoration of visual function. RNA sequencing (RNA-seq) identified a C3ar1-dependent network shown to regulate microglial activation and astrocyte gliosis formation. Mechanistically, we found that STAT3 functioned downstream of the C3-C3ar1 pathway and that the C3ar1-STAT3 pathway functionally mediated the immune response and photoreceptor cell degeneration in response to oxidative stress. These findings reveal an important role of C3ar1 in oxidative-induced retinal degeneration and suggest that intervention of the C3ar1 pathway may alleviate retinal degeneration.

Optogenetic approaches to therapy for inherited retinal degenerations.

Inherited retinal degenerations such as retinitis pigmentosa (RP) affect around one in 4000 people and are the leading cause of blindness in working age adults in several countries. In these typically monogenic conditions, there is progressive degeneration of photoreceptors; however, inner retinal neurons such as bipolar cells and ganglion cells remain largely structurally intact, even in end-stage disease. Therapeutic approaches aiming to stimulate these residual cells, independent of the underlying genetic cause, could potentially restore visual function in patients with advanced vision loss, and benefit many more patients than therapies directed at the specific gene implicated in each disorder. One approach investigated for this purpose is that of optogenetics, a method of neuromodulation that utilises light to activate neurons engineered to ectopically express a light-sensitive protein. Using gene therapy via adeno-associated viral vectors, a range of photosensitive proteins have been expressed in remaining retinal cells in advanced retinal degeneration with in vivo studies demonstrating restoration of visual function. Developing an effective optogenetic strategy requires consideration of multiple factors, including the light-sensitive protein that is used, the vector and method for gene delivery, and the target cell for expression because these in turn may affect the quality of vision that can be restored. Currently, at least four clinical trials are ongoing to investigate optogenetic therapies in patients, with the ultimate aim of reversing visual loss in end-stage disease.

Regulation of rod photoreceptor function by farnesylated G-protein γ-subunits.

Heterotrimeric G-protein transducin, Gt, is a key signal transducer and amplifier in retinal rod and cone photoreceptor cells. Despite similar subunit composition, close amino acid identity, and identical posttranslational farnesylation of their Gγ subunits, rods and cones rely on unique Gγ1 (Gngt1) and Gγc (Gngt2) isoforms, respectively. The only other farnesylated G-protein γ-subunit, Gγ11 (Gng11), is expressed in multiple tissues but not retina. To determine whether Gγ1 regulates uniquely rod phototransduction, we generated transgenic rods expressing Gγ1, Gγc, or Gγ11 in Gγ1-deficient mice and analyzed their properties. Immunohistochemistry and Western blotting demonstrated the robust expression of each transgenic Gγ in rod cells and restoration of Gαt1 expression, which is greatly reduced in Gγ1-deficient rods. Electroretinography showed restoration of visual function in all three transgenic Gγ1-deficient lines. Recordings from individual transgenic rods showed that photosensitivity impaired in Gγ1-deficient rods was also fully restored. In all dark-adapted transgenic lines, Gαt1 was targeted to the outer segments, reversing its diffuse localization found in Gγ1-deficient rods. Bright illumination triggered Gαt1 translocation from the rod outer to inner segments in all three transgenic strains. However, Gαt1 translocation in Gγ11 transgenic mice occurred at significantly dimmer background light. Consistent with this, transretinal ERG recordings revealed gradual response recovery in moderate background illumination in Gγ11 transgenic mice but not in Gγ1 controls. Thus, while farnesylated Gγ subunits are functionally active and largely interchangeable in supporting rod phototransduction, replacement of retina-specific Gγ isoforms by the ubiquitous Gγ11 affects the ability of rods to adapt to background light.

Repair of Retinal Degeneration by Human Amniotic Epithelial Stem Cell-Derived Photoreceptor-like Cells.

The loss of photoreceptors is a major event of retinal degeneration that accounts for most cases of untreatable blindness globally. To date, there are no efficient therapeutic approaches to treat this condition. In the present study, we aimed to investigate whether human amniotic epithelial stem cells (hAESCs) could serve as a novel seed cell source of photoreceptors for therapy. Here, a two–step treatment with combined Wnt, Nodal, and BMP inhibitors, followed by another cocktail of retinoic acid, taurine, and noggin induced photoreceptor–like cell differentiation of hAESCs. The differentiated cells demonstrated the morphology and signature marker expression of native photoreceptor cells and, intriguingly, bore very low levels of major histocompatibility complex (MHC) class II molecules and a high level of non–classical MHC class I molecule HLA–G. Importantly, subretinal transplantation of the hAESCs–derived PR–like cells leads to partial restoration of visual function and retinal structure in Royal College of Surgeon (RCS) rats, the classic preclinical model of retinal degeneration. Together, our results reveal hAESCs as a potential source of functional photoreceptor cells; the hAESCs–derived photoreceptor–like cells could be a promising cell–replacement candidate for therapy of retinal degeneration diseases.