Explore the vast range of titles available.

Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.

Usher syndrome type 1 (USH1) is a major cause of inherited deafness and blindness in humans. The eye disorder is often referred to as retinitis pigmentosa, which is characterized by a secondary cone degeneration following the rod loss. The development of treatments to prevent retinal degeneration has been hampered by the lack of clear evidence for retinal degeneration in mutant mice deficient for the Ush1 genes, which instead faithfully mimic the hearing deficit. We show that, under normal housing conditions, Ush1g −/− and Ush1c −/− albino mice have dysfunctional cone photoreceptors whereas pigmented knockout animals have normal photoreceptors. The key involvement of oxidative stress in photoreceptor apoptosis and the ensued retinal gliosis were further confirmed by their prevention when the mutant mice are reared under darkness and/or supplemented with antioxidants. The primary degeneration of cone photoreceptors contrasts with the typical forms of retinitis pigmentosa. Altogether, we propose that oxidative stress probably accounts for the high clinical heterogeneity among USH1 siblings, which also unveils potential targets for blindness prevention.

The use of human donor tissue has the potential to accelerate translational research and support the development of effective human medicines. However, post-mortem sample degradation and the loss of anatomical context limits the utility of primary tissue. Here, an ex vivo perfusion platform, the Advancing Straight-to-Human Eye Research (ASTHER) system, was designed to perfuse whole eyes with autologous blood to support ex vivo viability. The system was designed for portability and compatibility with modern surgical techniques. Feasibility trials of ophthalmic artery cannulation, arterial perfusion, retinal imaging, and electroretinography with the ASTHER platform were performed. Qualitative imaging and electroretinography confirmed post-enucleation retinal blood supply and neuronal function in perfused Yucatan mini pig eyes. Retinal surgery was performed in perfused eyes. A pilot study showed the applicability of the minipig enucleation and perfusion protocol in donated human tissue. Future validation studies of the ASTHER platform will quantify perfused tissue structure and function.

Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.

Since gene therapy does not allow replacement of cells, delivering the healthy gene would affect only the surviving photoreceptors. Because part of the visual loss in RPE65-associated retinal degeneration is due to dysfunction, this has been an ideal target for some recovery of visual function, and indeed treatment has resulted in substantial improvement in vision that has endured for at least 3 years.8 Choroideremia is a rare monogenic retinal degenerative disease, but its pattern of neurodegeneration is representative of a much larger group of photoreceptor degenerative disorders--ie, retinitis pigmentosa and other rod-cone dystrophies.

Background The development of a functional retinal prosthesis for acquired blindness is a great challenge. Rapid progress in the field over the last 15 years would not have been possible without extensive animal experimentation pertaining to device design and fabrication, biocompatibility, stimulation parameters and functional responses. This paper presents an overview of in vivo animal research related to retinal prosthetics, and aims to summarize the relevant studies. Methods A Pubmed search of the English language literature was performed. The key search terms were: retinal implant, retinal prosthesis, artificial vision, rat, rabbit, cat, dog, sheep, pig, minipig. In addition a manual search was performed based on references quoted in the articles retrieved through Pubmed. Results We identified 50 articles relevant to in vivo animal experimentation directly related to the development of a retinal implant. The highest number of publications related to the cat ( n  = 18). Conclusion The contribution of animal models to the development of retinal prosthetic devices has been enormous, and has led to human feasibility studies. Grey areas remain regarding long-term tissue-implant interactions, biomaterials, prosthesis design and neural adaptation. Animals will continue to play a key role in this rapidly evolving field.

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies. Nephrophthisis (NPH) is a common manifestation of ciliopathy diseases. Here the authors identify mutations in intraflagellar transport 54 (IFT54) in patients with NPH and discover an extra-ciliary role for IFT54 in regulating cytoplasmic microtubule dynamics, that contributes to the pathophysiology of this disease.

ObjectivesThis study aimed to evaluate the suitability of the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) for measuring vision-related quality of life (VRQoL) in patients with Leber hereditary optic neuropathy receiving lenadogene nolparvovec gene therapy in three Phase III randomised controlled clinical trials.MethodsVRQoL was assessed using the NEI-VFQ-25 at baseline (n=174) and 2 years after treatment (n=152). All participants received lenadogene nolparvovec in at least one eye. The scoring structure of the original NEI-VFQ-25 was evaluated for fit to the Rasch model, and a post hoc revision was created and psychometrically reevaluated. Stacked analysis was conducted to compare Rasch-revised scores at baseline and 2 years after treatment.ResultsThe original NEI-VFQ-25 exhibited multiple issues including limitations in response functioning and scale dimensionality. These issues were rectified by revising the NEI-VFQ25 into two separate unidimensional scales measuring ‘Vision-related Activity Limitation’ (VAL) and ‘Socioemotional Functioning’ (SEF). Participants’ mean VAL score at baseline on a Rasch-transformed 0–100 scale was 46.1 (11.7), improving to 48.4 (13.7) after treatment (F(1, 324) = 2.67, p=0.103). On the SEF scale, there was a significant difference 2 years after treatment, with participants improving from a mean score of 40.1 (14.1) at baseline to 49.6 (17.6) (F(1, 324) = 29.1, p<0.001).ConclusionsThe scoring structure of the original NEI-VFQ-25 has limitations that undermine its psychometric validity as a measure of VRQoL. Using the Rasch-revised NEI-VFQ-25, we determined that improvement in VRQoL after treatment with lenadogene nolparvovec was driven predominantly by an improvement in socioemotional functioning.

Cell death is often related to an abnormal increase in Ca(2+) flux. In the retina, Ca(2+) channels are mainly from the L-type that do not inactivate with time. Under excitotoxic and ischemic conditions, their continuous activation may therefore contribute significantly to the lethal Ca(2+) influx. To assess this hypothesis, the Ca(2+) channel blocker, diltiazem, was applied in excitotoxic and ischemic conditions. To induce excitotoxicity, retinal cell cultures from newborn rats were incubated with glutamate. The toxicity of glutamate was quantified by neuronal immunostaining with an antibody directed against the neuron specific enolase. Glutamate receptor function in vitro was assessed in pig retinal cell cultures by patch clamp recording. Retinal ischemia was induced by raising the intraocular pressure in adult rats. Retinal cell loss was quantified on retinal sections by measuring nuclear cell densities. In retinal cell culture, glutamate application induced a major cell loss. This cell loss was attributed to glutamate excitotoxicity because glutamate receptor blockers like MK-801 and CNQX increased significantly neuronal survival. MK-801 and CNQX, which block NMDA and AMPA/Kainate receptors, respectively, had additive effects. Expression of AMPA/Kainate glutamate receptors in mixed adult retinal cell cultures was attested by patch clamp recording. In newborn rat retinal culture, glutamate excitotoxicity was significantly reduced by addition of the L-type Ca(2+) channel blocker, diltiazem. In in vivo experiments, the increase in ocular pressure induced a decrease in cell number in the inner nuclear and ganglion cell layers. When animals received diltiazem injections, the ischemic treatment induced a less severe reduction in retinal cells; this neuroprotection was statistically significant in the ganglion cell layer. These results are consistent with previous studies suggesting that Ca(2+) channel activation contributes to retinal cell death following either glutamate excitotoxicity or retinal ischemia. Under both conditions, the L-type Ca(2+) channel blocker, diltiazem, can limit cell death. These results extend the potential application of diltiazem in retinal neuroprotection to retinal pathologies involving glutamate excitotoxicity and ischemia.

Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-[alpha], and TGF-[beta]2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.