Abstract: Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients. This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level, though the actual mechanism of repair still needs further investigations. The immune system responds in several ways upon photoreceptor engraftment, resulting in T-cell and macrophage infiltrations and, consequently, decrease in graft survival. Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting. Conversely, the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms. Here, Neves and colleagues explored the potential of cross-species studies and, to a certain extent, the concept of a protective immune system in retinal degeneration and therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF) was identified in this study as a novel factor that, by modulating the immune system, can slow down photoreceptor degeneration and improve transplantation outcome.
Background: Zellweger spectrum disorder (ZSD) is an autosomal recessive disease caused by mutations in any one of 13 PEX genes whose protein products are required for peroxisome assembly. Retinopathy leading to blindness is one of the major handicaps faced by affected individuals, but treatment for this is supportive only. To test whether we could improve visual function in ZSD, we performed a proof-of-concept trial for PEX1 gene augmentation therapy using the Pex1-G844D mouse model, which bears the equivalent to a common human mutation. This model exhibits a gradual decline in scotopic ffERG response, an always residual photopic ffERG response, diminished visual acuity, and cone and bipolar cell anomalies.
Methods: We administered subretinal injections of a PEX1-containing viral vector (AAV8.CMV.hPEX1.HA) to 2 mouse cohorts of 5 or 9 weeks of age. A GFP-containing vector was used as a control in the contralateral eye of each animal. Efficient expression of the virus was confirmed by retinal histology/immunohistochemistry, and its ability to recover peroxisome import was confirmed in vitro. Preliminary ffERG and optokinetic (OKN) analyses were performed on a subset of animals at 8, 16, and 20 weeks after gene delivery. Final ffERG and OKN measures were performed when each cohort reached 32 weeks of age (23 or 27 weeks post injection).
Results: Preliminary ffERG and OKN analyses at 8 weeks post injection showed mildly better retinal response and visual acuity, respectively, in the PEX1-injected eyes, as did ffERG analysis when each cohort reached 25 weeks of age (16 or 20 weeks after gene delivery). This effect was more pronounced in the cohort treated at 5 weeks of age, when ffERG response is highest in Pex1-G844D mice. At 32 weeks of age, the ffERG response in the PEX1-injected eyes was double that of GFP-injected eyes, on average, though there was no change in OKN. Furthermore, in PEX1-injected eyes the photopic ffERG response improved over time, and the decline in scotopic b-wave amplitude was ameliorated compared to un-injected eyes.
Conclusions: AAV8.CMV.hPEX1.HA was subretinally delivered into the left eye of 5- and 9-week-old Pex1-G844D retina. Successful expression of the protein with no gross histologic side effect was observed. Neither the injection, nor exposure to the AAV8 capsid or the transgenic protein negatively altered the ERG or OKN response. At 5–6 months after gene delivery, therapeutic vector-treated eyes showed improved ERG compared to control eyes, on average, in both the “prevention” and “recovery” cohorts. This implies clinical potential of gene delivery to improve vision in patients with ZSD. Retinal immunohistochemistry (to visualize retinal cell types) and biochemical analyses will be performed on treated and untreated retinas, and may inform the mechanism of ERG improvement.
Abstract: Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRD, with the first approved gene therapy and the commencement of multiple therapy trials. The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD. Herein we present in a comprehensive and concise manner the imaging findings of: (I) macular dystrophies (MD) [Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), pattern dystrophy (PRPH2), Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)], (II) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4 and RPGR), (III) cone dysfunction syndromes [achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6], blue-cone monochromatism (OPN1LW/OPN1MW array), oligocone trichromacy, bradyopsia (RGS9/R9AP) and Bornholm eye disease (OPN1LW/OPN1MW), (IV) Leber congenital amaurosis (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (V) rod-cone dystrophies [retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)], (VI) rod dysfunction syndromes (congenital stationary night blindness, fundus albipunctatus (RDH5), Oguchi disease (SAG, GRK1), and (VII) chorioretinal dystrophies [choroideremia (CHM), gyrate atrophy (OAT)].
Abstract: Hereditary, metabolic and toxic optic neuropathies cause bilateral, central vision loss and therefore can result in severe impairment in visual function. Accurate, early diagnosis is critical, as nutritional and toxic optic neuropathies may be reversible if identified early, and diagnosis of hereditary optic neuropathies can prevent unnecessary invasive workup, provide prognostic information, and allow for effective genetic counseling. Optical coherence tomography (OCT) is a valuable tool that aids in the diagnosis and prognostication of optic neuropathies as it allows for quantification of changes in the retinal ganglion cells (RGCs) and retinal nerve fiber layer (RNFL) over time. We review the characteristic clinical presentations of hereditary, metabolic and toxic optic neuropathies, with an emphasis on OCT findings.
Abstract: Effective and safe electrical stimulation of the retinal ganglion cells is at the heart of retinal prosthesis design. However, the effectiveness and safety demand of the electrical stimulation is often at odds against each other. Besides, the nerve fiber layer above retinal ganglion cells limits the spatial resolution of stimulation. Also, current retinal prosthesis still cannot selectively activate the ON or OFF visual pathways, thus cannot relay the correct luminance information to the brain. With decades of development, the stimulation protocol for retinal implants began to tackle these problems. We believe that a novel design of electrical stimulation scheme, combined with gene therapy technique, can improve the selectivity and spatial resolution of retinal implants and further lower the damage caused by electric stimulation.
Abstract: Age-related macular degeneration (AMD) remains a leading cause of severe visual impairment in developing countries. Although dry-type AMD and geographic atrophy (GA) are progressive conditions with the associated decrease of visual functions, no well-established treatment regimen was proposed for the disease. Wet-type AMD is effectively treated with intravitreal anti-angiogenic agents, but frequent injections are a major issue for the affected patients. Recent advances in AMD genetics have provided new insights into the pathogenesis and novel therapeutic targets of AMD, but the benefits of using genetic testing and genotype-based risk models for AMD development and progression still lacks evidence. Novel AMD treatments aim to increase the interval among intravitreal injections through new therapeutic agents and modern delivery devices. Simultaneously, gene therapy for dry and wet AMD is widely studied. Although gene therapy possesses a major superiority over other novel treatments regarding a persistent cure of disease, many challenges exist in the way of its broad impact on the ocular health of AMD patients.
Abstract: Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neurosensory retina. Currently, there are limited treatment options for dry AMD outside of lifestyle modification and nutrient supplementation. Risuteganib [Luminate (ALG-1001), Allegro Ophthalmics, CA, USA] is an intravitreally administered inhibitor of integrin heterodimers αVβ3, αVβ5, α5β1, and αMβ2. It is currently undergoing clinical trials for the treatment of dry AMD and diabetic macular edema (DME). Preclinical studies have shown that risuteganib has an effect on the pathways for angiogenesis, inflammation, and vascular permeability. Ongoing clinical trials have had promising results showing improvements in patient best corrected visual acuity (BCVA) and reduced central macular thickness measured by optical coherence tomography (OCT). There is a pressing need for treatments for dry AMD and while risuteganib appears to have a potential benefit for patients, more data are needed before one can truly evaluate its efficacy. This narrative review provides a concise summary of the most up to date data regarding the proposed mechanism of action of risuteganib in the treatment of nonexudative AMD and DME as well as the results from recent phase 1 and phase 2 clinical trials.
