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Emerging trends and hot topics in eye and vision research filled the sessions at this year’s meeting of the Association for Research in Vision and Ophthalmology.
From Ora Staff Reports
Seattle-The growing interest in personalized medicine-a main focus at this year’s meeting of the Association for Research in Vision and Ophthalmology (ARVO)-was reflected in a large number of presentations on genetic approaches to therapy.
Many of these featured applications of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. CRISPR allows for directed, specific “splicing” of disease-associated genes.
For example, Stone et al. investigated the use of CRISPR-based genomic editing for the treatment of CEP290-associated Leber’s congenital amaurosis. This study demonstrated that CRISPR-based genome editing deleted the most common human mutation in CEP290, suggesting a clinically meaningful way to restore CEP290 function without the risk of overexpression toxicity (Stone et al., E-Abstract 1838).
The use of CRISPR in the treatment of retinal degenerative diseases, such as retinitis pigmentosa, was also investigated. Wahlin et al. developed genetically modified, human retinal cell-reporters using CRISPR technology. Using this approach, they tracked retinal development patterns, providing clues that could potentially increase the efficiency and pace of therapeutic photoreceptor generation (Wahlin et al., E-Abstract 2820).
Visit: ARVO 2016 homepage
Several other presentations focused on traditional gene therapy through the use of viruses as delivery/vector systems (e.g., adeno-associated viruses or lentiviruses). Lentiviral vector expressing endostatin and angiostatin (RetinoStat) was administered by subretinal injection to 21 patients with advanced age-related macular degeneration (AMD) and poor anti-vascular endothelial growth factor (VEGF) response. The lentiviral vector safely delivered the two transgenes into aqueous fluid (Lauer A et al., ARVO E-Abstract 4719). Clinical benefits included visual acuity stabilization and a reduction in vascular leakage.
Stem cell therapy
Stem cell application was also a widespread topic, with more than 150 posters and presentations covering developmental biology, cell fate regulation, novel stem cell markers and populations, and therapeutic applications.
A particularly prevalent topic was the therapeutic application of pluripotent stem cell-derived retinal pigment epithelium (RPE). One study showed that autologous, induced pluripotent stem cells are viable and well tolerated 1 year after subretinal transplantation (Kurimoto et al., E-Abstract 3769).
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Two studies took the allogeneic route and used RPE derived from human embryonic stem cells for the treatment of wet AMD (Yin et al., E-Abstract 3742) or Stargardt’s disease (Mehat et al., E- Abstract 3768). Both studies showed that the stem cell-based therapies were well tolerated-suggesting that efficacy trials are on the way for the successful treatments of these blinding diseases.
Dry eye disease was another therapeutic target for stem cell treatment this year. Two notable studies used stem cells to either increase tear production or regenerate tear-producing tissue.
Aluri et al. (E-Abstract 4921) showed that intra-peritoneal injections of bone marrow-derived mesenchymal stem cells increased tear production in a mouse model of Sjögren’s syndrome-suggesting that mesenchymal stem cells have the potential to act at a distance to treat dry eye syndrome. Another study (Massie et al., E-Abstract 5223) combined mesenchymal stem cells with lacrimal gland epithelial cells and human endothelial cells to create secretory spheroids with functionalities similar to lacrimal glands.
Expanding anti-VEGF therapy
Though anti-VEGF therapy is an established therapeutic approach for retinal disorders, treatment options continue to be expanded and refined. Several studies examined whether switching from one VEGF inhibitor to another can be of value to patients who become refractory to treatments. Two presentations showed that aflibercept may provide additional therapeutic benefit to those who are unresponsive to ranibizumab (Kohno T et al., ARVO E-Abstract 514; Gallemore R et al., ARVO E-Abstract 4986).
A phase III efficacy and safety study of a new anti-VEGF is currently ongoing with brolucizumab. Earlier work suggests this new therapy may have a longer duration of effect, allowing for fewer injections and a reduction in the treatment burden for patients (Dugel P et al., ARVO E-Abstract 5018).
Other variations on anti-VEGF therapies explored in studies presented this year include use of combination therapies. For example, addition of topical dorzolamide-timolol therapy to anti-VEGF treatment in 10 subjects with neovascular AMD yielded a significant reduction in macular edema and subretinal fluid (Sridhar J et al., E-Abstract 4441).
Another study, composed of 24 subjects with wet AMD, evaluated efficacy of the anti-angiopoietin (Ang2) monoclonal antibody (RG7716) delivered with an anti-VEGF therapy. This combination therapy was well tolerated and improved both BCVA and OCT parameters (Chakravarthy U et al., E-Abstract 4718).
Another anti-angiogenic, VEGF-independent compound (SH-11037) was studied in combination with aflibercept. This combination appeared to act synergistically in the inhibition of human retinal endothelial cell proliferation and suppression of CNV lesions in vivo (Sulaiman R et al., E-Abstract 1108).
Early results of prosthetic implant studies in retinal disease showed promise. The Argus II electronic epi-retinal prosthesis was successful in the integration of artificial (central) and natural (peripheral) vision when placed within regions of geographic atrophy in late-stage dry AMD patients (Stanga et al., E-Abstract 3733).
In a related approach, Fujikado et al. (E-Abstract 5203) implanted a prosthesis in 3 patients with advanced retinitis pigmentosa and reported data after a 1-year follow-up period. This suprachoroidal-transretinal stimulating prosthesis elicited phosphenes in all 3 patients. The greatest improvements in visual tasks were observed in patients with the electrode array implanted closer to the fovea centralis.
Developing new ways to treat presbyopia is another hot topic, fueled in part by an aging global population. One study investigated several important lens parameters in an attempt to further understand the role of the lens in the process of accommodation (Martinez-Enriquez et al., E-Abstract 1380). More precise estimations of geometrical parameters of the whole lens may be important to providing better IOL selection and customization of premium presbyopia correction solutions.
Another group investigated presbyopic correction using optoelectronic lenses driven by pupil size (Mompeanet al., E-Abstract 1816). Though patients with presbyopia are not able to accommodate to near objects, they usually exhibit almost intact convergence and near-pupil response capabilities. Researchers capitalized on these characteristics to design a device where the optical power of optoelectronic lenses was driven by pupil size. This system was successful in a controlled experimental setting in providing real-time, focused images for objects placed at a variety of distances for presbyopic subjects.
Guoqiang and colleagues proposed a different approach to lens design for presbyopia treatment through a new concept: harmonic diffractive liquid crystal (LC) lenses (Guoqiang et al., E-Abstract 2990). Currently, switchable electro-optic LC lenses offer a revolutionary solution for presbyopia by overcoming the shortcomings of current therapies.
However, developing LC lenses with high-optical quality is difficult to achieve since LC lenses cannot provide the aperture and power needed for spectacle lenses. This group demonstrated harmonic diffractive LC lenses can accomplish vision correction that is not possible with conventional diffractive LC lenses, thereby providing a promising new therapy for the future correction of presbyopia.
The prominent role of interleukins in allergy and inflammation was the subject of several presentations. Notably, one of the more understudied interleukins (IL-33) was shown to have a significant role in an animal model of ragweed conjunctivitis (Asada et al., E-Abstract 306). A different model of allergic conjunctivitis using a papain-soaked contact lens demonstrated that IL-33 knock-out mice had greatly reduced numbers of basophils, indicating for the first time the role of IL-33 in the mediation of cellular chemotaxis in allergic tissue (Sugita et al., E-Abstract 304).
In regard to vernal keratoconjunctivitis, several interleukins (IL-4, 5, 9, 13, and 23)-along with chemokines, such as CCL13, 18, 24, and others-were found to be at a three- to 20-fold increase in RNA expression in conjunctival impression cytology samples from normal subjects.
In contrast, many other inflammatory markers, such as caspase 1 and toll-like receptor 5, were down-regulated (Leonardi et al., E-Abstract 302). The ability to profile RNA from clinical ocular surface samples will allow us to elucidate the mechanisms of allergic disease more easily and precisely.
Inflammation is commonly thought of as a key predicator of disease. However, it is becoming increasingly recognized that a low level of immune activation maintains homeostasis and can restore cellular functionality in chronic stress conditions, such as diabetes. This view of para-inflammation (Xu H, E-Abstract 1398) provides a beneficial role for inflammation that is in contrast to the ever-progressive chronic inflammation associated with diseases, such as AMD.
Science of aging
New pathways associated with the inflammatory response have been identified in recent years, including the cellular autonomous pathway autophagy. Originally recognized as an innate immune defense to infection, autophagy is now recognized as a key pathway in the maintenance of cellular stress and a regulatory of inflammation. Autophagy functions to clean up degraded or damaged mitochondria (mitophagy) or other cellular components.
Several investigators observed how disruptions in this pathway can lead to autophagic “traffic jams” in diseases of retinal degeneration like AMD (Ferrington D, E-Abstract 5650), and in glaucoma (Liton P, E-Abstract 5651) and corneal dystrophies (Kim E, E-Abstract 5652). Due to the role of autophagy in clearing intracellular components, it is not surprising that Kaarniranta (E-Abstract 1400) proposed the role of autophagy in lysosomal clearance and AMD development.
Another common theme was recent advances in the science of aging-including studies of CNS neurodegeneration, age-related changes in the RPE, the influence of aging on the immune system, epigenetic changes with age, and oxidative damage in the retina.
Therapies impacting these age-related defects include SkQ1, a novel antioxidant that accumulates in mitochondria where it is reduced and regenerated, making it a potentially effective target for the treatment of the many disease of oxidative stress. Topical application of SkQ1 caused significant reduction in fibrin and flare reactions using an anterior chamber paracentesis rabbit model (Belen et al., E-Abstract 5414). SkQ1 was also shown to significantly enhance corneal wound healing through enhancement of cell proliferation and migration in an in vitro model (Wei et al., E-Abstract 1255).
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The neural aspects of dry eye were a major topic, with many studies of anatomical and physiological changes in corneal nerve function and how these may impact dry eye disease. In one study, hyperosmolar stress was shown to damage corneal nerve fibers (Mizerska, E-Abstract403), while a second study demonstrated a role for vitamin D deficiency in nerve function (Deshmukh, E-Abstract 2854).
Several presentations established the importance of TrpM8 and TrpV1, membrane sensors responsible for thermo-sensation, as potential players in the signaling pathways impacted by dry eye (Rocha E-Abstract 393, Song, E-Abstract 416, Situ, E-Abstract 2849, Corcoran E-Abstract 2873). In parallel to these studies were those examining thermal imaging techniques to quantify minute temperature changes of the tear film, and their potential impact on evaporative dry eye (Sundstrom, E-Abstract 2851; Li, E-Abstract 2850; Watson, E-Abstract 2858).