2021

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Wendt S, Abdullah Z, Barrett S, Daruwalla C, Go JA, Le B, Li E, Livingston C, Miller M, Nakhleh L, Pecha J, Pothula S, Pradhan S, Sathappan V, Shah A, Sonuyi A-M, Ugoh P, Wang Q, Weber N, Succar T, Blieden L, Mortensen P, Elkin Z, Sun G, Lee AG. A virtual COVID-19 ophthalmology rotation. Surv Ophthalmol 2021;66(2):354-361.Abstract
The coronavirus (COVID-19) pandemic temporarily suspended medical student involvement in clinical rotations, resulting in the need to develop virtual clinical experiences. The cancellation of clinical ophthalmology electives and away rotations reduces opportunities for exposure to the field, to network with faculty, conduct research, and prepare for residency applications. We review the literature and discuss the impact and consequences of COVID-19 on undergraduate medical education with an emphasis on ophthalmic undergraduate medical education. We also discuss innovative learning modalities used from medical schools around the world during the COVID-19 pandemic such as virtual didactics, online cases, and telehealth. Finally, we describe a novel, virtual neuro-ophthalmology elective created to educate medical students on neuro-ophthalmology foundational principles, provide research and presentation opportunities, and build relationships with faculty members. These innovative approaches represent a step forward in further improving medical education in ophthalmology during COVID-19 pandemic and beyond.
White TL, Deshpande N, Kumar V, Gauthier AG, Jurkunas UV. Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy. Free Radic Biol Med 2021;164:34-43.Abstract
Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, with both genetic and environmental factors. In this study, we have provided further insights into the pathogenesis of the disease, showing a causal relationship between senescence and endothelial-mesenchymal transition (EMT) using in vitro and in vivo models. Ultraviolet A (UVA) light induced EMT and senescence in CEnCs. Senescent cells were arrested in G2/M phase of the cell cycle and responsible for the resulting profibrotic phenotype. Inhibiting ATR signaling and subsequently preventing G2/M arrest attenuated EMT. In vivo, UVA irradiation induced cell cycle re-entry in post mitotic CEnCs, resulting in senescence and fibrosis at 1- and 2-weeks post-UVA. Selectively eliminating senescent cells using the senolytic cocktail of dasatinib and quercetin attenuated UVA-induced fibrosis, highlighting the potential for a new therapeutic intervention for FECD.
Whitman MC. Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders. Annu Rev Vis Sci 2021;7:827-850.Abstract
Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.
Whitmore HAB, Amarnani D, O'Hare M, Delgado-Tirado S, Gonzalez-Buendia L, An M, Pedron J, Bushweller JH, Arboleda-Velasquez JF, Kim LA. TNF-α signaling regulates RUNX1 function in endothelial cells. FASEB J 2021;35(2):e21155.Abstract
Runt-related transcription factor 1 (RUNX1) acts as a mediator of aberrant retinal angiogenesis and has been implicated in the progression of proliferative diabetic retinopathy (PDR). Patients with PDR, retinopathy of prematurity (ROP), and wet age-related macular degeneration (wet AMD) have been found to have elevated levels of Tumor Necrosis Factor-alpha (TNF-α) in the eye. In fibrovascular membranes (FVMs) taken from patients with PDR RUNX1 expression was increased in the vasculature, while in human retinal microvascular endothelial cells (HRMECs), TNF-α stimulation causes increased RUNX1 expression, which can be modulated by RUNX1 inhibitors. Using TNF-α pathway inhibitors, we determined that in HRMECs, TNF-α-induced RUNX1 expression occurs via JNK activation, while NF-κB and p38/MAPK inhibition did not affect RUNX1 expression. JNK inhibitors were also effective at stopping high D-glucose-stimulated RUNX1 expression. We further linked JNK to RUNX1 through Activator Protein 1 (AP-1) and investigated the JNK-AP-1-RUNX1 regulatory feedback loop, which can be modulated by VEGF. Additionally, stimulation with TNF-α and D-glucose had an additive effect on RUNX1 expression, which was downregulated by VEGF modulation. These data suggest that the downregulation of RUNX1 in conjunction with anti-VEGF agents may be important in future treatments for the management of diseases of pathologic ocular angiogenesis.
Whitmore HAB, Kim LA. Understanding the Role of Blood Vessels in the Neurological Manifestations of COVID-19. Am J Pathol 2021;Abstract
SARS-CoV-2 was originally identified as an outbreak in Wuhan, China towards the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and MERS type viruses, concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain-barrier. Severe symptoms of infection, termed COVID-19, often result in neurological complications, regardless of patient age. These neurological complications range from mild to severe across all demographics, however, the long-term repercussions of neurological involvement on patient health are still unknown.
Wiegand I, Wolfe JM. Target value and prevalence influence visual foraging in younger and older age. Vision Res 2021;186:87-102.Abstract
The prevalence and reward-value of targets have an influence on visual search. The strength of the effect of an item's reward-value on attentional selection varies substantially between individuals and is potentially sensitive to aging. We investigated individual and age differences in a hybrid foraging task, in which the prevalence and value of multiple target types was varied. Using optimal foraging theory measures, foraging was more efficient overall in younger than older observers. However, the influence of prevalence and value on target selections was similar across age groups, suggesting that the underlying cognitive mechanisms are preserved in older age. When prevalence was varied but target value was balanced, younger and older observers preferably selected the most frequent target type and were biased to select another instance of the previously selected target type. When value was varied, younger and older observers showed a tendency to select high-value targets, but preferences were more diverse between individuals. When value and prevalence were inversely related, some observers showed particularly strong preferences for high-valued target types, while others showed a preference for high-prevalent, albeit low-value, target types. In younger adults, individual differences in the selection choices correlated with a personality index, suggesting that avoiding selections of low-value targets may be related to reward-seeking behaviour.
Wiegand I, Westenberg E, Wolfe JM. Order, please! Explicit sequence learning in hybrid search in younger and older age. Mem Cognit 2021;49(6):1220-1235.Abstract
Sequence learning effects in simple perceptual and motor tasks are largely unaffected by normal aging. However, less is known about sequence learning in more complex cognitive tasks that involve attention and memory processes and how this changes with age. In this study, we examined whether incidental and intentional sequence learning would facilitate hybrid visual and memory search in younger and older adults. Observers performed a hybrid search task, in which they memorized four or 16 target objects and searched for any of those target objects in displays with four or 16 objects. The memorized targets appeared either in a repeating sequential order or in random order. In the first experiment, observers were not told about the sequence before the experiment. Only a subset of younger adults and none of the older adults incidentally learned the sequence. The "learners" acquired explicit knowledge about the sequence and searched faster in the sequence compared to random condition. In the second experiment, observers were told about the sequence before the search task. Both younger and older adults searched faster in sequence blocks than random blocks. Older adults, however, showed this sequence-learning effect only in blocks with smaller target sets. Our findings indicate that explicit sequence knowledge can facilitate hybrid search, as it allows observers to predict the next target and restrict their visual and memory search. In older age, the sequence-learning effect is constrained by load, presumably due to age-related decline in executive functions.
Williams IM, Pineda R, Neerukonda VK, Stagner AM. Mucopolysaccharidosis type I associated corneal disease: A clinicopathologic study. Am J Ophthalmol 2021;Abstract
PURPOSE: To report the anterior segment clinical features as well as histopathologic and histochemical characteristics of corneal findings associated with the largest reported cohort of patients with Hurler Syndrome and other variants of mucopolysaccharidosis (MPS) I undergoing corneal transplantation. DESIGN: Retrospective observational case series. METHODS: SETTING: Institutional PATIENT OR STUDY POPULATION: 15 corneas from 9 patients with MPS-I spectrum disease who underwent corneal transplant to treat corneal clouding between May 2011 and October 2020. INTERVENTION OR OBSERVATION PROCEDURE(S): Review of clinical data, hematoxylin and eosin (H&E) stained sections and histochemical stains, including those for mucopolysaccharides (Alcian blue and/or collodial iron). MAIN OUTCOME MEASURE(S): Pathology observed under light microscopy, as well as, post-surgical clinical outcomes. RESULTS: Nine patients underwent fifteen corneal transplants for corneal clouding (14/15 procedures were deep anterior lamellar keratoplasty). All corneas had mucopolysaccharide deposition visible on H&E stained sections, which was highlighted in blue with histochemical stains. All corneas also showed alterations in Bowman's layer and the majority also showed epithelial abnormalities. CONCLUSION: MPS I shows significant corneal clouding which is successfully treated with deep anterior lamellar keratoplasty. The excised corneas show characteristic epithelial changes, disruption or breaks in Bowman's membrane and amphophilic collections of stromal granular mucopolysaccharides which are visible on H&E stained sections and highlighted by special histochemical stains (Alcian blue and collodial iron). These changes, although subtle, should alert the pathologist to the possibility of an underlying lysosomal storage disorder.
Winter A, Chwalisz B. MRI Characteristics of NMO, MOG and MS Related Optic Neuritis. Semin Ophthalmol 2021;:1-10.Abstract
Acute isolated optic neuritis can be the initial presentation of demyelinating inflammatory central nervous system disease related to multiple sclerosis (MS), neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to the well-characterized brain and spinal cord imaging features, important and characteristic differences in the radiologic appearance of the optic nerves in these disorders are being described, and magnetic resonance imaging (MRI) of the optic nerves is becoming an essential tool in the differential diagnosis of optic neuritis. Whereas typical demyelinating optic neuritis is a relatively mild and self-limited disease, atypical optic neuritis in NMO and MOG-AD is potentially much more vision-threatening and merits a different treatment approach. Thus, differentiation based on MRI features may be particularly important during the first attack of optic neuritis, when antibody status is not yet known. This review discusses the optic nerve imaging in the major demyelinating disorders with an emphasis on clinically relevant differences that can help clinicians assess and manage these important neuro-ophthalmic disorders. It also reviews the utility of optic nerve MRI as a prognostic indicator in acute optic neuritis.
Winter CC, He Z, Jacobi A. Axon Regeneration: A Subcellular Extension in Multiple Dimensions. Cold Spring Harb Perspect Biol 2021;Abstract
Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional deficits. Thus, developing strategies that promote effective axon regeneration for functional restoration is highly desirable. One fruitful approach is to dissect the regenerative mechanisms used by some types of neurons in both mammalian and nonmammalian systems that exhibit spontaneous regenerative capacity. Additionally, numerous efforts have been devoted to deciphering the barriers that prevent successful axon regeneration in the most regeneration-refractory system-the adult mammalian central nervous system. As a result, several regeneration-promoting strategies have been developed, but significant limitations remain. This review is aimed to summarize historic progression and current understanding of this exciting yet incomplete endeavor.
Wishart TFL, Flokis M, Shu DY, Das SJ, Lovicu FJ. Hallmarks of lens aging and cataractogenesis. Exp Eye Res 2021;210:108709.Abstract
Lens homeostasis and transparency are dependent on the function and intercellular communication of its epithelia. While the lens epithelium is uniquely equipped with functional repair systems to withstand reactive oxygen species (ROS)-mediated oxidative insult, ROS are not necessarily detrimental to lens cells. Lens aging, and the onset of pathogenesis leading to cataract share an underlying theme; a progressive breakdown of oxidative stress repair systems driving a pro-oxidant shift in the intracellular environment, with cumulative ROS-induced damage to lens cell biomolecules leading to cellular dysfunction and pathology. Here we provide an overview of our current understanding of the sources and essential functions of lens ROS, antioxidative defenses, and changes in the major regulatory systems that serve to maintain the finely tuned balance of oxidative signaling vs. oxidative stress in lens cells. Age-related breakdown of these redox homeostasis systems in the lens leads to the onset of cataractogenesis. We propose eight candidate hallmarks that represent common denominators of aging and cataractogenesis in the mammalian lens: oxidative stress, altered cell signaling, loss of proteostasis, mitochondrial dysfunction, dysregulated ion homeostasis, cell senescence, genomic instability and intrinsic apoptotic cell death.
Wladis EJ, Aakalu VK, Sobel RK, McCulley TJ, Foster JA, Tao JP, Freitag SK, Yen MT. Interventions for Indirect Traumatic Optic Neuropathy: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(6):928-937.Abstract
PURPOSE: To review the literature on the efficacy and safety of medical and surgical interventions for indirect traumatic optic neuropathy (TON), defined as injury to the nerve that occurs distal to the optic nerve head. METHODS: A literature search was conducted on October 22, 2019, and updated on April 8, 2020, in the PubMed database for English language original research that assessed the effect of various interventions for indirect TON. One hundred seventy-two articles were identified; 41 met the inclusion criteria outlined for assessment and were selected for full-text review and abstraction. On full-text review, a total of 32 studies met all of the study criteria and were included in the analysis. RESULTS: No study met criteria for level I evidence. Seven studies (1 level II study and 6 level III studies) explored corticosteroid therapy that did not have uniformly better outcomes than observation. Twenty studies (3 level II studies and 17 level III studies) assessed optic canal decompression and the use of corticosteroids. Although visual improvement was noted after decompression, studies that directly compared surgery with medical therapy did not report uniformly improved outcomes after decompression. Four studies (1 level II study and 3 level III studies) evaluated the use of erythropoietin. Although initial studies demonstrated benefit, a direct comparison of its use with observation and corticosteroids failed to confirm the usefulness of this medication. One study (level II) documented visual improvement with levodopa plus carbidopa. Complication rates were variable with all of these interventions. Pharmacologic interventions generally were associated with few complications, whereas optical canal decompression carried risks of serious side effects, including hemorrhages and cerebrospinal fluid leakage. CONCLUSIONS: Despite reports of visual improvement with corticosteroids, optic canal decompression, and medical therapy for indirect TON, the weight of published evidence does not demonstrate a consistent benefit for any of these interventions. In summary, no consensus exists from studies published to date on a preferred treatment for TON. Treatment strategies should be customized for each individual patient. More definitive treatment trials will be needed to identify optimal treatment strategies for indirect TON.
Wolfe JM. Guided Search 6.0: An updated model of visual search. Psychon Bull Rev 2021;28(4):1060-1092.Abstract
This paper describes Guided Search 6.0 (GS6), a revised model of visual search. When we encounter a scene, we can see something everywhere. However, we cannot recognize more than a few items at a time. Attention is used to select items so that their features can be "bound" into recognizable objects. Attention is "guided" so that items can be processed in an intelligent order. In GS6, this guidance comes from five sources of preattentive information: (1) top-down and (2) bottom-up feature guidance, (3) prior history (e.g., priming), (4) reward, and (5) scene syntax and semantics. These sources are combined into a spatial "priority map," a dynamic attentional landscape that evolves over the course of search. Selective attention is guided to the most active location in the priority map approximately 20 times per second. Guidance will not be uniform across the visual field. It will favor items near the point of fixation. Three types of functional visual field (FVFs) describe the nature of these foveal biases. There is a resolution FVF, an FVF governing exploratory eye movements, and an FVF governing covert deployments of attention. To be identified as targets or rejected as distractors, items must be compared to target templates held in memory. The binding and recognition of an attended object is modeled as a diffusion process taking > 150 ms/item. Since selection occurs more frequently than that, it follows that multiple items are undergoing recognition at the same time, though asynchronously, making GS6 a hybrid of serial and parallel processes. In GS6, if a target is not found, search terminates when an accumulating quitting signal reaches a threshold. Setting of that threshold is adaptive, allowing feedback about performance to shape subsequent searches. Simulation shows that the combination of asynchronous diffusion and a quitting signal can produce the basic patterns of response time and error data from a range of search experiments.
Woodward AM, Senchyna M, Argüeso P. Short-Term Reproducibility of MUC5AC Measurement in Human Tear Fluid. Diagnostics (Basel) 2021;11(1)Abstract
The assessment of tear fluid components is a common and valuable approach to understanding ocular surface disease and testing the efficacy of novel therapeutic strategies. However, the interpretation and utility of the findings can be limited by changes in the composition of the tear film, particularly in studies requiring repetitive patient sampling. Here, tear samples were collected twice within a one-hour interval to evaluate the short-term reproducibility of an immunoassay aimed to measure the amount of MUC5AC mucin. We found no statistical difference in total protein or MUC5AC content between the two consecutive collections of tear fluid, although the inter-individual variability in each group was high, with coefficients of variation exceeding 30% and 50%, respectively. Scatterplots showed a significant correlation in both protein and MUC5AC following collection within a one-hour interval. These data indicate that, regardless of the high inter-individual variability, repeated collection of tear fluid within an hour interval produces reproducible intra-individual data in terms of MUC5AC mucin content, and suggest that the normal mucin composition of the tear fluid can be re-established within an hour of the initial collection.
Wu DM, Ji X, Ivanchenko MV, Chung M, Piper M, Rana P, Wang SK, Xue Y, West E, Zhao SR, Xu H, Cicconet M, Xiong W, Cepko CL. Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa. JCI Insight 2021;6(2)Abstract
Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2-treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).
Wu W, Xia X, Tang L, Yao F, Xu H, Lei H. Normal vitreous promotes angiogenesis via activation of Axl. FASEB J 2021;35(1):e21152.Abstract
Vitreous has been reported to prevent tumor angiogenesis, but our previous findings indicate that vitreous activate the signaling pathway of phosphoinositide 3-kinase (PI3K)/Akt, which plays a critical role in angiogenesis. The goal of this research is to determine which role of vitreous plays in angiogenesis-related cellular responses in vitro. We found that in human retinal microvascular endothelial cells (HRECs) vitreous activates a number of receptor tyrosine kinases including Anexelekto (Axl), which plays an important role in angiogenesis. Subsequently, we discovered that depletion of Axl using CRISPR/Cas9 and an Axl-specific inhibitor R428 suppress vitreous-induced Akt activation and cell proliferation, migration, and tuber formation of HRECs. Therefore, this line of research not only demonstrate that vitreous promotes angiogenesis in vitro, but also reveal that Axl is one of receptor tyrosine kinases to mediate vitreous-induced angiogenesis in vitro, thereby providing a molecular basis for removal of vitreous as cleanly as possible when vitrectomy is performed in treating patients with proliferative diabetic retinopathy.
Wu C, VanderVeen DK. Impact of higher oxygen saturation levels on postnatal weight gain to predict retinopathy of prematurity. Acta Paediatr 2021;110(8):2348-2349.
Wu F, Goldenberg PC, Mukai S. Bilateral anterior segment dysgenesis and peripheral avascular retina with tractional retinal detachment in an infant with multiple congenital anomalies-hypotony-seizures syndrome 3. Ophthalmic Genet 2021;42(3):334-337.Abstract
Background: Multiple congenital anomalies-hypotony-seizures syndrome 3 (MCAHS3) is a rare autosomal recessive disorder caused by mutations in the PIGT gene. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, which plays a crucial role in protein anchoring to cell membranes. The clinical presentation of MCAHS3 is variable in expression and severity, but can be characterized by developmental delay, seizures, hypotonia, facial dysmorphism, and other abnormalities.Materials and Methods: Case report.Results: We report unusual ocular findings including bilateral anterior segment dysgenesis, avascular retinal periphery, and tractional retinal detachment in a 1-month-old male infant with compound heterozygous PIGT mutations consistent with MCAHS3. Whole-exome sequencing did not detect any other genetic abnormalities.Conclusions: This case expands the clinical spectrum of MCAHS3 to include anomalies in ocular anterior segment and retinal vascular development. Given the rarity and the genetic heterogeneity of MCAHS3, giving rise to varied non-ocular phenotypes, it is possible that milder intraocular phenotypes could have gone unrecognized in the past.
WuDunn D, Takusagawa HL, Sit AJ, Rosdahl JA, Radhakrishnan S, Hoguet A, Han Y, Chen TC. OCT Angiography for the Diagnosis of Glaucoma: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(8):1222-1235.Abstract
PURPOSE: To review the current published literature on the use of OCT angiography (OCTA) to help detect changes associated with the diagnosis of primary open-angle glaucoma. METHODS: Searches of the peer-reviewed literature were conducted in March 2018, June 2018, April 2019, December 2019, and June 2020 in the PubMed and Cochrane Library databases. Abstracts of 459 articles were examined to exclude reviews and non-English articles. After inclusion and exclusion criteria were applied, 75 articles were selected and the panel methodologist rated them for strength of evidence. Three articles were rated level I and 57 articles were rated level II. The 15 level III articles were excluded. RESULTS: OCT angiography can detect decreased capillary vessel density within the peripapillary nerve fiber layer (level II) and macula (level I and II) in patients with suspected glaucoma, preperimetric glaucoma, and perimetric glaucoma. The degree of vessel density loss correlates significantly with glaucoma severity both overall and topographically (level II) as well as longitudinally (level I). For differentiating glaucomatous from healthy eyes, some studies found that peripapillary and macular vessel density measurements by OCTA show a diagnostic ability (area under the receiver operating characteristic curve) that is comparable with structural OCT retinal nerve fiber and ganglion cell thickness measurements, whereas other studies found that structural OCT measurements perform better. Choroidal or deep-layer microvasculature dropout as measured by OCTA is also associated with glaucoma damage (level I and II). Lower peripapillary and macular vessel density and choroidal microvasculature dropout are associated with faster rates of disease progression (level I and II). CONCLUSIONS: Vessel density loss associated with glaucoma can be detected by OCTA. Peripapillary, macular, and choroidal vessel density parameters may complement visual field and structural OCT measurements in the diagnosis of glaucoma.
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Xie L, Yin Y, Benowitz L. Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy. Proc Natl Acad Sci U S A 2021;118(9)Abstract
Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we investigated whether CNTF gene therapy acts indirectly through other immune mediators. The beneficial effects of CNTF gene therapy remained unchanged after deleting CNTF receptor alpha (CNTFRα) in retinal ganglion cells (RGCs), the projection neurons of the retina, but were diminished by depleting neutrophils or by genetically suppressing monocyte infiltration. CNTF gene therapy increased expression of C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, and recombinant CCL5 induced extensive axon regeneration. Conversely, CRISPR-mediated knockdown of the cognate receptor (CCR5) in RGCs or treating wild-type mice with a CCR5 antagonist repressed the effects of CNTF gene therapy. Thus, CCL5 is a previously unrecognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy.

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