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Ophthalmology

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REP1-deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia
Dulce Lima Cunha, … , Ailsa A. Welch, Mariya Moosajee
Dulce Lima Cunha, … , Ailsa A. Welch, Mariya Moosajee
Published March 23, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146934.
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REP1-deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

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Abstract

Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy caused by mutations in CHM, encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE) and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated, hence, in this study whole metabolomic analysis of plasma samples from 25 CHM patients versus age and gender matched controls was performed. Results showed plasma alterations in oxidative stress-related metabolites, coupled with alterations in tryptophan metabolism leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, and imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chmru848 zebrafish provided further evidence for dysfunction, with the use of Fenofibrates over Simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes novel pathomechanisms and targets for therapeutic consideration.

Authors

Dulce Lima Cunha, Rose Richardson, Dhani Tracey-White, Alessandro Abbouda, Andreas Mitsios, Verena Horneffer-van der Sluis, Panteleimon Takis, Nicholas Owen, Jane Skinner, Ailsa A. Welch, Mariya Moosajee

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Autophagy stimulation reduces ocular hypertension in murine glaucoma model via autophagic degradation of mutant myocilin
Ramesh B. Kasetti, … , Val C. Sheffield, Gulab S. Zode
Ramesh B. Kasetti, … , Val C. Sheffield, Gulab S. Zode
Published February 4, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.143359.
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Autophagy stimulation reduces ocular hypertension in murine glaucoma model via autophagic degradation of mutant myocilin

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Abstract

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) damage is associated with Primary Open Angle Glaucoma (POAG). Myocilin mutations resulting in elevated IOP are the most common genetic cause of POAG. We have previously shown that mutant myocilin accumulates in the endoplasmic reticulum (ER) and induces chronic ER stress, leading to TM damage and IOP elevation. However, it is not understood how chronic ER stress leads to TM dysfunction and loss. Here, we report that mutant myocilin activates autophagy but it is functionally impairecd in cultured human trabecular meshwork (TM) cells and in a mouse model of myocilin-associated POAG (Tg-MYOCY437H). Genetic and pharmacological inhibition of autophagy worsens mutant myocilin accumulation and exacerbates IOP elevation in Tg-MYOCY437H mice. Remarkably, impaired autophagy is associated with chronic ER stress-induced transcriptional factor, CHOP. Deletion of CHOP corrects impaired autophagy, enhances recognition and degradation of mutant myocilin by autophagy,and reduces glaucoma in Tg-MYOCY437H mice. Stimulating autophagic flux via Tat-beclin 1 peptide or torin 2, promotes autophagic degradation of mutant myocilin and reduces elevated IOP in Tg-MYOCY437H mice. Together, our studies provide a novel treatment strategy for myocilin-associated POAG by correcting impaired autophagy in the TM.

Authors

Ramesh B. Kasetti, Prabhavathi Maddineni, Charles C. Kiehlbauch, Shruti Patil, Charles C. Searby, Beth Levine, Val C. Sheffield, Gulab S. Zode

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Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa
David M. Wu, … , Wenjun Xiong, Constance L. Cepko
David M. Wu, … , Wenjun Xiong, Constance L. Cepko
Published January 25, 2021
Citation Information: JCI Insight. 2021;6(2):e145029. https://doi.org/10.1172/jci.insight.145029.
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Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

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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).

Authors

David M. Wu, Xuke Ji, Maryna V. Ivanchenko, Michelle Chung, Mary Piper, Parimal Rana, Sean K. Wang, Yunlu Xue, Emma West, Sophia R. Zhao, Hongbin Xu, Marcelo Cicconet, Wenjun Xiong, Constance L. Cepko

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Evolution of ocular defects in infant macaques following in utero zika virus infection
Glenn Yiu, … , Lark L. Coffey, Koen K.A. Van Rompay
Glenn Yiu, … , Lark L. Coffey, Koen K.A. Van Rompay
Published November 12, 2020
Citation Information: JCI Insight. 2020. https://doi.org/10.1172/jci.insight.143947.
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Evolution of ocular defects in infant macaques following in utero zika virus infection

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Abstract

Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously-described model of CZS by infecting pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester, we characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of these animals exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging, as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared to healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies, but does not appear to affect postnatal ocular growth.

Authors

Glenn Yiu, Sara M. Thomasy, M. Isabel Casanova, Alexander M. Rusakevich, Rebekah I. Keesler, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Erin E. Ball, Eliza Bliss-Moreau, Wendi Guo, Helen Webster, Tulika Singh, Sallie R. Permar, Amir Ardeshir, Lark L. Coffey, Koen K.A. Van Rompay

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IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants
Bertan Cakir, … , Chatarina Löfqvist, Lois E.H. Smith
Bertan Cakir, … , Chatarina Löfqvist, Lois E.H. Smith
Published October 2, 2020
Citation Information: JCI Insight. 2020;5(19):e140363. https://doi.org/10.1172/jci.insight.140363.
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IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants

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Abstract

BACKGROUND Hyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood.METHODS In 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy.RESULTS The highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r(39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001).CONCLUSION In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.TRIAL REGISTRATION ClinicalTrials.gov NCT02760472 (Donna Mega).FUNDING This study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner.

Authors

Bertan Cakir, William Hellström, Yohei Tomita, Zhongjie Fu, Raffael Liegl, Anna Winberg, Ingrid Hansen-Pupp, David Ley, Ann Hellström, Chatarina Löfqvist, Lois E.H. Smith

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Organogenesis and distribution of the ocular lymphatic vessels in the anterior eye
Yifan Wu, … , Alex S. Huang, Young-Kwon Hong
Yifan Wu, … , Alex S. Huang, Young-Kwon Hong
Published July 9, 2020
Citation Information: JCI Insight. 2020;5(13):e135121. https://doi.org/10.1172/jci.insight.135121.
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Organogenesis and distribution of the ocular lymphatic vessels in the anterior eye

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Abstract

Glaucoma surgeries, such as trabeculectomy, are performed to lower intraocular pressure to reduce risk of vision loss. These surgeries create a new passage in the eye that reroutes the aqueous humor outflow to the subconjunctival space, where the fluid is presumably absorbed by the conjunctival lymphatics. Here, we characterized the development and function of the ocular lymphatics using transgenic lymphatic reporter mice and rats. We found that the limbal and conjunctival lymphatic networks are progressively formed from a primary lymphatic vessel that grows from the nasal-side medial canthus region at birth. This primary lymphatic vessel immediately branches out, invades the limbus and conjunctiva, and bidirectionally encircles the cornea. As a result, the distribution of the ocular lymphatics is significantly polarized toward the nasal side, and the limbal lymphatics are directly connected to the conjunctival lymphatics. New lymphatic sprouts are produced mainly from the nasal-side limbal lymphatics, posing the nasal side of the eye as more responsive to fluid drainage and inflammatory stimuli. Consistent with this polarized distribution of the ocular lymphatics, a higher drainage efficiency was observed in the nasal side than the temporal side of the eye when injected with a fluorescent tracer. In contrast, blood vessels are evenly distributed at the anterior surface of the eyes. Also, we found that these distinct vascular distribution patterns were conserved in human eyes. Together, our study demonstrated that the ocular surface lymphatics are more densely present in the nasal side and uncovered the potential clinical benefits in selecting the nasal side as a glaucoma surgery site to improve fluid drainage.

Authors

Yifan Wu, Young Jin Seong, Kin Li, Dongwon Choi, Eunkyung Park, George H. Daghlian, Eunson Jung, Khoa Bui, Luping Zhao, Shrimika Madhavan, Saren Daghlian, Patill Daghlian, Desmond Chin, Il-Taeg Cho, Alex K. Wong, Martin Heur, Sandy Zhang-Nunes, James C. Tan, Masatsugu Ema, Tina T. Wong, Alex S. Huang, Young-Kwon Hong

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Selective LXR agonist DMHCA corrects retinal and bone marrow dysfunction in type 2 diabetes
Cristiano P. Vieira, … , Julia V. Busik, Maria B. Grant
Cristiano P. Vieira, … , Julia V. Busik, Maria B. Grant
Published July 9, 2020
Citation Information: JCI Insight. 2020;5(13):e137230. https://doi.org/10.1172/jci.insight.137230.
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Selective LXR agonist DMHCA corrects retinal and bone marrow dysfunction in type 2 diabetes

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Abstract

In diabetic dyslipidemia, cholesterol accumulates in the plasma membrane, decreasing fluidity and thereby suppressing the ability of cells to transduce ligand-activated signaling pathways. Liver X receptors (LXRs) make up the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N, N-dimethyl-3β-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. In this study, we use a multisystem approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic (db/db) mice and human circulating angiogenic cells (CACs), which are hematopoietic progenitor cells with vascular reparative capacity. We found that DMHCA is sufficient to correct retinal and BM dysfunction in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis; rejuvenating membrane fluidity in CACs; hampering systemic inflammation; and correcting BM pathology. Using single-cell RNA sequencing on lineage–sca1+c-Kit+ (LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide potentially novel insights into hematopoiesis and reveal DMHCA’s mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the beneficial effects of DMHCA treatment on diabetes-induced retinal and BM pathology.

Authors

Cristiano P. Vieira, Seth D. Fortmann, Masroor Hossain, Ana Leda Longhini, Sandra S. Hammer, Bright Asare-Bediako, David K. Crossman, Micheli S. Sielski, Yvonne Adu-Agyeiwaah, Mariana Dupont, Jason L. Floyd, Sergio Li Calzi, Todd Lydic, Robert S. Welner, Gary J. Blanchard, Julia V. Busik, Maria B. Grant

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Retinal microglia are critical for subretinal neovascular formation
Ayumi Usui-Ouchi, … , Stephen Bravo, Martin Friedlander
Ayumi Usui-Ouchi, … , Stephen Bravo, Martin Friedlander
Published May 21, 2020
Citation Information: JCI Insight. 2020. https://doi.org/10.1172/jci.insight.137317.
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Retinal microglia are critical for subretinal neovascular formation

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Abstract

Abnormal subretinal neovascularization is characteristic of vision-threatening retinal diseases including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very low-density lipoprotein receptor mutant mice (Vldlr–/–). These changes mirror those observed in MacTel and RAP patients, but the pathogenesis is largely unknown. In this study, we show that retinal microglia are closely associated with retinal neovascular tufts in Vldlr–/– mice and retinal tissue from MacTel patients; ablation of microglia/macrophages dramatically prevents formation of retinal neovascular tufts and improves neuronal function as assessed by electroretinography. VMD2-driven retinal pigmented epithelium (RPE)-specific knockouts of VEGF greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing NV tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of NV, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in MacTel and RAP patients, and suggest that targeting microglia activation may be a therapeutic option in these diseases.

Authors

Ayumi Usui-Ouchi, Yoshihiko Usui, Toshihide Kurihara, Edith Aguilar, Michael I. Dorrell, Yoichiro Ideguchi, Susumu Sakimoto, Stephen Bravo, Martin Friedlander

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In vivo directed evolution of AAV in the primate retina
Leah C. Byrne, … , David V. Schaffer, John G. Flannery
Leah C. Byrne, … , David V. Schaffer, John G. Flannery
Published April 9, 2020
Citation Information: JCI Insight. 2020. https://doi.org/10.1172/jci.insight.135112.
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In vivo directed evolution of AAV in the primate retina

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Abstract

Efficient AAV-mediated gene delivery remains a significant obstacle to effective retinal gene therapies. Here, we apply directed evolution - guided by deep sequencing and followed by direct in vivo secondary selection of high-performing vectors with a GFP-barcoded library - to create AAV viral capsids with new capabilities to deliver genes to the outer retina in primates. A replication incompetent library, produced via providing rep in trans, was created to mitigate risk of AAV propagation. Six rounds of in vivo selection with this library in primates, involving intravitreal library administration, recovery of genomes from outer retina, and extensive next generation sequencing of each round, resulted in vectors with redirected tropism to the outer retina and increased gene delivery efficiency to retinal cells. These new viral vectors expand the toolbox of vectors available for primate retina, and may enable less invasive delivery of therapeutic genes to patients, potentially offering retina-wide infection at a similar dosage to vectors currently in clinical use.

Authors

Leah C. Byrne, Timothy P. Day, Meike Visel, Cécile Fortuny, Deniz Dalkara, William H. Merigan, David V. Schaffer, John G. Flannery

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Multiexon deletion alleles of ATF6 linked to achromatopsia
Eun-Jin Lee, … , Joseph Carroll, Jonathan H. Lin
Eun-Jin Lee, … , Joseph Carroll, Jonathan H. Lin
Published April 9, 2020
Citation Information: JCI Insight. 2020;5(7):e136041. https://doi.org/10.1172/jci.insight.136041.
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Multiexon deletion alleles of ATF6 linked to achromatopsia

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Abstract

Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8–14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease.

Authors

Eun-Jin Lee, Wei-Chieh Jerry Chiang, Heike Kroeger, Chloe Xiaoke Bi, Daniel L. Chao, Dorota Skowronska-Krawczyk, Rebecca R. Mastey, Stephen H. Tsang, Leon Chea, Kyle Kim, Scott R. Lambert, Julia M.D. Grandjean, Britta Baumann, Isabelle Audo, Susanne Kohl, Anthony T. Moore, R. Luke Wiseman, Joseph Carroll, Jonathan H. Lin

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