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1. Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10

Author

Pechhacker, Monika K Grudzinska, Jacobson, Samuel G, Drack, Arlene V, Di Scipio, Matteo, Strubbe, Ine, Pfeifer, Wanda, Duncan, Jacque L, Dollfus, Helene, Goetz, Nathalie, Muller, Jean, Vincent, Andrea L, Aleman, Tomas S, Tumber, Anupreet, Van Cauwenbergh, Caroline, De Baere, Elfride, Bedoukian, Emma, Leroy, Bart P, Maynes, Jason T, Munier, Francis L, Tavares, Erika, Saleh, Eman, Vincent, Ajoy, and Heon, Elise

Subjects
Rare Diseases, Neurosciences, Eye Disease and Disorders of Vision, Clinical Research, Eye, Adolescent, Adult, Bardet-Biedl Syndrome, Chaperonins, Child, Child, Preschool, Electroretinography, Female, Humans, Male, Microtubule-Associated Proteins, Middle Aged, Mutation, Missense, Optical Imaging, Refraction, Ocular, Retina, Retinal Dystrophies, Retrospective Studies, Tomography, Optical Coherence, Visual Acuity, Visual Field Tests, Visual Fields, blindness, Bardet Biedl syndrome, retinal degeneration, genetics, natural history, end points, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

PurposeThe purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10.MethodsPatients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected.ResultsSixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1.ConclusionsRetinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS.

Published
2021

2. The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy

Author

Wissinger, Bernd, Baumann, Britta, Buena-Atienza, Elena, Ravesh, Zeinab, Cideciyan, Artur V., Stingl, Katarina, Audo, Isabelle, Meunier, Isabelle, Bocquet, Beatrice, Traboulsi, Elias I., Hardcastle, Alison J., Gardner, Jessica C., Michaelides, Michel, Branham, Kari E., Rosenberg, Thomas, Andreasson, Sten, Dollfus, Hélène, Birch, David, Vincent, Andrea L., Martorell, Loreto, Mora, Jaume Català, Kellner, Ulrich, Rüther, Klaus, Lorenz, Birgit, Preising, Markus N., Manfredini, Emanuela, Zarate, Yuri A., Vijzelaar, Raymon, Zrenner, Eberhart, Jacobson, Samuel G., and Kohl, Susanne

Published
2022

4. Night vision restored in days after decades of congenital blindness

Author

Jacobson, Samuel G., Cideciyan, Artur V., Ho, Allen C., Roman, Alejandro J., Wu, Vivian, Garafalo, Alexandra V., Sumaroka, Alexander, Krishnan, Arun K., Swider, Malgorzata, Mascio, Abraham A., Kay, Christine N., Yoon, Dan, Fujita, Kenji P., Boye, Sanford L., Peshenko, Igor V., Dizhoor, Alexander M., and Boye, Shannon E.

Published
2022
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5. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

Author

Russell, Stephen R., Drack, Arlene V., Cideciyan, Artur V., Jacobson, Samuel G., Leroy, Bart P., Van Cauwenbergh, Caroline, Ho, Allen C., Dumitrescu, Alina V., Han, Ian C., Martin, Mitchell, Pfeifer, Wanda L., Sohn, Elliott H., Walshire, Jean, Garafalo, Alexandra V., Krishnan, Arun K., Powers, Christian A., Sumaroka, Alexander, Roman, Alejandro J., Vanhonsebrouck, Eva, Jones, Eltanara, Nerinckx, Fanny, De Zaeytijd, Julie, Collin, Rob W. J., Hoyng, Carel, Adamson, Peter, Cheetham, Michael E., Schwartz, Michael R., den Hollander, Wilhelmina, Asmus, Friedrich, Platenburg, Gerard, Rodman, David, and Girach, Aniz

Published
2022
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8. Translational Retinal Research and Therapies.

Author

Hardcastle, Alison J, Sieving, Paul A, Sahel, José-Alain, Jacobson, Samuel G, Cideciyan, Artur V, Flannery, John G, Beltran, William A, and Aguirre, Gustavo D

Subjects
Leber congenital amaurosis, X-linked Retinoschisis, animal models, retinitis pigmentosa, Biomedical Engineering, Opthalmology and Optometry
Abstract

The following review summarizes the state of the art in representative aspects of gene therapy/translational medicine and evolves from a symposium held at the School of Veterinary Medicine, University of Pennsylvania on November 16, 2017 honoring Dr. Gustavo Aguirre, recipient of ARVO's 2017 Proctor Medal. Focusing on the retina, speakers highlighted current work on moving therapies for inherited retinal degenerative diseases from the laboratory bench to the clinic.

Published
2018

13. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report

Author

Cideciyan, Artur V., Jacobson, Samuel G., Ho, Allen C., Garafalo, Alexandra V., Roman, Alejandro J., Sumaroka, Alexander, Krishnan, Arun K., Swider, Malgorzata, Schwartz, Michael R., and Girach, Aniz

Subjects
Gene therapy -- Case studies, Ophthalmic drugs -- Case studies -- Usage, Leber's congenital amaurosis -- Case studies -- Drug therapy, Biological sciences, Health
Abstract

Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors. Post hoc analyses and follow-up of a patient with Leber congenital amaurosis treated with the antisense oligonucleotide sepofarsen as part of a clinical trial indicates sustained improvement of vision 15 months after receiving a single dose of the drug., Author(s): Artur V. Cideciyan [sup.1] , Samuel G. Jacobson [sup.1] , Allen C. Ho [sup.2] , Alexandra V. Garafalo [sup.1] , Alejandro J. Roman [sup.1] , Alexander Sumaroka [sup.1] , [...]

Published
2021
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14. Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14

Author

Scholl, Hendrik P.N., Strauss, Rupert W., Wolfson, Yulia, Bittencourt, Millena, Shah, Syed Mahmood, Ahmed, Mohamed, Schönbach, Etienne, Fujinami, Kaoru, Traboulsi, Elias, Ehlers, Justis, Marino, Meghan, Crowe, Susan, Briggs, Rachael, Borer, Angela, Pinter, Anne, Fecko, Tami, Burgnoni, Nikki, Sunness, Janet S., Applegate, Carol, Russell, Leslie, Michaelides, Michel, Degli Esposti, Simona, Moore, Anthony, Webster, Andrew, Connor, Sophie, Barnfield, Jade, Salchi, Zaid, Alfageme, Clara, McCudden, Victoria, Pefkianaki, Maria, Aboshiha, Jonathan, Liew, Gerald, Holder, Graham, Robson, Anthony, King, Alexa, Cajas Narvaez, Daniela Ivanova, Barnard, Katy, Grigg, Catherine, Dunbar, Hannah, Obadeyi, Yetunde, Girard-Claudon, Karine, Swann, Hilary, Rughani, Avani, Amoah, Charles, Carrington, Dominic, Bibi, Kanom, Ting, Emerson, Illiyas, Mohamed Nafaz, Begum, Hamida, Carter, Andrew, Georgiou, Anne, Lewism, Selma, Shaheen, Saddaf, Shinmar, Harpreet, Burton, Linda, Bernstein, Paul, Wegner, Kimberley, Sawyer, Briana Lauren, Carlstrom, Bonnie, Farnsworth, Kellian, Fry, Cyrie, Chandler, Melissa, Jenkins, Glen, Creel, Donnel, Birch, David, Wang, Yi-Zhong, Rodriguez, Luis, Locke, Kirsten, Klein, Martin, Mejia, Paulina, Cideciyan, Artur V., Jacobson, Samuel G., Schwartz, Sharon B., Matsui, Rodrigo, Gruzensky, Michaela, Charng, Jason, Roman, Alejandro J., Zrenner, Eberhart, Nasser, Fadi, Hahn, Gesa Astrid, Wilhelm, Barbara, Peters, Tobias, Beier, Benjamin, Koenig, Tilman, Kramer, Susanne, Sahel, José-Alain, Mohand-Said, Saddek, Audo, Isabelle, Laurent-Coriat, Caroline, Sliesoraityte, Ieva, Zeitz, Christina, Boyard, Fiona, Tran, Minh Ha, Chapon, Mathias, Chaumette, Céline, Amaudruz, Juliette, Ganem, Victoria, Sancho, Serge, Girmens, Aurore, Wojciechowski, Robert, Khan, Shazia, Emmert, David G., Cain, Dennis, Herring, Mark, Bassinger, Jennifer, Liberto, Lisa, West, Sheila, Ervin, Ann-Margret, Munoz, Beatriz, Kong, Xiangrong, Dreger, Kurt, Jones, Jennifer, Sadda, Srinivas, Ip, Michael S., Jha, Anamika, Ho, Alex, Kramer, Brendan, Lam, Ngoc, Tawdros, Rita, Zhou, Yong Dong, Carmona, Johana, Uji, Akihito, Hariri, Amirhossein, Lock, Amy, Elshafei, Anthony, Ganegoda, Anushika, Petrossian, Christine, Jenkins, Dennis, Strnad, Edward, Baghdasaryan, Elmira, Ito, Eric, Samson, Feliz, Blanquel, Gloria, Akil, Handan, Melendez, Jhanisus, Lei, Jianqin, Huang, Jianyan, Chau, Jonathan, Falavarjani, Khalil G., Espino, Kristina, Li, Manfred, Mendoza, Maria, Nittala, Muneeswar Gupta, Roded, Netali, Saleh, Nizar, Huang, Ping, Pitetta, Sean, Balasubramanian, Siva, Leahy, Sophie, Srinivas, Sowmya J., Velaga, Swetha B., Margaryan, Teresa, Tepelus, Tudor, Brown, Tyler, Fan, Wenying, Murillo, Yamileth, Shi, Yue, Aguilar, Katherine, Chan, Cynthia, Santos, Lisa, Seo, Brian, Sison, Christopher, Perez, Silvia, Chao, Stephanie, Miyasato, Kelly, Higgins, Julia, Luna, Zoila, Menchaca, Anita, Gonzalez, Norma, Robledo, Vicky, Carig, Karen, Baker, Kirstie, Ellenbogen, David, Bluemel, Daniel, Sanford, Theo, Linares, Daisy, Tran, Mei, Nava, Lorane, Oberoi, Michelle, Romero, Mark, Chiguil, Vivian, Bynum-Bain, Grantley, Kim, Monica, Mendiguren, Carolina, Huang, Xiwen, Smith, Monika, Sarreal, Natalie, Schönbach, Etienne M., Ibrahim, Mohamed A., Janes, Jessica L., Birch, David G., Muñoz, Beatriz, and Sadda, SriniVas R.

Published
2020
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18. Functional Rescue of Retinal Degeneration-Associated Mutant RPE65 Proteins

Author

Jin, Minghao, Li, Songhua, Hu, Jane, Jin, Heather H, Jacobson, Samuel G, and Bok, Dean

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurodegenerative, Eye Disease and Disorders of Vision, Neurosciences, Genetics, Rare Diseases, Eye, Blotting, Western, Catalytic Domain, Cell Line, Cells, Cultured, Cold Temperature, HEK293 Cells, Humans, Microscopy, Confocal, Mutant Proteins, Mutation, Phenylbutyrates, Proteasome Endopeptidase Complex, RNA Interference, Retinal Degeneration, Retinal Pigment Epithelium, cis-trans-Isomerases, Chemical chaperone, Gene therapy, Leber congenital amaurosis, Low temperature, PSMD13, Proteasome, RPE65, Retina, Retinitis pigmentosa, Retinoid, Visual cycle, Medical and Health Sciences, General & Internal Medicine, Biological sciences, Biomedical and clinical sciences
Abstract

More than 100 different mutations in the RPE65 gene are associated with inherited retinal degeneration. Although some missense mutations have been shown to abolish isomerase activity of RPE65, the molecular bases leading to loss of function and retinal degeneration remain incompletely understood. Here we show that several missense mutations resulted in significant decrease in expression level of RPE65 in the human retinal pigment epithelium cells. The 26S proteasome non-ATPase regulatory subunit 13, a newly identified negative regulator of RPE65, mediated degradation of mutant RPE65s, which were misfolded and formed aggregates in the cells. Many mutations, including L22P, T101I, and L408P, were mapped on nonactive sites of RPE65. Enzyme activities of these mutant RPE65s were significantly rescued at low temperature, whereas mutant RPE65s with a distinct active site mutation could not be rescued under the same conditions. 4-phenylbutyrate (PBA) displayed a significant synergistic effect on the low temperature-mediated rescue of the mutant RPE65s. Our results suggest that a low temperature eye mask and PBA, a FDA-approved oral medicine, may provide a promising "protein repair therapy" that can enhance the efficacy of gene therapy for delaying retinal degeneration caused by RPE65 mutations.

Published
2016

22. Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Author

Ratnapriya, Rinki, Zhan, Xiaowei, Fariss, Robert N, Branham, Kari E, Zipprer, David, Chakarova, Christina F, Sergeev, Yuri V, Campos, Maria M, Othman, Mohammad, Friedman, James S, Maminishkis, Arvydas, Waseem, Naushin H, Brooks, Matthew, Rajasimha, Harsha K, Edwards, Albert O, Lotery, Andrew, Klein, Barbara E, Truitt, Barbara J, Li, Bingshan, Schaumberg, Debra A, Morgan, Denise J, Morrison, Margaux A, Souied, Eric, Tsironi, Evangelia E, Grassmann, Felix, Fishman, Gerald A, Silvestri, Giuliana, Scholl, Hendrik PN, Kim, Ivana K, Ramke, Jacqueline, Tuo, Jingsheng, Merriam, Joanna E, Merriam, John C, Park, Kyu Hyung, Olson, Lana M, Farrer, Lindsay A, Johnson, Matthew P, Peachey, Neal S, Lathrop, Mark, Baron, Robert V, Igo, Robert P, Klein, Ronald, Hagstrom, Stephanie A, Kamatani, Yoichiro, Martin, Tammy M, Jiang, Yingda, Conley, Yvette, Sahel, Jose-Alan, Zack, Donald J, Chan, Chi-Chao, Pericak-Vance, Margaret A, Jacobson, Samuel G, Gorin, Michael B, Klein, Michael L, Allikmets, Rando, Iyengar, Sudha K, Weber, Bernhard H, Haines, Jonathan L, Léveillard, Thierry, Deangelis, Margaret M, Stambolian, Dwight, Weeks, Daniel E, Bhattacharya, Shomi S, Chew, Emily Y, Heckenlively, John R, Abecasis, Gonçalo R, and Swaroop, Anand

Subjects
Eye Disease and Disorders of Vision, Human Genome, Neurodegenerative, Genetics, Clinical Research, Macular Degeneration, Aging, 2.1 Biological and endogenous factors, Aetiology, Eye, Adult, Aged, Amino Acid Sequence, Bruch Membrane, DNA Mutational Analysis, Exome, Extracellular Matrix, Fibrillin-2, Fibrillins, Genetic Association Studies, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Male, Meta-Analysis as Topic, Microfilament Proteins, Middle Aged, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein Stability, Retina, Sequence Alignment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Published
2014

23. Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: Replication in two eyes

Author

Cideciyan, Artur V., primary, Jacobson, Samuel G., additional, Ho, Allen C., additional, Swider, Malgorzata, additional, Sumaroka, Alexander, additional, Roman, Alejandro J., additional, Wu, Vivian, additional, Russell, Robert C., additional, Viarbitskaya, Iryna, additional, Garafalo, Alexandra V., additional, Schwartz, Michael R., additional, and Girach, Aniz, additional

Published
2023
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26. Longitudinal Changes of Fixation Location and Stability Within 12 Months in Stargardt Disease: ProgStar Report No. 12

Author

Scholl, Hendrik P.N., Strauss, Rupert W., Wolfson, Yulia, Bittencourt, Millena, Shah, Syed Mahmood, Ahmed, Mohamed, Schönbach, Etienne, Fujinami, Kaoru, Traboulsi, Elias, Ehlers, Justis, Marino, Meghan, Crowe, Susan, Briggs, Rachael, Borer, Angela, Pinter, Anne, Fecko, Tami, Burgnoni, Nikki, Sunness, Janet S., Applegate, Carol, Russell, Leslie, Michaelides, Michel, Esposti, Simona Degli, Moore, Anthony, Webster, Andrew, Connor, Sophie, Barnfield, Jade, Salchi, Zaid, Alfageme, Clara, McCudden, Victoria, Pefkianaki, Maria, Aboshiha, Jonathan, Liew, Gerald, Holder, Graham, Robson, Anthony, King, Alexa, Narvaez, Daniela Ivanova Cajas, Barnard, Katy, Grigg, Catherine, Dunbar, Hannah, Obadeyi, Yetunde, Girard-Claudon, Karine, Swann, Hilary, Rughani, Avani, Amoah, Charles, Carrington, Dominic, Bibi, Kanom, Co, Emerson Ting, Illiyas, Mohamed Nafaz, Begum, Hamida, Carter, Andrew, Georgiou, Anne, Lewism, Selma, Shaheen, Saddaf, Shinmar, Harpreet, Burton, Linda, Bernstein, Paul, Wegner, Kimberley, Sawyer, Briana Lauren, Carlstrom, Bonnie, Farnsworth, Kellian, Fry, Cyrie, Chandler, Melissa, Jenkins, Glen, Creel, Donnel, Birch, David, Wang, Yi-Zhong, Rodriguez, Luis, Locke, Kirsten, Klein, Martin, Mejia, Paulina, Cideciyan, Artur V., Jacobson, Samuel G., Schwartz, Sharon B., Matsui, Rodrigo, Gruzensky, Michaela, Charng, Jason, Roman, Alejandro J., Zrenner, Eberhart, Nasser, Fadi, Hahn, Gesa Astrid, Wilhelm, Barbara, Peters, Tobias, Beier, Benjamin, Koenig, Tilman, Kramer, Susanne, Sahel, José-Alain, Mohand-Said, Saddek, Audo, Isabelle, Laurent-Coriat, Caroline, Sliesoraityte, Ieva, Zeitz, Christina, Boyard, Fiona, Tran, Minh Ha, Chapon, Mathias, Chaumette, Céline, Amaudruz, Juliette, Ganem, Victoria, Sancho, Serge, Girmens, Aurore, Wojciechowski, Robert, Khan, Shazia, Emmert, David G., Cain, Dennis, Herring, Mark, Bassinger, Jennifer, Liberto, Lisa, West, Sheila, Ervin, Ann-Margret, Munoz, Beatriz, Kong, Xiangrong, Dreger, Kurt, Jones, Jennifer, Sadda, Srinivas, Ip, Michael S., Jha, Anamika, Ho, Alex, Kramer, Brendan, Lam, Ngoc, Tawdros, Rita, Zhou, Yong Dong, Carmona, Johana, Uji, Akihito, Hariri, Amirhossein, Lock, Amy, Elshafei, Anthony, Ganegoda, Anushika, Petrossian, Christine, Jenkins, Dennis, Strnad, Edward, Baghdasaryan, Elmira, Ito, Eric, Samson, Feliz, Blanquel, Gloria, Akil, Handan, Melendez, Jhanisus, Lei, Jianqin, Huang, Jianyan, Chau, Jonathan, Falavarjani, Khalil G., Espino, Kristina, Li, Manfred, Mendoza, Maria, Nittala, Muneeswar Gupta, Roded, Netali, Saleh, Nizar, Huang, Ping, Pitetta, Sean, Balasubramanian, Siva, Leahy, Sophie, Srinivas, Sowmya J., Velaga, Swetha B., Margaryan, Teresa, Tepelus, Tudor, Brown, Tyler, Fan, Wenying, Murillo, Yamileth, Shi, Yue, Aguilar, Katherine, Chan, Cynthia, Santos, Lisa, Seo, Brian, Sison, Christopher, Perez, Silvia, Chao, Stephanie, Miyasato, Kelly, Higgins, Julia, Luna, Zoila, Menchaca, Anita, Gonzalez, Norma, Robledo, Vicky, Carig, Karen, Baker, Kirstie, Ellenbogen, David, Bluemel, Daniel, Sanford, Theo, Linares, Daisy, Tran, Mei, Nava, Lorane, Oberoi, Michelle, Romero, Mark, Chiguil, Vivian, Bynum-Bain, Grantley, Kim, Monica, Mendiguren, Carolina, Huang, Xiwen, Smith, Monika, Sarreal, Natalie, Schönbach, Etienne M., Muñoz, Beatriz, Ibrahim, Mohamed A., Birch, David G., Hahn, Gesa-Astrid, Sadda, SriniVas R., and West, Sheila K.

Published
2018
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30. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect

Author

Cideciyan, Artur V., Jacobson, Samuel G., Drack, Arlene V., Ho, Allen C., Charng, Jason, Garafalo, Alexandra V., and Roman, Alejandro J.

Subjects
Antisense drugs -- Dosage and administration, Child health -- Analysis, Blindness -- Genetic aspects -- Drug therapy, Photoreceptors -- Research, Genes, Medical schools, Genetic disorders, Clinical trials, RNA, Biological sciences, Health
Abstract

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. (https://clinicaltrials.gov/ct2/show/NCT03140969)) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness., Author(s): Artur V. Cideciyan [sup.1] , Samuel G. Jacobson [sup.1] , Arlene V. Drack [sup.2] , Allen C. Ho [sup.3] , Jason Charng [sup.1] , Alexandra V. Garafalo [sup.1] , [...]

Published
2019
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31. Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

Author

Cideciyan, Artur V, Hufnagel, Robert B, Carroll, Joseph, Sumaroka, Alexander, Luo, Xunda, Schwartz, Sharon B, Dubra, Alfredo, Land, Megan, Michaelides, Michel, Gardner, Jessica C, Hardcastle, Alison J, Moore, Anthony T, Sisk, Robert A, Ahmed, Zubair M, Kohl, Susanne, Wissinger, Bernd, and Jacobson, Samuel G

Subjects
Rare Diseases, Neurosciences, Orphan Drug, Eye Disease and Disorders of Vision, Gene Therapy, Genetics, Eye, Adolescent, Adult, Animals, Child, Child, Preschool, Color Vision Defects, Female, Gene Deletion, Genetic Therapy, Humans, Mice, Middle Aged, Mutation, Retinal Cone Photoreceptor Cells, Rod Opsins
Abstract

Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.

Published
2013

32. Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative DiseaseX-Linked Mutations in Simplex Males

Author

Branham, Kari, Othman, Mohammad, Brumm, Matthew, Karoukis, Athanasios J, Atmaca-Sonmez, Pelin, Yashar, Beverly M, Schwartz, Sharon B, Stover, Niamh B, Trzupek, Karmen, Wheaton, Dianna, Jennings, Barbara, Ciccarelli, Maria Laura, Jayasundera, K Thiran, Lewis, Richard A, Birch, David, Bennett, Jean, Sieving, Paul A, Andreasson, Sten, Duncan, Jacque L, Fishman, Gerald A, Iannaccone, Alessandro, Weleber, Richard G, Jacobson, Samuel G, Heckenlively, John R, and Swaroop, Anand

Subjects
Neurosciences, Rare Diseases, Clinical Research, Genetics, Neurodegenerative, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, DNA Mutational Analysis, Eye Proteins, Female, GTP-Binding Proteins, Genetic Diseases, X-Linked, Genetic Testing, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mutation, Pedigree, Random Amplified Polymorphic DNA Technique, Registries, Retinitis Pigmentosa, Sex Distribution, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

PurposeTo determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2.MethodsSimplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA.ResultsWe identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region).ConclusionsThis study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration.

Published
2012

33. The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65

Author

Lopes, Vanda S, Gibbs, Daniel, Libby, Richard T, Aleman, Tomas S, Welch, Darcy L, Lillo, Concepción, Jacobson, Samuel G, Radu, Roxana A, Steel, Karen P, and Williams, David S

Subjects
Eye Disease and Disorders of Vision, Rare Diseases, Neurosciences, Eye, Animals, Cell Line, Disease Models, Animal, Eye Proteins, Humans, Intracellular Space, Light, Mice, Mice, Inbred C57BL, Mice, Knockout, Myosin VIIa, Myosins, Protein Binding, Protein Transport, Retina, Retinal Degeneration, Usher Syndromes, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Mutations in the MYO7A gene cause a deaf-blindness disorder, known as Usher syndrome 1B.  In the retina, the majority of MYO7A is in the retinal pigmented epithelium (RPE), where many of the reactions of the visual retinoid cycle take place.  We have observed that the retinas of Myo7a-mutant mice are resistant to acute light damage. In exploring the basis of this resistance, we found that Myo7a-mutant mice have lower levels of RPE65, the RPE isomerase that has a key role in the retinoid cycle.  We show for the first time that RPE65 normally undergoes a light-dependent translocation to become more concentrated in the central region of the RPE cells.  This translocation requires MYO7A, so that, in Myo7a-mutant mice, RPE65 is partly mislocalized in the light.  RPE65 is degraded more quickly in Myo7a-mutant mice, perhaps due to its mislocalization, providing a plausible explanation for its lower levels.  Following a 50-60% photobleach, Myo7a-mutant retinas exhibited increased all-trans-retinyl ester levels during the initial stages of dark recovery, consistent with a deficiency in RPE65 activity.  Lastly, MYO7A and RPE65 were co-immunoprecipitated from RPE cell lysate by antibodies against either of the proteins, and the two proteins were partly colocalized, suggesting a direct or indirect interaction.  Together, the results support a role for MYO7A in the translocation of RPE65, illustrating the involvement of a molecular motor in the spatiotemporal organization of the retinoid cycle in vision.

Published
2011

36. Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations

Author

Beltran, William A., Cideciyan, Artur V., Boye, Shannon E., Ye, Guo-Jie, Iwabe, Simone, Dufour, Valerie L., Marinho, Luis Felipe, Swider, Malgorzata, Kosyk, Mychajlo S., Sha, Jin, Boye, Sanford L., Peterson, James J., Witherspoon, C. Douglas, Alexander, John J., Ying, Gui-Shuang, Shearman, Mark S., Chulay, Jeffrey D., Hauswirth, William W., Gamlin, Paul D., Jacobson, Samuel G., and Aguirre, Gustavo D.

Published
2017
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42. Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease.

Author

Gao, Yong-Qing, Danciger, Michael, Özgül, Riza Köksal, Gribanova, Yekaterina E, Jacobson, Samuel G, and Farber, Debora B

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Eye Disease and Disorders of Vision, Neurosciences, Clinical Research, Rare Diseases, Genetics, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Eye, Adenine, Asparagine, Blindness, Cohort Studies, Exons, GTP-Binding Protein beta Subunits, Genetic Variation, Guanine, Hispanic or Latino, Humans, Introns, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Retinal Degeneration, Serine, Sp4 Transcription Factor, Opthalmology and Optometry, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

PurposeSP4 is a transcription factor abundantly expressed in retina that binds to the GC promoter region of photoreceptor signal transduction genes. We have previously shown that SP4 may be involved in the transcriptional activation of these genes alone or together with other transcription factors such as SP1, neural retina leucine zipper protein (NRL), and cone-rod homeobox gene (CRX). Since mutations in NRL and CRX are involved in inherited retinal degenerations, SP4 was considered a good candidate for mutation screening in patients with this type of diseases. The purpose of this work, therefore, was to investigate possible mutations in SP4 in a cohort of patients affected with different forms of retinal degenerations.Methods270 unrelated probands with various forms of retinal degeneration including autosomal dominant and autosomal recessive retinitis pigmentosa (RP), autosomal dominant and autosomal recessive cone-rod dystrophy (CRD), and Leber's congenital amaurosis (LCA), were screened for mutations in the SP4 gene. Single strand conformation polymorphism (SSCP) analysis was performed on the six SP4 gene exons including flanking regions followed by direct sequencing of SSCP variants.ResultsNine different sequence variants were found in 29 patients, four in introns and five in exons. Many of the probands were previously screened for mutations in the genes encoding the alpha-, beta- and gamma-subunits of rod-specific cGMP phosphodiesterase (PDE6A, PDE6B, PDE6G), the beta-subunit of rod-specific transducin (GNB1), and peripherin/rds (RDS). One group of seven probands of Hispanic background that included five with arRP, one with RP of unknown inheritance (isolate) and 1 with arCRD carried an Asn306Ser mutation in SP4. Of the seven, the isolate case was homozygous and the other 6 heterozygous for the variant. Two arRP and the arCRD probands carried an additional intronic GNB1 variant. DNA from the family members of the arCRD proband could not be obtained, but for the other two families, all affected members and none of the unaffected carried both the SP4 Asn306Ser allele and the GNB1 intronic variant.ConclusionsIf mutations in SP4 do cause retinal degenerative disease, their frequency would be low. While digenic disease with the SP4 Asn306Ser and the GNB1 intronic variant alleles has not been established, neither has it been ruled out. This leaves open the possibility of a cooperative involvement of SP4 and GNB1 in the normal function of the retina.

Published
2007

48. Visual Acuity Loss and Associated Risk Factors in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 2)

Author

Scholl, Hendrik P.N., Strauss, Rupert W., Wolfson, Yulia, Bittencourt, Millena, Shah, Syed Mahmood, Ahmed, Mohammed, Schonbach, Etienne, Fujinami, Kaoru, Traboulsi, Elias, Ehlers, Justis, Marino, Meghan, Crowe, Susan, Briggs, Rachael, Borer, Angela, Pinter, Anne, Fecko, Tami, Brugnoni, Nikki, Sunness, Janet S., Applegate, Carol, Russell, Leslie, Michaelides, Michel, Moore, Anthony, Webster, Andrew, Connor, Sophie, McCudden, Victoria, Pefkianaki, Maria, Aboshiha, Jonathan, Liew, Gerald, Holder, Graham, Robson, Anthony, King, Alexa, Cajas Narvaez, Daniela Ivanova, Barnard, Katy, Grigg, Catherine, Dunbar, Hannah, Obadeyi, Yetunde, Girard-Claudon, Karine, Swann, Hilary, Rughani, Avani, Amoah, Charles, Carrington, Dominic, Bibi, Kanom, Co, Emerson Ting, Carter, Andrew, Georgiou, Anne, Lewis, Selma, Shaheen, Saddaf, Shinmar, Harpreet, Burton, Linda, Bernstein, Paul, Wegner, Kimberley, Sawyer, Briana Lauren, Carlstrom, Bonnie, Farnsworth, Kellian, Fry, Cyrie, Chandler, Melissa, Jenkins, Glen, Creel, Donnel, Birch, David, Wang, Yi-Zhong, Rodriguez, Luis, Locke, Kirsten, Klein, Martin, Mejia, Paulina, Cideciyan, Artur V., Jacobson, Samuel G., Schwartz, Sharon B., Matsui, Rodrigo, Gruzensky, Michaela, Roman, Alejandro J., Zrenner, Eberhart, Nasser, Fadi, Hahn, Gesa Astrid, Wilhelm, Barbara, Peters, Tobias, Beier, Benjamin, Koenig, Tilman, Kramer, Susanne, Sahel, José-Alain, Mohand-Said, Saddek, Audo, Isabelle, Laurent-Coriat, Caroline, Sliesoraityte, Ieva, Zeitz, Christina, Boyard, Fiona, Tran, Minh Ha, Chapon, Mathias, Chaumette, Céline, Amaudruz, Juliette, Ganem, Victoria, Sancho, Serge, Girmens, Aurore, Wojciechowski, Robert, Khan, Shazia, Emmert, David G., Cain, Dennis, Herring, Mark, Bassinger, Jennifer, Liberto, Lisa, West, Sheila, Ervin, Ann-Margret, Munoz, Beatriz, Kong, Xiangrong, Dreger, Kurt, Jones, Jennifer, Sadda, Srinivas, Jha, Anamika, Ho, Alex, Kramer, Brendan, Hariri, Amirhossein, Blanquel, Gloria Rebecca, Lam, Ngoc, Pitetta, Sean, Shi, Yue, Tawdros, Rita, Petrossian, Christine, Jenkins, Dennis, Gupta, Muneeswar, Zhou, Yong Dong, Aguilar, Katherine, Chan, Cynthia, Santos, Lisa, Seo, Brian, Sison, Christopher, Perez, Silvia, Chao, Stephanie, Miyasato, Kelly, Higgins, Julia, Luna, Zoila, Menchaca, Anita, Gonzalez, Norma, Robledo, Vicky, Carig, Karen, Baker, Kirstie, Ellenbogen, David, Russell, James, Bluemel, Daniel, Moreno, Alex, Pham, Royal, Sanford, Theo, Linares, Daisy, Tran, Mei, and Muñoz, Beatriz

Published
2016
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49. DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome

Author

Joshi, Ricky S., Garg, Paras, Zaitlen, Noah, Lappalainen, Tuuli, Watson, Corey T., Azam, Nidha, Ho, Daniel, Li, Xin, Antonarakis, Stylianos E., Brunner, Han G., Buiting, Karin, Cheung, Sau Wai, Coffee, Bradford, Eggermann, Thomas, Francis, David, Geraedts, Joep P., Gimelli, Giorgio, Jacobson, Samuel G., Le Caignec, Cedric, de Leeuw, Nicole, Liehr, Thomas, Mackay, Deborah J., Montgomery, Stephen B., Pagnamenta, Alistair T., Papenhausen, Peter, Robinson, David O., Ruivenkamp, Claudia, Schwartz, Charles, Steiner, Bernhard, Stevenson, David A., Surti, Urvashi, Wassink, Thomas, and Sharp, Andrew J.

Published
2016
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50. Durable Vision Improvement After a Single Intravitreal Treatment With Antisense Oligonucleotide in CEP290-Lca: Replication in Two Eyes

Author

Cideciyan, Artur V, Jacobson, Samuel G, Ho, Allen, Swider, Malgorzata, Sumaroka, Alexander, Roman, Alejandro J, Wu, Vivian, Russell, Robert C, Viarbitskaya, Iryna, Garafalo, Alexandra V, Schwartz, Michael R, Girach, Aniz, Cideciyan, Artur V, Jacobson, Samuel G, Ho, Allen, Swider, Malgorzata, Sumaroka, Alexander, Roman, Alejandro J, Wu, Vivian, Russell, Robert C, Viarbitskaya, Iryna, Garafalo, Alexandra V, Schwartz, Michael R, and Girach, Aniz

Abstract

PURPOSE: An intravitreally injected antisense oligonucleotide, sepofarsen, was designed to modulate splicing within retinas of patients with severe vision loss due to deep intronic c.2991 + 1655A > G variant in the OBSERVATIONS: Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at ∼2 years, and returning to baseline by 3-4 years after each single injection. CONCLUSIONS AND IMPORTANCE: These results suggest that sepofarsen reinjection intervals may need to be longer than 2 years.

Published
2023

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