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1. 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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2. 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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5. 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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8. Human Gene Therapy for RPE65 Isomerase Deficiency Activates the Retinoid Cycle of Vision but with Slow Rod Kinetics

Author

Cideciyan, Artur V., Aleman, Tomas S., Boye, Sanford L., Schwartz, Sharon B., Kaushal, Shalesh, Roman, Alejandro J., Pang, Ji-jing, Sumaroka, Alexander, Windsor, Elizabeth A. M., Wilson, James M., Flotte, Terence R., Fishman, Gerald A., Heon, Elise, Stone, Edwin M., Byrne, Barry J., Jacobson, Samuel G., and Hauswirth, William W.

Published
2008
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9. Human Cone Photoreceptor Dependence on RPE65 Isomerase

Author

Jacobson, Samuel G., Aleman, Tomas S., Cideciyan, Artur V., Heon, Elise, Golczak, Marcin, Beltran, William A., Sumaroka, Alexander, Schwartz, Sharon B., Roman, Alejandro J., Windsor, Elizabeth A. M., Wilson, James M., Aguirre, Gustavo D., Stone, Edwin M., and Palczewski, Krzysztof

Published
2007
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12. Safety of Recombinant Adeno-Associated Virus Type 2–RPE65 Vector Delivered by Ocular Subretinal Injection

Author

Jacobson, Samuel G., Acland, Gregory M., Aguirre, Gustavo D., Aleman, Tomas S., Schwartz, Sharon B., Cideciyan, Artur V., Zeiss, Caroline J., Komaromy, Andras M., Kaushal, Shalesh, Roman, Alejandro J., Windsor, Elizabeth A.M., Sumaroka, Alexander, Pearce-Kelling, Susan E., Conlon, Thomas J., Chiodo, Vincent A., Boye, Sanford L., Flotte, Terence R., Maguire, Albert M., Bennett, Jean, and Hauswirth, William W.

Published
2006
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13. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants

Author

Jacobson, Samuel G., Cideciyan, Artur V., Peshenko, Igor V., Sumaroka, Alexander, Olshevskaya, Elena V., Cao, Lihui, Schwartz, Sharon B., Roman, Alejandro J., Olivares, Melani B., Sadigh, Sam, Yau, King-Wai, Heon, Elise, Stone, Edwin M., and Dizhoor, Alexander M.

Published
2013
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14. Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years

Author

Jacobson, Samuel G., Cideciyan, Artur V., Ratnakaram, Ramakrishna, Heon, Elise, Schwartz, Sharon B., Roman, Alejandro J., Peden, Marc C., Aleman, Tomas S., Boye, Sanford L., Sumaroka, Alexander, Conlon, Thomas J., Calcedo, Roberto, Pang, Ji-Jing, Erger, Kirsten E., Olivares, Melani B., Mullins, Cristina L., Swider, Malgorzata, Kaushal, Shalesh, Feuer, William J., Iannaccone, Alessandro, Fishman, Gerald A., Stone, Edwin M., Byrne, Barry J., and Hauswirth, William W.

Published
2012
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17. ABCA4 disease progression and a proposed strategy for gene therapy

Author

Cideciyan, Artur V., Swider, Malgorzata, Aleman, Tomas S., Tsybovsky, Yaroslav, Schwartz, Sharon B., Windsor, Elizabeth A.M., Roman, Alejandro J., Sumaroka, Alexander, Steinberg, Janet D., Jacobson, Samuel G., Stone, Edwin M., and Palczewski, Krzysztof

Published
2009

25. SPATA7: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa.

Author

Matsui, Rodrigo, McGuigan III, David B., Gruzensky, Michaela L., Aleman, Tomas S., Schwartz, Sharon B., Sumaroka, Alexander, Koenekoop, Robert K., Cideciyan, Artur V., and Jacobson, Samuel G.

Subjects
PHENOTYPES, RETINITIS pigmentosa, GENETIC mutation, OPTICAL coherence tomography, ELECTRORETINOGRAPHY, GENETICS, DIAGNOSIS
Abstract

Background: SPATA7 mutations have been associated with different autosomal recessive retinal degeneration phenotypes. Long-term follow-up has not been described in detail. Materials and methods: A Hispanic patient with SPATA7 mutations was evaluated serially over a 12-year period with kinetic and static chromatic perimetry, optical coherence tomography (OCT), and fundus autofluorescence (AF) imaging. Electroretinography (ERG) was performed at the initial visit. Results: The patient was homozygous for a mutation in SPATA7 (p.V458fs). At age 9, the ERG showed an abnormally reduced but preserved rod b-wave and no detectable cone signals. There were two islands of vision: a midperipheral island with greater cone than rod dysfunction and a central island with normal cone but no rod function. Serial measures of rod and cone vision and co-localized retinal structure showed that the midperipheral island slowly became undetectable. By age 21, only the central island and its cone function remained, but it had become more abnormal in structure and function. Conclusion: The disease resulting from SPATA7 mutations in this patient initially presented as a cone-rod dystrophy (CRD), but changed over time into a phenotype more reminiscent of late-stage retinitis pigmentosa (RP). The differential diagnosis for both CRD and RP should include this rare molecular cause of autosomal retinal degeneration. An evolving phenotype complicates not only clinical diagnosis and patient counselling but also future strategies aimed at treating specific retinal regions. [ABSTRACT FROM AUTHOR]

Published
2016
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26. Outcome measure for the treatment of cone photoreceptor diseases: orientation to a scene with cone-only contrast.

Author

Roman, Alejandro J., Cideciyan, Artur V., Matsui, Rodrigo, Sheplock, Rebecca, Schwartz, Sharon B., and Jacobson, Samuel G.

Subjects
PHOTORECEPTORS, GENETICS of retinal degeneration, COLOR blindness, LEBER'S congenital amaurosis, LOW vision, DISEASES
Abstract

Background: Inherited retinal degenerations (IRDs) preferentially affecting cone photoreceptor function are being considered for treatment trials aiming to improve day vision. The purpose of the current work was to develop cone-specific visual orientation outcomes that can differentiate day vision improvement in the presence of retained night vision. Methods: A lighted wall (1.4 m wide, 2 m high) resembling a beaded curtain was formed with 900 individually addressable red, blue and green LED triplets placed in 15 vertical strips hanging 0.1 m apart. Under computer control, different combination of colors and intensities were used to produce the appearance of a door on the wall. Scotopically-matched trials were designed to be perceptible to the cone-, but not rod-, photoreceptor based visual systems. Unmatched control trials were interleaved at each luminance level to determine the existence of any vision available for orientation. Testing started with dark-adapted eyes and a scene luminance attenuated 8 log units from the maximum attainable, and continued with progressively increasing levels of luminance. Testing was performed with a three-alternative forced choice method in healthy subjects and patients with Leber congenital amaurosis (LCA) caused by mutations in GUCY2D, the gene that encodes retinal guanylate cyclase-1. Results: Normal subjects could perform the orientation task using cone vision at 5 log attenuation and brighter luminance levels. Most GUCY2D-LCA patients failed to perform the orientation task with scotopically-matched test trials at any luminance level even though they were able to perform correctly with unmatched control trials. These results were consistent with a lack of cone system vision and use of the rod system under ambient conditions normally associated with cone system activity. Two GUCY2D-LCA patients demonstrated remnant cone vision but at a luminance level 2 log brighter than normal. Conclusions: The newly developed device can probe the existence or emergence of cone-based vision in patients for an orientation task involving the identification of a door on the wall under free-viewing conditions. This key advance represents progress toward developing an appropriate outcome measure for a clinical trial to treat currently incurable eye diseases severely affecting cone vision despite retained rod vision. [ABSTRACT FROM AUTHOR]

Published
2015
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28. Blue Cone Monochromacy: Visual Function and Efficacy Outcome Measures for Clinical Trials.

Author

Luo, Xunda, Cideciyan, Artur V., Iannaccone, Alessandro, Roman, Alejandro J., Ditta, Lauren C., Jennings, Barbara J., Yatsenko, Svetlana A., Sheplock, Rebecca, Sumaroka, Alexander, Swider, Malgorzata, Schwartz, Sharon B., Wissinger, Bernd, Kohl, Susanne, and Jacobson, Samuel G.

Subjects
CLINICAL trials, HEALTH outcome assessment, X-linked genetic disorders, GENETIC mutation, OPSINS, PHOTORECEPTORS, RETINAL diseases, TREATMENT of eye diseases, GENE therapy
Abstract

Background: Blue Cone Monochromacy (BCM) is an X-linked retinopathy caused by mutations in the OPN1LW / OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength sensitive cone opsins. Recent evidence shows sufficient structural integrity of cone photoreceptors in BCM to warrant consideration of a gene therapy approach to the disease. In the present study, the vision in BCM is examined, specifically seeking clinically-feasible outcomes for a future clinical trial. Methods: BCM patients (n = 25, ages 5–72) were studied with kinetic and static chromatic perimetry, full-field sensitivity testing, and eye movement recordings. Vision at the fovea and parafovea was probed with chromatic microperimetry. Results: Kinetic fields with a Goldmann size V target were generally full. Short-wavelength (S-) sensitive cone function was normal or near normal in most patients. Light-adapted perimetry results on conventional background lights were abnormally reduced; 600-nm stimuli were seen by rods whereas white stimuli were seen by both rods and S-cones. Under dark-adapted conditions, 500-nm stimuli were seen by rods in both BCM and normals. Spectral sensitivity functions in the superior retina showed retained rod and S-cone functions in BCM under dark-adapted and light-adapted conditions. In the fovea, normal subjects showed L/M-cone mediation using a 650-nm stimulus under dark-adapted conditions, whereas BCM patients had reduced sensitivity driven by rod vision. Full-field red stimuli on bright blue backgrounds were seen by L/M-cones in normal subjects whereas BCM patients had abnormally reduced and rod-mediated sensitivities. Fixation location could vary from fovea to parafovea. Chromatic microperimetry demonstrated a large loss of sensitivity to red stimuli presented on a cyan adapting background at the anatomical fovea and surrounding parafovea. Conclusions: BCM rods continue to signal vision under conditions normally associated with daylight vision. Localized and retina-wide outcome measures were examined to evaluate possible improvement of L/M-cone-based vision in a clinical trial. [ABSTRACT FROM AUTHOR]

Published
2015
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30. Gene Therapy for Retinitis Pigmentosa Caused by MFRPMutations: Human Phenotype and Preliminary Proof of Concept.

Author

Dinculescu, Astra, Estreicher, Jackie, Zenteno, Juan C., Aleman, Tomas S., Schwartz, Sharon B., Huang, Wei Chieh, Roman, Alejandro J., Sumaroka, Alexander, Li, Qiuhong, Deng, Wen-Tao, Min, Seok-Hong, Chiodo, Vince A., Neeley, Andy, Liu, Xuan, Shu, Xinhua, Matias-Florentino, Margarita, Buentello-Volante, Beatriz, Boye, Sanford L., Cideciyan, Artur V., and Hauswirth, William W.

Published
2012
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33. Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome.

Author

Wright, Alan F., Reddick, Adam C., Schwartz, Sharon B., Ferguson, Julie S., Aleman, Tomas S., Kellner, Ulrich, Jurklies, Bernhard, Schuster, Andreas, Zrenner, Eberhart, Wissinger, Bernd, Lennon, Alan, Shu, Xinhua, Cideciyan, Artur V., Stone, Edwin M., Jacobson, Samuel G., and Swaroop, Anand

Abstract

Ten new and seventeen previously reported Enhanced S Cone Syndrome (ESCS) subjects were used to search for genetic heterogeneity. All subjects were diagnosed with ESCS on the basis of clinical, psychophysical and/or electroretinography testing using published criteria. Mutation analysis was performed on the NR2E3 nuclear receptor gene by single strand conformation analysis and direct sequencing, which revealed either homozygous (N=13) or compound heterozygous (N=11) mutations in 24 subjects (89%), heterozygous mutations in 2 subjects (7%) and no mutations in 1 subject (4%). Fifteen different mutations were identified, including six not previously reported. The subject (Patient A) with no detected NR2E3 mutation had features not usually associated with ESCS, in particular moderate rod photoreceptor function in peripheral retina and an abnormally thick retinal nerve fibre layer. Mutation analysis of the NRL, CRX, NR1D1 and THRB genes in this individual revealed a heterozygous one base-pair insertion in exon 2 of the NRL gene, which results in a predicted truncation of the NRL protein. Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2004
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34. Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness

Author

Zeitz, Christina, Jacobson, Samuel G., Hamel, Christian P., Bujakowska, Kinga, Neuillé, Marion, Orhan, Elise, Zanlonghi, Xavier, Lancelot, Marie-Elise, Michiels, Christelle, Schwartz, Sharon B., Bocquet, Béatrice, Antonio, Aline, Audier, Claire, Letexier, Mélanie, Saraiva, Jean-Paul, Luu, Tien D., Sennlaub, Florian, Nguyen, Hoan, Poch, Olivier, and Dollfus, Hélène

Subjects
*NIGHT blindness, *GENETIC mutation, *VISUAL acuity, *LEUCINE, *IMMUNOGLOBULINS, *MEMBRANE proteins, *RETINAL diseases
Abstract

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440∗]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384∗]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs∗59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated. [ABSTRACT FROM AUTHOR]

Published
2013
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35. Multiple transmissions of Barth syndrome through an oocyte donor with a de novo TAZ mutation

Author

Kirwin, Susan M., Vinette, Kathy M., Schwartz, Sharon B., Funanage, Vicky L., and Gonzalez, Iris L.

Subjects
*GENETIC mutation, *DISEASES, *GENETICS, *OVUM
Abstract

Objective: To report recurrent transmissions of Barth syndrome through a single oocyte donor carrying a de novo TAZ mutation. Design: Case report. Setting: Clinical molecular diagnostics laboratory. Patient(s): Oocyte donor and individuals conceived with her oocytes. Intervention(s): Molecular testing. Main Outcome Measure(s): Detection of TAZ mutation. Result(s): Multiple individuals affected with Barth syndrome conceived from a single oocyte donor who is a carrier of a de novo TAZ mutation. Conclusion(s): We report multiple transmissions of Barth syndrome through a single oocyte donor with a de novo TAZ mutation. [Copyright &y& Elsevier]

Published
2007
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36. A Missense Mutation in DHDDS, Encoding Dehydrodolichyl Diphosphate Synthase, Is Associated with Autosomal-Recessive Retinitis Pigmentosa in Ashkenazi Jews

Author

Zelinger, Lina, Banin, Eyal, Obolensky, Alexey, Mizrahi-Meissonnier, Liliana, Beryozkin, Avigail, Bandah-Rozenfeld, Dikla, Frenkel, Shahar, Ben-Yosef, Tamar, Merin, Saul, Schwartz, Sharon B., Cideciyan, Artur V., Jacobson, Samuel G., and Sharon, Dror

Subjects
*RETINITIS pigmentosa, *MISSENSE mutation, *GENETIC code, *PYROPHOSPHATES, *ETIOLOGY of diseases, *CHROMOSOMES, *REVERSE transcriptase polymerase chain reaction, *PHOTORECEPTORS
Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 50 genes. Using homozygosity mapping in Ashkenazi Jewish (AJ) patients with autosomal-recessive RP (arRP), we identified a shared 1.7 Mb homozygous region on chromosome 1p36.11. Sequence analysis revealed a founder homozygous missense mutation, c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene (DHDDS) in 20 AJ patients with RP of 15 unrelated families. The mutation was not identified in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins. The mutation was found heterozygously in 1 out of 322 ethnically matched normal control individuals. RT-PCR analysis in 21 human tissues revealed ubiquitous expression of DHDDS. Immunohistochemical analysis of the human retina with anti-DHDDS antibodies revealed intense labeling of the cone and rod photoreceptor inner segments. Clinical manifestations of patients who are homozygous for the c.124A>G mutation were within the spectrum associated with arRP. Most patients had symptoms of night and peripheral vision loss, nondetectable electroretinographic responses, constriction of visual fields, and funduscopic hallmarks of retinal degeneration. DHDDS is a key enzyme in the pathway of dolichol, which plays an important role in N-glycosylation of many glycoproteins, including rhodopsin. Our results support a pivotal role of DHDDS in retinal function and may allow for new therapeutic interventions for RP. [ABSTRACT FROM AUTHOR]

Published
2011
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37. Leber Congenital Amaurosis Caused by an RPGRIP1 Mutation Shows Treatment Potential

Author

Jacobson, Samuel G., Cideciyan, Artur V., Aleman, Tomas S., Sumaroka, Alexander, Schwartz, Sharon B., Roman, Alejandro J., and Stone, Edwin M.

Subjects
*GENE therapy, *BLINDNESS, *OPTICAL coherence tomography, *VISUAL acuity
Abstract

Purpose: To determine the treatment potential in Leber congenital amaurosis (LCA) resulting from an RPGRIP1 (retinitis pigmentosa GTPase regulating–interacting protein 1) mutation, a form of LCA with recent gene therapy success in an animal model. Design: Case report of a rare genetic eye disease investigated for intervention potential. Participants: A 19-year-old man with LCA. Methods: We studied the retinal structure and function in an LCA patient with a novel homozygous Val1211Glu mutation in the RPGRIP1 gene using optical coherence tomography and colocalized dark-adapted thresholds. Main Outcome Measure: Optical coherence tomography results. Results: Central retinal laminar architecture was preserved, and there was a measurable outer nuclear layer. The retained retinal structure corresponded to the region of visual sensitivity. With increasing eccentricity, there was no measurable visual function, and retinal laminar disorganization suggested a remodeling process. Conclusions: The RPGRIP1-LCA patient has treatment potential for a gene replacement strategy if targeted to central, but not pericentral or peripheral, retina. The results differ from similarly studied RPE65-LCA and CRB1-LCA patients. Preclinical progress toward therapy in LCA patients warrants detailed structure-function studies in humans to determine feasibility and candidacy for clinical trials. [Copyright &y& Elsevier]

Published
2007
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38. 881. Safety, Efficacy and Biodistribution of Recombinant AAV2-RPE65 Vector Delivered by Ocular Subretinal Injection.

Author

Jacobson, Samuel G., Acland, Gregory M., Aguirre, Gustavo D., Aleman, Tomas S., Boye, Sanford L., Schwartz, Sharon B., Cideciyan, Artur V., Zeiss, Caroline J., Komaromy, Andras M., Roman, Alejandro J., Windsor, Elizabeth A. M., Sumaroka, Alexander, Pearce-Kelling, Susan E., Conlon, Thomas J., Quihong Li, Chiodo, Vincent A., Flotte, Terence R., Maguire, Albert M., Bennett, Jean, and Hauswirth, William W.

Subjects
*TOXICOLOGY, *HISTOPATHOLOGY, *PATHOLOGY, *BLINDNESS, *DNA
Abstract

Introduction: AAV2 delivery of the RPE65 cDNA to the retina of blind RPE65-deficient dogs or rd12 mice restores vision as determined electrophysiologically and behaviorally. This strategy is being considered for human trials in RPE65-associated Leber congenital amaurosis, but safety and dose-efficacy within a non-toxic range with this vector have not been defined. Here we report the results of toxicology and biodistribution studies in two mammalian species, dogs and rats. Methods: Vector related pathology and spread after subretinal delivery of AAV2-CBA-RPE65 was studied in RPE65-mutant dogs and normal Spague-Dawley rats. Doses of vector delivered bracketed those intended for the clinical study. Results: There was no systemic toxicity at any vector dose in either species. In dogs ocular examinations showed mild or moderate inflammation that resolved over an initial 3-month period. Retinal histopathology indicated that traumatic lesions from the injection were common, but retinal thinning within the injection region only occurred at the highest vector doses. Biodistribution studies were also performed in RPE65-mutant dogs at various times after vector injection and in normal rats at about 2 weeks and 2 months post-injection. Vector DNA was not widespread outside the injected eye with blood and gonadal tissue consistently negative. Concomitant dose-response results in the RPE65-mutant dogs indicated that the highest 1.5 log unit range of vector doses was efficacious. Conclusions: Given the efficacy and toxicity limits defined in this study, a range for safe vector dose escalation of subretinal AAV2-CBA-RPE65 is suggested for initial human trials.Molecular Therapy (2006) 13, S339–S339; doi: 10.1016/j.ymthe.2006.08.970 [ABSTRACT FROM AUTHOR]

Published
2006
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