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3. Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

Author

Hsueh, Henry T., Chou, Renee Ti, Rai, Usha, Liyanage, Wathsala, Kim, Yoo Chun, Appell, Matthew B., Pejavar, Jahnavi, Leo, Kirby T., Davison, Charlotte, Kolodziejski, Patricia, Mozzer, Ann, Kwon, HyeYoung, Sista, Maanasa, Anders, Nicole M., Hemingway, Avelina, Rompicharla, Sri Vishnu Kiran, Edwards, Malia, Pitha, Ian, Hanes, Justin, Cummings, Michael P., and Ensign, Laura M.

Published
2023
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5. Engineered peptide-drug conjugate provides sustained protection of retinal ganglion cells with topical administration in rats

Author

Hsueh, Henry T., Chou, Renee Ti, Rai, Usha, Kolodziejski, Patricia, Liyanage, Wathsala, Pejavar, Jahnavi, Mozzer, Ann, Davison, Charlotte, Appell, Matthew B., Kim, Yoo Chun, Leo, Kirby T., Kwon, HyeYoung, Sista, Maanasa, Anders, Nicole M., Hemingway, Avelina, Rompicharla, Sri Vishnu Kiran, Pitha, Ian, Zack, Donald J., Hanes, Justin, Cummings, Michael P., and Ensign, Laura M.

Published
2023
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7. A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Author

Kim, Yoo Chun, Hsueh, Henry T., Shin, Matthew D., Berlinicke, Cynthia A., Han, Hyounkoo, Anders, Nicole M., Hemingway, Avelina, Leo, Kirby T., Chou, Renee Ti, Kwon, HyeYoung, Appell, Matthew B., Rai, Usha, Kolodziejski, Patricia, Eberhart, Charles, Pitha, Ian, Zack, Donald J., Hanes, Justin, and Ensign, Laura M.

Published
2022
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9. Gelling hypotonic polymer solution for extended topical drug delivery to the eye

Author

Kim, Yoo Chun, Shin, Matthew D., Hackett, Sean F., Hsueh, Henry T., Lima e Silva, Raquel, Date, Abhijit, Han, Hyounkoo, Kim, Byung-Jin, Xiao, Amy, Kim, Youngwook, Ogunnaike, Laolu, Anders, Nicole M., Hemingway, Avelina, He, Ping, Jun, Albert S., McDonnell, Peter J., Eberhart, Charles, Pitha, Ian, Zack, Donald J., Campochiaro, Peter A., Hanes, Justin, and Ensign, Laura M.

Published
2020
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11. Supplementary materials for machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

Author

Chou, Renee Ti, Cummings, Michael P., Ensign, Laura M., Chou, Renee Ti, Hsueh, Henry T., Rai, Usha, Liyanage, Wathsala, Kim, Yoo Chun, Appell, Matthew B., Pejavar, Jahnavi, Leo, Kirby T., Davison, Charlotte, Kolodziejski, Patricia, Mozzer, Ann, Kwon, HyeYoung, Sista, Maanasa, Anders, Nicole M., Hemingway, Avelina, Rompicharla, Sri Vishnu Kiran, Edwards, Malia, Pitha, Ian, Hanes, Justin, Chou, Renee Ti, Cummings, Michael P., Ensign, Laura M., Chou, Renee Ti, Hsueh, Henry T., Rai, Usha, Liyanage, Wathsala, Kim, Yoo Chun, Appell, Matthew B., Pejavar, Jahnavi, Leo, Kirby T., Davison, Charlotte, Kolodziejski, Patricia, Mozzer, Ann, Kwon, HyeYoung, Sista, Maanasa, Anders, Nicole M., Hemingway, Avelina, Rompicharla, Sri Vishnu Kiran, Edwards, Malia, Pitha, Ian, and Hanes, Justin

Abstract

Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We developed a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) was conjugated to brimonidine, an intraocular pressure (IOP)-lowering drug that is prescribed for three times per day topical dosing, IOP reduction was observed for up to 18 days after a single intracameral HR97-brimonidine injection in rabbits. Further, the cumulative IOP-lowering effect was increased ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.

Published
2023

13. Nanofiber‐based glaucoma drainage implant improves surgical outcomes by modulating fibroblast behavior

Author

Josyula, Aditya, primary, Mozzer, Ann, additional, Szeto, Julia, additional, Ha, Youlim, additional, Richmond, Nicole, additional, Chung, Seung Woo, additional, Rompicharla, Sri Vishnu Kiran, additional, Narayan, Janani, additional, Ramesh, Samiksha, additional, Hanes, Justin, additional, Ensign, Laura, additional, Parikh, Kunal, additional, and Pitha, Ian, additional

Published
2023
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16. Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Author

Bacharach, Jason, Tatham, Andrew, Ferguson, Gloria, Belalcázar, Sandra, Thieme, Hagen, Goodkin, Margot L., Chen, Michelle Y., Guo, Qiang, Liu, Jeen, Robinson, Michael R., Bejanian, Marina, Wirta, David L., Alezzandrini, Arturo, Bercovich, Gabriel, Deromedis, Pablo, Furno Sola, Federico, Gentile, Carolina, Lerner, Simon, Lupinacci, Anahi, Zeolite, Carlos, Birt, Catherine, Crichton, Andrew, Gagne, Sebastien, Giunta, Michael, Harasymowycz, Paul, Jinapriya, Delan, Nicolela, Marcelo, Nixon, Donald, Saurel, Patrick, Yan, David, Yuen, Darana, Arango, Santiago, Martinez, Alexander, Parra Restrepo, Juan C., Korda, Vladimir, Kadlecova, Jana, Svacinova, Jitka, Khairy, Hany, El Ibiary, Hani, El Sanabary, Zeinab, Bell, Katharina, Greslechner, Roman, Koch, Jöerg, Lorenz, Katrin, Oberacher-Velten, Isabel, Schmickler, Stefanie, Schuart, Claudie, Bandello, Francesco, Cagini, Carlos, Figus, Michele, Mastropasqua, Leonardo, Rossetti, Luca, Uva, Maurizio G., Thayanithi, Sandragasu, Wells, Anthony, Husain, Rahat, Koh, Victor, Lim, Dawn, Tin, Aung, Gous, Petrus, Venter, Lynette, Kee, Changwon, Kook, Michael, Park, Ki-Ho, Eraslan, Muhsin, Kayikcioglu, Ozcan, Yildirim, Nilgun, Bourne, Rupert R. A., Choudhary, Anshoo, Cordeiro, Francesca, Dubois, Vincent, Kirwan, James, Lim, Sheng, Martin, Keith, Nithy, Antony, Prabhu, Avinash, Amir, Ahmad, Barnebey, Howard, Beck, Allen, Bergstrom, Lance, Borisuth, Navaneet, Branch, James D., Briggs, Jonathan, Bylsma, Stephen, Chang, Peter, Christie, William, Cotter, Frank, Depenbusch, Michael, Goldberg, Damien F., Greiner, Jack, Gupta, Shailesh, Gutmark, Ron, Han, Ying, Heersink, Sebastian, Kahook, Malik, Khouri, Albert, Kim, Joshua, Kushnick, Howard, Lin, Christopher, Luchs, Jodi, Maharaj, Arindel, Mansberger, Steven L., Mares, Frank, Miller-Ellis, Eydie, Modi, Satish, Paul, Matthew, Pitha, Ian, Saltzmann, Robert, Sato, Michelle, Savestsky, Michael, Segal, Bruce, Segal, Zachary, Serle, Janet, Sherwood, Mark, Singh, Inder, Smith, Stephen E., Song, Julia, Sorenson, Robert, Tenkman, Lawrence, Tekwani, Navin, Tubbs, Carl, Tyson, Farrell, Vizzeri, Gianmarco, Vold, Steven, Vu, Qui, Warren, Kimberly S., and Wirta, David

Subjects
genetic structures, sense organs, eye diseases
Abstract

Objective-\ud \ud To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).\ud \ud Methods-\ud \ud This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD).\ud \ud Results-\ud \ud Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group.\ud \ud Conclusions-\ud \ud The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma.

Published
2021

17. List of Contributors

Author

Abrams-Tobe, Leslie, primary, Abuswider, Samer A, additional, Acosta, Jorge, additional, Agrawal, Pavi, additional, Albis-Donado, Oscar, additional, Alencar, Luciana M, additional, Allingham, R Rand, additional, Amireskandari, Annahita, additional, Anand, Nitin, additional, Aptel, Florent, additional, Araie, Makoto, additional, Arcieri, Enyr S, additional, Assia, Ehud I, additional, Aung, Tin, additional, Baerveldt, George, additional, Baig, Nafees, additional, Baik, Annie K, additional, Bansal, Rajendra K, additional, Babic, Mirko, additional, Barikian, Anita, additional, Barnebey, Howard, additional, Barton, Keith, additional, Baudouin, Christophe, additional, Beck, Allen, additional, Bennett, Sonya L, additional, Berke, Stanley J, additional, Bevin, Tui H, additional, Bhartiya, Shibal, additional, Bloom, Philip A, additional, Blumberg, Dana M, additional, Bollinger, Kathryn, additional, Bowd, Christopher, additional, Boyle, John W, additional, Brandt, James D, additional, Broadway, David C, additional, Brocchini, Stephen, additional, Bron, Alain M, additional, Budenz, Donald L, additional, Bunce, Catey, additional, Burgoyne, Claude F, additional, Burr, Jennifer, additional, Buys, Yvonne M, additional, Cantor, Louis B, additional, Caprioli, Joseph, additional, Carassa, Roberto G, additional, Casper, Daniel S, additional, Catoira-Boyle, Yara Paula, additional, Ceruti, Piero, additional, Chakrabarti, Debasis, additional, Chakrabarti, Raka, additional, Challa, Pratap, additional, Chan, Errol, additional, Chang, Peter T, additional, Chang, Robert T, additional, Chauhan, Balwantray C, additional, Chen, Aiyin, additional, Cheng, Jason, additional, Chew, Paul TK, additional, Chiang, Mark, additional, Chihara, Etsuo, additional, Choplin, Neil T, additional, Cioffi, George A, additional, Clement, Colin I, additional, Coleman, Anne L, additional, Congdon, Nathan G, additional, Coote, Michael A, additional, Costa, Vital P, additional, Crabb, David P, additional, Crandall, Alan S, additional, Craven, E Randy, additional, Crawley, Laura, additional, Crowston, Jonathan G, additional, Cunningham, Emmett T, additional, Dahan, Elie, additional, Dahlmann-Noor, Annegret H, additional, Damji, Karim F, additional, Day, Alexander, additional, Day, Me'Ja, additional, Denis, Philippe, additional, Dorairaj, Syril, additional, Downs, J Crawford, additional, Dutton, Gordon N, additional, Eldaly, Hassan, additional, El Sayyad, Fathi F, additional, Falsini, Benedetto, additional, Fantes, Francisco, additional, Fechter, Herbert P, additional, Fechtner, Robert D, additional, Fellman, Ronald L, additional, Fenwick, Eva, additional, Fernando, Arosha, additional, Fisher, Ann Caroline, additional, Fitzke, Frederick W, additional, Fortune, Brad, additional, Foster, Paul, additional, Founti, Panayiota, additional, Freedman, Jeffrey, additional, Gandolfi, Stefano A, additional, García-Feijoó, Julián, additional, Garway-Heath, David, additional, Gazzard, Gus, additional, Gedde, Steven J, additional, Geffen, Noa, additional, Georgoulas, Stelios, additional, Giangiacomo, Annette, additional, Gill, Katie, additional, Gkatzioufas, Zisis, additional, Goldberg, Ivan, additional, Gouws, Pieter, additional, Graham, Stuart L, additional, Grajewski, Alana L, additional, Greenfield, David S, additional, Grehn, Franz, additional, Grigera, Daniel E, additional, Gross, Ronald L, additional, Grover, Davinder S, additional, Grytz, Rafael, additional, Gupta, Meenakashi, additional, Gupta, Neeru, additional, de Moraes, Carlos Gustavo, additional, Hafez, Ali S, additional, Hafezi, Farhad, additional, Hamanaka, Teruhiko, additional, Harris, Alon, additional, Hatanaka, Marcelo, additional, Hawker, Matthew J, additional, Healey, Paul R, additional, Heatley, The late Catherine J, additional, Heuer, Dale K, additional, Higginbotham, Eve J, additional, Hirn, Cornelia, additional, Hitchings, Roger A, additional, Holló, Gábor, additional, Hoste, Ann M, additional, Huck, Andrew, additional, Hutnik, Cindy ML, additional, Hylton, Camille, additional, Ittoop, Sabita M, additional, Ja'afar, Farrah, additional, Jampel, Henry, additional, Johnson, Thomas V, additional, Jonas, Jost B, additional, Kahook, Malik Y, additional, Kass, Michael A, additional, Katsanos, Andreas, additional, Katz, L Jay, additional, Keeffe, Jill E, additional, Kersey, Thomas, additional, Khachatryan, Naira, additional, Khaw, Sir Peng Tee, additional, Khouri, Albert S, additional, Kiage, Dan, additional, Kiang, Lee, additional, Kim, Danny, additional, Kiuchi, Yoshiaki, additional, Klink, Thomas, additional, Koenigsman, Helen, additional, Konstas, Anastasios GP, additional, Kotecha, Aachal, additional, Kulkarni, Avinash, additional, Kuroyedov, Alexander V, additional, Labbé, Antoine, additional, Lacey, Alan, additional, Lam, Dennis SC, additional, Lamourex, Ecosse L, additional, Lee, Graham, additional, Lee, Paul, additional, Lemij, Hans G, additional, Leoncavallo, Anthony, additional, Lesk, Mark R, additional, Leung, Christopher KS, additional, Leung, Dexter YL, additional, Levin, Leonard A, additional, Lewis, Richard A, additional, Lim, K Sheng, additional, Lim, Ridia, additional, Lima, Ricardo de, additional, Liu, Yutao, additional, Lockwood, Alastair, additional, Low, Sancy, additional, Mabuchi, Fumihiko, additional, Mackey, David A, additional, Malik, Rizwan, additional, Mandal, Anil K, additional, Mansberger, Steven L, additional, Mansouri, Kaweh, additional, Marchini, Giorgio, additional, Marella, Manjula, additional, Martin, Keith R, additional, McGlynn, Robert H, additional, McKinley, Steven H, additional, McKinnon, Stuart J, additional, McManus, J Ryan, additional, Medeiros, Felipe A, additional, Mermoud, André, additional, Migdal, Clive S, additional, Minckler, Don, additional, Molteno, Anthony CB, additional, Mora, Paolo, additional, Moreno-Montañés, Javier, additional, Morgan, James E, additional, Mosaed, Sameh, additional, Moschos, Marilita M, additional, Muir, Kelly W, additional, Muñoz, Gonzalo, additional, Muñoz-Negrete, Francisco J, additional, Neelakantan, Arvind, additional, Negi, Anil K, additional, Netland, Peter A, additional, Newman-Casey, Paula Anne, additional, Nicolela, Marcelo T, additional, Niyadurupola, Nuwan, additional, Nofal, Magdy A, additional, Nolan, Winnie, additional, Nongpiur, Monisha E, additional, Noureddin, Baha'a N, additional, Novack, Gary D, additional, Nuyen, Brenda, additional, Palaniswamy, Krishnamurthy, additional, Palma, Camille, additional, Park, Ki Ho, additional, Parrish, Richard K, additional, Papadopoulos, Maria, additional, Parikh, Rajul S, additional, Pasquale, Louis R, additional, Pébay, Alice, additional, Petrov, Sergey, additional, Piltz-Seymour, Jody, additional, Pinto, Luís Abegão, additional, Pitha, Ian F, additional, Pfeiffer, Norbert, additional, Quaranta, Luciano, additional, Ramulu, Pradeep Y, additional, Ravinet, Emilie, additional, Realini, Tony, additional, Rebolleda, Gema, additional, Reus, Nic J, additional, Reynolds, Adam C, additional, Rhee, Douglas J, additional, Riss, Isabelle, additional, Ritch, Robert, additional, Riva, Charles E, additional, Roberti, Gloria, additional, Roberts, Cynthia J, additional, Robin, Alan L, additional, Rojanapongpun, Prin, additional, Roy, Sylvain, additional, Salmon, John F, additional, Sampaolesi, Juan Roberto, additional, Sangermani, Chiara, additional, Sarodia, Usman A, additional, Schaefer, Jamie Lea, additional, Schloetzer-Schrehardt, Ursula, additional, Schultz, Gregory S, additional, Schuman, Joel S, additional, Seibold, Leonard K, additional, Shaarawy, Tarek M, additional, Shah, Peter, additional, Sherwood, Mark B, additional, Shiroma, Lineu Oto, additional, Siesky, Brent, additional, Silva, Sergio Estrela, additional, Singh, Annapurna, additional, Singh, Arun D, additional, Singh, Kuldev, additional, Sng, Chelvin CA, additional, Song, Brian J, additional, Spaeth, George L, additional, Spratt, Alexander, additional, Stalmans, Ingeborg, additional, Stamper, Robert L, additional, Sugiyama, Kazuhisa, additional, Susanna, Remo, additional, Suwanpimolkul, Orathai, additional, Swanson, William H, additional, Tamm, Ernst R, additional, Tania Tai, Tak Yee, additional, Tanna, Angelo P, additional, Teekhasaenee, Chaiwat, additional, Tham, Clement CY, additional, Thieme, Hagen, additional, Thomas, Ravi, additional, Thompson, Andrew M, additional, Thulasiraj, Ravilla D, additional, Thygesen, John, additional, Tomey, Karim, additional, Ton, Yokrat, additional, Topouzis, Fotis, additional, Toris, Carol B, additional, Tosi, Roberto, additional, Tsai, James C, additional, Tuli, Sonal S, additional, Tuulonen, Anja, additional, Ungaro, Nicola, additional, Vale, Luke, additional, van Koolwijk, Leonieke ME, additional, Vaswani, Reena S, additional, Venkatesh, Rengaraj, additional, Venturini, Cristina, additional, Vernon, Stephen A, additional, Vithana, Eranga N, additional, Vijaya, Lingam, additional, Viswanathan, Ananth C, additional, Vizzari, Gabriele, additional, Voudouragkaki, Irini C, additional, Waisbourd, Michael, additional, Walland, Mark J, additional, Weinreb, Robert N, additional, Werner, Mark, additional, Wells, Anthony, additional, Wiafe, Boateng, additional, Wilensky, Jacob, additional, Wong, Tina T, additional, WuDunn, Darrell, additional, Yip, Jennifer LY, additional, Yucel, Yeni, additional, Zangwill, Linda M, additional, Zanutigh, Virginia E, additional, Zelefsky, Joseph R, additional, and Zeyen, Thierry, additional

Published
2015
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20. Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

Author

Hsueh, Henry T., primary, Kim, Yoo-Chun, additional, Pitha, Ian, additional, Shin, Matthew D., additional, Berlinicke, Cynthia A., additional, Chou, Renee Ti, additional, Kimball, Elizabeth, additional, Schaub, Julie, additional, Quillen, Sarah, additional, Leo, Kirby T., additional, Han, Hyounkoo, additional, Xiao, Amy, additional, Kim, Youngwook, additional, Appell, Matthew, additional, Rai, Usha, additional, Kwon, HyeYoung, additional, Kolodziejski, Patricia, additional, Ogunnaike, Laolu, additional, Anders, Nicole M., additional, Hemingway, Avelina, additional, Jefferys, Joan L., additional, Date, Abhijit A., additional, Eberhart, Charles, additional, Johnson, Thomas V., additional, Quigley, Harry A., additional, Zack, Donald J., additional, Hanes, Justin, additional, and Ensign, Laura M., additional

Published
2021
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21. A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Author

Kim, Yoo Chun, primary, Hsueh, Henry T., additional, Shin, Matthew D., additional, Berlinicke, Cynthia A., additional, Han, Hyounkoo, additional, Anders, Nicole M., additional, Hemingway, Avelina, additional, Leo, Kirby T., additional, Chou, Renee Ti, additional, Kwon, HyeYoung, additional, Appell, Matthew B., additional, Rai, Usha, additional, Kolodziejski, Patricia, additional, Eberhart, Charles, additional, Pitha, Ian, additional, Zack, Donald J., additional, Hanes, Justin, additional, and Ensign, Laura M., additional

Published
2021
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23. A novel bilayered expanded polytetrafluoroethylene glaucoma implant creates a permeable thin capsule independent of aqueous humor exposure

Author

Bicket, Amanda Kiely, primary, Szeto, Julia, additional, Roeber, Peter, additional, Towler, Jeff, additional, Troutman, Mitch, additional, Craven, E. Randy, additional, Khatana, Anup, additional, Ahmed, Ike, additional, Quigley, Harry, additional, Ramulu, Pradeep, additional, and Pitha, Ian F., additional

Published
2020
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27. Reply

Author

Iyer, Jayant V., primary, Pitha, Ian, additional, Jampel, Henry D., additional, and Boland, Michael V., additional

Published
2020
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29. A novel bilayered expanded polytetrafluoroethylene glaucoma implant creates a permeable thin capsule independent of aqueous humor exposure.

Author

Bicket, Amanda Kiely, Szeto, Julia, Roeber, Peter, Towler, Jeff, Troutman, Mitch, Craven, E. Randy, Khatana, Anup, Ahmed, Ike, Quigley, Harry, Ramulu, Pradeep, and Pitha, Ian F.

Subjects
AQUEOUS humor, GLAUCOMA, PHYSIOLOGIC salines, INTRAOCULAR pressure, STEADY-state flow, PRESSURE control, POLYTEF, FLUORESCEIN
Abstract

The purpose of these studies was to evaluate clinical, functional, and histopathological features of glaucoma drainage implants (GDIs) fabricated from novel, custom‐tailored expanded polytetrafluoroethylene (ePTFE). Implants of matching footprints were fabricated from silicone (Control) and novel, bilayered ePTFE. ePTFE implants included: (a) one that inflated with aqueous humor (AH) (High), (b) one that inflated with a lower profile (Low), (c) an uninflated implant not connected to the anterior chamber (Flat), and (d) one filled with material that did not allow AH flow (Filled). All implants were placed in adult New Zealand White rabbits and followed over 1–3 months with clinical exams and intraocular pressure. The permeability of tissue capsules surrounding GDIs was assessed using constant‐flow perfusion with fluoresceinated saline at physiologic flow rates. After sacrifice, quantitative histopathological measures of capsule thickness were compared among devices, along with qualitative assessment of cellular infiltration and inflammation. Capsular thickness was significantly reduced in blebs over ePTFE (61.4 ± 53 μm) versus silicone implants (193.6 ± 53 μm, p =.0086). AH exposure did not significantly alter capsular thickness, as there was no significant difference between High and Filled (50.9 ± 29, p =.34) implants. Capsules around ePTFE implants demonstrated permeability with steady‐state pressure: flow relationships at physiologic flow rates and rapid pressure decay with flow cessation, while pressure in control blebs increased even at low flow rates and showed little decay. Perfused fluorescein dye appeared beyond the plate border only in ePTFE implants. ePTFE implants are associated with thinner, more permeable capsules compared to silicone implants simulating presently used devices. [ABSTRACT FROM AUTHOR]

Published
2021
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37. Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma

Author

Quigley, Harry A., primary, Pitha, Ian F., additional, Welsbie, Derek S., additional, Nguyen, Cathy, additional, Steinhart, Matthew R., additional, Nguyen, Thao D., additional, Pease, Mary Ellen, additional, Oglesby, Ericka N., additional, Berlinicke, Cynthia A., additional, Mitchell, Katherine L., additional, Kim, Jessica, additional, Jefferys, Joan J., additional, and Kimball, Elizabeth C., additional

Published
2015
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39. The Mechanisms of Neuroprotection by Topical Rho Kinase Inhibition in Experimental Mouse Glaucoma and Optic Neuropathy.

Author

Quillen SE, Kimball EC, Ritter-Gordy KA, Du L, Yuan Z, Pease ME, Madhoun S, Nguyen TD, Johnson TV, Quigley HA, and Pitha IF

Subjects
Animals, Mice, Neuroprotective Agents administration & dosage, Optic Nerve Diseases prevention & control, Optic Nerve Diseases metabolism, Optic Nerve Diseases drug therapy, Optic Nerve Diseases etiology, Neuroprotection drug effects, Male, Blotting, Western, Ophthalmic Solutions, Administration, Topical, Axonal Transport drug effects, Astrocytes metabolism, Astrocytes drug effects, rho-Associated Kinases antagonists & inhibitors, Glaucoma drug therapy, Glaucoma metabolism, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells pathology, Retinal Ganglion Cells metabolism, Disease Models, Animal, Isoquinolines pharmacology, Isoquinolines administration & dosage, Intraocular Pressure physiology, Intraocular Pressure drug effects, Mice, Inbred C57BL, Sulfonamides administration & dosage, Sulfonamides pharmacology
Abstract

Purpose: The purpose of this study was to delineate the neuroprotective mechanisms of topical 2% ripasudil (Rip), a Rho kinase (ROCK) inhibitor., Methods: In 340 mice, scheduled 2% Rip or balanced salt solution (BSS) saline drops were intermittently, unilaterally delivered. Intracameral microbead glaucoma (GL) injection increased intraocular pressure (IOP) from 1 day to 6 weeks (6W), whereas other mice underwent optic nerve (ON) crush. Retinal ganglion cell (RGC) loss was assessed using retinal wholemount anti-RNA Binding Protein with Multiple Splicing (RBPMS) labeling and ON axon counts. Axonal transport was quantified with β-amyloid precursor protein (APP) immunolocalization. Micro-Western (Wes) analysis quantified protein expression. Immunofluorescent expression of ROCK pathway molecules, quantitative astrocyte structural changes, and ON biomechanical strains (explanted eyes) were evaluated. ROCK activity assays were conducted in separate ON regions., Results: At 6W GL, mean RGC axon loss was 6.6 ± 13.3% in Rip and 36.3 ± 30.9% in BSS (P = 0.04, n = 10/group). RGC soma loss after crush was lower with Rip (68.6 ± 8.2%) than BSS (80.5 ± 5.7%, P = 0.006, n = 10/group). After 6W GL, RGC soma loss was lower with Rip (34 ± 5.0%) than BSS (51 ± 8.1%, P = 0.03, n = 10/group). Axonal transport of APP within the unmyelinated ON (UON) was unaffected by Rip. Maximum principal mechanical strains increased similarly in Rip and BSS-treated mice. Retinal ROCK 1 and 2 activity was reduced by Rip in GL eyes. The pROCK2/ROCK2 protein ratio rose in the retina of BSS GL eyes, but not in Rip GL eyes., Conclusions: Topical Rip reduced RGC loss in GL and ON crush, with suppression of ROCK signaling in the retina and ON. The neuroprotection mechanisms appear to involve effects on both RGC and astrocyte responses to IOP elevation.

Published
2024
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