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2. SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance

Author

Wykoff, Charles C., Avery, Robert L., Barakat, Mark R., Boyer, David S., Brown, David M., Brucker, Alexander J., Cunningham, Emmett T., Jr, Heier, Jeffrey S., Holekamp, Nancy M., Kaiser, Peter K., Khanani, Arshad M., Kim, Judy E., Demirci, Hakan, Regillo, Carl D., Yiu, Glenn C., and Ciulla, Thomas A.

Published
2024
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6. Host Immune Responses after Suprachoroidal Delivery of AAV8 in Nonhuman Primate Eyes

Author

Chung, Sook Hyun, Mollhoff, Iris Natalie, Mishra, Alaknanda, Sin, Tzu-Ni, Ngo, Taylor, Ciulla, Thomas, Sieving, Paul, Thomasy, Sara M, and Yiu, Glenn

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Immunology, Ophthalmology and Optometry, Neurosciences, Eye Disease and Disorders of Vision, Gene Therapy, Biotechnology, Genetics, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Eye, Animals, Dependovirus, Genetic Vectors, Immunity, Macaca mulatta, Tissue Distribution, suprachoroidal injection, AAV, ocular gene therapy, host immune response, Clinical Sciences, Medical biotechnology
Abstract

The suprachoroid is a potential space located between the sclera and choroid of the eye, which provides a novel route for ocular drug or viral vector delivery. Suprachoroidal injection of adeno-associated virus (AAV)8 using transscleral microneedles enables widespread transgene expression in eyes of nonhuman primates, but may cause intraocular inflammation. We characterized the host humoral and cellular immune responses after suprachoroidal delivery of AAV8 expressing green fluorescent protein (GFP) in rhesus macaques, and found that it can induce mild chorioretinitis that resolves after systemic corticosteroid administration, with recovery of photoreceptor morphology, but persistent immune cell infiltration after 3 months, corresponding to a loss of GFP expression from retinal pigment epithelial cells, but persistent expression in scleral fibroblasts. Suprachoroidal AAV8 triggered B cell and T cell responses against GFP, but only mild antibody responses to the viral capsid compared to intravitreal injections of the same vector and dose. Systemic biodistribution studies showed lower AAV8 levels in liver and spleen after suprachoroidal injection compared with intravitreal delivery. Our findings suggest that suprachoroidal AAV8 primarily triggers host immune responses to GFP, likely due to sustained transgene expression in scleral fibroblasts outside the blood-retinal barrier, but elicits less humoral immune reactivity to the viral capsid than intravitreal delivery due to lower egress into systemic circulation. As GFP is not native to primates and not a clinically relevant transgene, suprachoroidal AAV delivery of human transgenes may have significant translational potential for retinal gene therapy.

Published
2021

7. Prediction for 2-Year Vision Outcomes Using Early Morphologic and Functional Responses in the Comparison of Age-related Macular Degeneration Treatments Trials

Author

Williams, David F., Beardsley, Sara, Bennett, Steven, Cantrill, Herbert, Chan-Tram, Carmen, Cheshier, Holly, Damato, Kathyrn, Davies, John, Dev, Sundeep, Enloe, Julianne, Follano, Gennaro, Gilbert, Peggy, Johnson, Jill, Jones, Tori, Mayleben, Lisa, Mittra, Robert, Moos, Martha, Neist, Ryan, Oestreich, Neal, Quiram, Polly, Ramsay, Robert, Ryan, Edwin, Schindeldecker, Stephanie, Snater, John, Steele, Trenise, Selders, Dwight, Tonsfeldt, Jessica, Valardi, Shelly, Fish, Gary Edd, Aguado, Hank A., Arceneaux, Sally, Arnwine, Jean, Bell, Kim, Bell, Tina, Boleman, Bob, Bradley, Patricia, Callanan, David, Coors, Lori, Creighton, Jodi, Crew, Timothy, Cummings, Kimberly, Dock, Christopher, Duignan, Karen, Fuller, Dwain, Gray, Keith, Hendrix, Betsy, Hesse, Nicholas, Jaramillo, Diana, Jost, Bradley, Lash, Sandy, Lonsdale, Laura, Mackens, Michael, Mutz, Karin, Potts, Michael, Sanchez, Brenda, Snyder, William, Solley, Wayne, Tarter, Carrie, Wang, Robert, Williams, Patrick, Perkins, Stephen L., Anderson, Nicholas, Arnold, Ann, Blais, Paul, Googe, Joseph, Higdon, Tina T., Hunt, Cecile, Johnson, Mary, Miller, James, Moore, Misty, Morris, Charity K., Morris, Christopher, Oelrich, Sarah, Oliver, Kristina, Seitz, Vicky, Whetstone, Jerry, Doft, Bernard H., Bedel, Jay, Bergren, Robert, Borthwick, Ann, Conrad, Paul, Fec, Amanda, Fulwylie, Christina, Ingram, Willia, Latham, Shawnique, Lester, Gina, Liu, Judy, Lobes, Louis, Lucko, Nicole M., Mechling, Holly, Merlotti, Lori, McBroom, Keith, Olsen, Karl, Puskas, Danielle, Rath, Pamela, Schmucker, Maria, Schueckler, Lynn, Schultz, Christina, Shultz, Heather, Steinberg, David, Vyas, Avni, Whale, Kim, Yeckel, Kimberly, Orth, David H., Arredondo, Linda S., Brown, Susan, Ciscato, Barbara J., Civantos, Joseph M., Figliulo, Celeste, Hasan, Sohail, Kosinski, Belinda, Muir, Dan, Nelson, Kiersten, Packo, Kirk, Pollack, John S., Rezaei, Kourous, Shelton, Gina, Townsend-Patrick, Shannya, Walsh, Marian, McDonald, H. Richard, Ansari, Nina, Bye, Amanda, Fu, Arthur D., Grout, Sean, Indermill, Chad, Johnson, Robert N., Jumper, J. Michael, Linares, Silvia, Lujan, Brandon J., Munden, Ames, Persons, Meredith, Rodriguez, Rosa, Rose, Jennifer M., Teske, Brandi, Urias, Yesmin, Young, Stephen, Dreyer, Richard F., Daniel, Howard, Connaughton, Michele, Handelman, Irvin, Hobbs, Stephen, Hoerner, Christine, Hudson, Dawn, Kopfer, Marcia, Lee, Michael, Lemley, Craig, Logan, Joe, Ma, Colin, Mallet, Christophe, Milliron, Amanda, Peters, Mark, Wohlsein, Harry, Pearlman, Joel A., Andrews, Margo, Bartlett, Melissa, Carlson, Nanette, Cox, Emily, Equi, Robert, Gonzalez, Marta, Griffin, Sophia, Hogue, Fran, Kennedy, Lance, Kryuchkov, Lana, Lopez, Carmen, Lopez, Danny, Luevano, Bertha, McKenna, Erin, Patel, Arun, Reed, Brian, Secor, Nyla, Sison, Iris R., Tsai, Tony, Varghis, Nina, Waller, Brooke, Wendel, Robert, Yebra, Reina, Roth, Daniel B., Deinzer, Jane, Fine, Howard, Green, Flory, Green, Stuart, Keyser, Bruce, Leff, Steven, Leviton, Amy, Martir, Amy, Mosenthine, Kristin, Muscle, Starr, Okoren, Linda, Parker, Sandy, Prenner, Jonathan, Price, Nancy, Rogers, Deana, Rosas, Linda, Schlosser, Alex, Studenko, Loretta, Tantum, Thea, Wheatley, Harold, Trese, Michael T., Aaberg, Thomas, Bezaire, Denis, Bridges, Craig, Bryant, Doug, Capone, Antonio, Coleman, Michelle, Consolo, Christina, Cook, Cindy, DuLong, Candice, Garretson, Bruce, Grooten, Tracy, Hammersley, Julie, Hassan, Tarek, Jessick, Heather, Jones, Nanette, Kinsman, Crystal, Krumlauf, Jennifer, Lewis, Sandy, Locke, Heather, Margherio, Alan, Markus, Debra, Marsh, Tanya, Neal, Serena, Noffke, Amy, Oh, Kean, Pence, Clarence, Preston, Lisa, Raphaelian, Paul, Regan, Virginia R., Roberts, Peter, Ruby, Alan, Sarrafizadeh, Ramin, Scherf, Marissa, Scott, Sarita, Sneed, Scott, Staples, Lisa, Terry, Brad, Trese, Matthew T., Videtich, Joan, Williams, George, Zajechowski, Mary, Joseph, Daniel P., Blinder, Kevin, Boyd, Lynda, Buckley, Sarah, Crow, Meaghan, Dinatale, Amanda, Engelbrecht, Nicholas, Forke, Bridget, Gabel, Dana, Grand, Gilbert, Grillion-Cerone, Jennifer, Holekamp, Nancy, Kelly, Charlotte, Nobel, Ginny, Pepple, Kelly, Raeber, Matt, Rao, P. Kumar, Ressel, Tammy, Schremp, Steven, Sgorlon, Merrilee, Shears, Shantia, Thomas, Matthew, Timma, Cathy, Vaughn, Annette, Walters, Carolyn, Weeks, Rhonda, Wehmeier, Jarrod, Wright, Tim, Berinstein, Daniel M., Ayyad, Aida, Barazi, Mohammed K., Bickhart, Erica, Brady, Tracey, Byank, Lisa, Cronise, Alysia, Denny, Vanessa, Dunn, Courtney, Flory, Michael, Frantz, Robert, Garfinkel, Richard A., Gilbert, William, Lai, Michael M., Melamud, Alexander, Newgen, Janine, Newton, Shamekia, Oliver, Debbie, Osman, Michael, Sanders, Reginald, von Fricken, Manfred, Dugel, Pravin, Arenas, Sandra, Balea, Gabe, Bartoli, Dayna, Bucci, John, Cornelius, Jennifer A., Dickens, Scheleen, Doherty, Don, Dunlap, Heather, Goldenberg, David, Jamal, Karim, Jimenez, Norma, Kavanagh, Nicole, Kunimoto, Derek, Martin, John, Miner, Jessica, Mobley, Sarah, Park, Donald, Quinlan, Edward, Sipperley, Jack, Slagle, Carol, Smith, Danielle, Yafchak, Miguelina, Yager, Rohana, Flaxel, Christina J., Bailey, Steven, Francis, Peter, Howell, Chris, Hwang, Thomas, Ira, Shirley, Klein, Michael, Lauer, Andreas, Liesegang, Teresa, Lundquist, Ann, Nolte, Sarah, Nolte, Susan K., Pickell, Scott, Pope, Susan, Rossi, Joseph, Schain, Mitchell, Steinkamp, Peter, Toomey, Maureen D., Vahrenwald, Debora, West, Kelly, Hubbard, Baker, Andelman, Stacey, Bergstrom, Chris, Brower, Judy, Cribbs, Blaine, Curtis, Linda, Dobbs, Jannah, DuBois, Lindreth, Gaultney, Jessica, Gibbs, Deborah, Jordan, Debora, Leef, Donna, Martin, Daniel F., Myles, Robert, Olsen, Timothy, Schwent, Bryan, Srivastava, Sunil, Waldron, Rhonda, Antoszyk, Andrew N., Balasubramaniam, Uma, Brooks, Danielle, Brown, Justin, Browning, David, Clark, Loraine, Ennis, Sarah, Held, Susannah, Helms, Jennifer V., Herby, Jenna, Karow, Angie, Leotaud, Pearl, Massimino, Caterina, McClain, Donna, McOwen, Michael, Mindel, Jennifer, Pereira, Candace, Pierce, Rachel, Powers, Michele, Price, Angela, Rohrer, Jason, Sanders, Jason, Avery, Robert L., Avery, Kelly, Basefsky, Jessica, Beckner, Liz, Castellarin, Alessandro, Couvillion, Stephen, Giust, Jack, Giust, Matthew, Nasir, Maan, Pieramici, Dante, Rabena, Melvin, Risard, Sarah, See, Robert, Smith, Jerry, Wan, Lisha, Bakri, Sophie J., Abu-Yaghi, Nakhleh, Barkmeier, Andrew, Berg, Karin, Burrington, Jean, Edwards, Albert, Goddard, Shannon, Howard, Shannon, Iezzi, Raymond, Lewison, Denise, Link, Thomas, McCannel, Colin A., Overend, Joan, Pach, John, Ruszczyk, Margaret, Shultz, Ryan, Stephan, Cindy, Vogen, Diane, Bradford, Reagan H., Jr., Bergman, Vanessa, Burris, Russ, Butt, Amanda, Daniels, Beth, Dwiggins, Connie, Fransen, Stephen, Guerrero, Tiffany, Haivala, Darin, Harris, Amy, Icks, Sonny, Kingsley, Ronald, Redden, Lena, Richmond, Rob, Ross, Brittany, White, Kammerin, Youngberg, Misty, Topping, Trexler M., Bennett, Steve, Chong, Sandy, Ciotti, Mary, Cleary, Tina, Corey, Emily, Donovan, Dennis, Frederick, Albert, Freese, Lesley, Graham, Margaret, Gud, Natalya, Howard, Taneika, Jones, Mike, Morley, Michael, Moses, Katie, Stone, Jen, Ty, Robin, Wiegand, Torsten, Williams, Lindsey, Winder, Beth, Awh, Carl C., Amonette, Michelle, Arrindell, Everton, Beck, Dena, Busbee, Brandon, Dilback, Amy, Downs, Sara, Guidry, Allison, Gutow, Gary, Hardin, Jackey, Hines, Sarah, Hutchins, Emily, LaCivita, Kim, Lester, Ashley, Malott, Larry, McCain, MaryAnn, Miracle, Jayme, Moffat, Kenneth, Palazzotta, Lacy, Robinson, Kelly, Sonkin, Peter, Travis, Alecia, Wallace, Roy Trent, Winters, Kelly J., Wray, Julia, Harris, April E., Bunnell, Mari, Crooks, Katrina, Fitzgerald, Rebecca, Javid, Cameron, Kew, Corin, Kill, Erica, Kline, Patricia, Kreienkamp, Janet, Martinez, Maricruz, Moore, Roy Ann, Saavedra, Egbert, Taylor, LuAnne, Walsh, Mark, Wilson, Larry, Ciulla, Thomas A., Coyle, Ellen, Harrington, Tonya, Harris, Charlotte, Hood, Cindi, Kerr, Ingrid, Maturi, Raj, Moore, Dawn, Morrow, Stephanie, Savage, Jennifer, Sink, Bethany, Steele, Tom, Thukral, Neelam, Wilburn, Janet, Walker, Joseph P., Banks, Jennifer, Ciampaglia, Debbie, Dyshanowitz, Danielle, Frederick, Jennifer, Ghuman, A. Tom, Grodin, Richard, Kiesel, Cheryl, Knips, Eileen, McCue, Jonathan, Ortiz, Maria, Peters, Crystal, Raskauskas, Paul, Schoeman, Etienne, Sharma, Ashish, Wing, Glenn, Youngblood, Rebecca, Chandra, Suresh R., Altaweel, Michael, Blodi, Barbara, Burke, Kathryn, Dietzman, Kristine A., Gottlieb, Justin, Knutson, Gene, Krolnik, Denise, Nork, T. Michael, Olson, Shelly, Peterson, John, Reed, Sandra, Soderling, Barbara, Somers, Guy, Stevens, Thomas, Wealti, Angela, Bearelly, Srilaxmi, Branchaud, Brenda, Bryant, Joyce W., Crowell, Sara, Fekrat, Sharon, Gammage, Merritt, Harrison, Cheala, Jones, Sarah, McClain, Noreen, McCuen, Brooks, Mruthyunjaya, Prithvi, Queen, Jeanne, Sarin, Neeru, Skalak, Cindy, Skelly, Marriner, Suner, Ivan, Tomany, Ronnie, Welch, Lauren, Park, Susanna S., Cassidy, Allison, Chandra, Karishma, Good, Idalew, Imson, Katrina, Sashi, Kaur, Metzler, Helen, Morse, Lawrence, Redenbo, Ellen, Salvador, Marisa, Telander, David, Thomas, Mark, Wallace, Cindy, Barr, Charles C., Battcher, Amanda, Bottorff, Michelle, Chasteen, Mary, Clark, Kelly, Denning, Diane, Schoen, Debra, Schultz, Amy, Tempel, Evie, Wheeler, Lisa, Whittington, Greg K., Stone, Thomas W., Blevins, Todd, Buck, Michelle, Cruz, Lynn, Heath, Wanda, Holcomb, Diana, Isernhagen, Rick, Kidd, Terri, Kitchens, John, Sears, Cathy, Slade, Ed, Van Arsdall, Jeanne, VanHoose, Brenda, Wolfe, Jenny, Wood, William, Zilis, John, Crooks, Carol, Disney, Larry, Liu, Mimi, Petty, Stephen, Sall, Sandra, Folk, James C., Aly, Tracy, Brotherton, Abby, Critser, Douglas, Hinz, Connie J., Karakas, Stefani, Kirschner, Valerie, Lester, Cheyanne, Montague, Cindy, Russell, Stephen, Stockman, Heather, Taylor, Barbara, Verdick, Randy, Walshire, Jean, Thompson, John T., Connell, Barbara, Constantine, Maryanth, Davis, John L., Jr., Gwen Holsapple, Hunter, Lisa, Lenane, C. Nicki, Mitchell, Robin, Russel, Leslie, Sjaarda, Raymond, Brown, David M., Benz, Matthew, Burns, Llewellyn, Carranza, JoLene G., Fish, Richard, Goates, Debra, Hay, Shayla, Jeffers, Theresa, Kegley, Eric, Kubecka, Dallas, McGilvra, Stacy, Richter, Beau, Sneed, Veronica, Stoever, Cary, Tellez, Isabell, Wong, Tien, Kim, Ivana, Andreoli, Christopher, Barresi, Leslie, Brett, Sarah, Callahan, Charlene, Capaccioli, Karen, Carli, William, Coppola, Matthew, Emmanuel, Nicholas, Evans, Claudia, Fagan, Anna, Grillo, Marcia, Head, John, Kieser, Troy, Lee, Elaine, Lord, Ursula, Miretsky, Edward, Palitsch, Kate, Petrin, Todd, Reader, Liz, Reznichenko, Svetlana, Robertson, Mary, Smith, Justin, Vavvas, Demetrios, Wells, John, Cahill, Cassie, Clark, W. Lloyd, Henry, Kayla, Johnson, David, Miller, Peggy, Oliver, LaDetrick, Spivey, Robbin, Swinford, Tiffany, Taylor, Mallie, Lambert, Michael, Chase, Kris, Fredrickson, Debbie, Khawly, Joseph, Lazarte, Valerie, Lowd, Donald, Miller, Pam, Willis, Arthur, Ferrone, Philip J., Almonte, Miguel, Arnott, Rachel, Aviles, Ingrid, Carbon, Sheri, Chitjian, Michael, DAmore, Kristen, Elliott, Christin, Fastenberg, David, Golub, Barry, Graham, Kenneth, Lavorna, AnnMarie, Murphy, Laura, Palomo, Amanda, Puglisi, Christina, Rhee, David, Romero, Juan, Rosenblatt, Brett, Salcedo, Glenda, Schlameuss, Marianne, Shakin, Eric, Sookhai, Vasanti, Kaiser, Richard, Affel, Elizabeth, Brown, Gary, Centinaro, Christina, Fine, Deborah, Fineman, Mitchell, Formoso, Michele, Garg, Sunir, Grande, Lisa, Herbert, Carolyn, Ho, Allen, Hsu, Jason, Jay, Maryann, Lavetsky, Lisa, Liebenbaum, Elaine, Maguire, Joseph, Monsonego, Julia, O’Connor, Lucia, Pierce, Lisa, Regillo, Carl, Rosario, Maria, Spirn, Marc, Vander, James, Walsh, Jennifer, Davidorf, Frederick H., Barnett, Amanda, Chang, Susie, Christoforidis, John, Elliott, Joy, Justice, Heather, Letson, Alan, McKinney, Kathryne, Perry, Jeri, Salerno, Jill A., Savage, Scott, Shelley, Stephen, Singerman, Lawrence J., Coney, Joseph, DuBois, John, DuBois, Kimberly, Greanoff, Gregg, Himmelman, Dianne, Ilc, Mary, McNamara, Elizabeth, Novak, Michael, Pendergast, Scott, Rath, Susan, Smith-Brewer, Sheila, Tanner, Vivian, Weiss, Diane E., Zegarra, Hernando, Halperin, Lawrence, Aramayo, Patricia, Dhalla, Mandeep, Fernandez, Brian, Fernandez, Cindy, Lopez, Jaclyn, Lopez, Monica, Mariano, Jamie, Murphy, Kellie, Sherley, Clifford, Veksler, Rita, Rahhal, Firas, Babikian, Razmig, Boyer, David, Hami, Sepideh, Kessinger, Jeff, Kurokouchi, Janet, Mukarram, Saba, Pachman, Sarah, Protacio, Eric, Sierra, Julio, Tabandeh, Homayoun, Zamboni, Adam, Elman, Michael, Belz, Jennifer, Butcher, Tammy, Cain, Theresa, Coffey, Teresa, Firestone, Dena, Gore, Nancy, Singletary, Pamela, Sotirakos, Peter, Starr, JoAnn, Meredith, Travis A., Barnhart, Cassandra J., Cantrell, Debra, Esquejo-Leon, RonaLyn, Houghton, Odette, Kaur, Harpreet, NDure, Fatoumatta, Glatzer, Ronald, Joffe, Leonard, Schindler, Reid, Xue, Katie, Hua, Peiying, Maguire, Maureen G., Daniel, Ebenezer, Jaffe, Glenn J., Grunwald, Juan E., and Ying, Gui-shuang

Published
2023
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10. Safety and Efficacy of CLS-TA by Anatomic Location of Inflammation: Results from the Phase 3 PEACHTREE Clinical Trial.

Author

Shah, Milan, Albini, Thomas, Nguyen, Quan, Wykoff, Charles, Barakat, Mark, Khurana, Rahul N., Kapik, Barry, and Ciulla, Thomas A.

Subjects
TRIAMCINOLONE acetonide, CLINICAL trials, MACULAR edema, UVEITIS, INFLAMMATION
Abstract

Purpose: To explore the efficacy of CLS-TA, a proprietary suprachoroidal injectable suspension of triamcinolone acetonide, in noninfectious uveitis (NIU) with macular edema (ME), categorized by anatomic subtype. Methods: Patients diagnosed with ME associated with NIU of any etiology and anatomic subtype were eligible for the phase 3 PEACHTREE trial of CLS-TA. Post-hoc analyses were performed, stratified by discrete anatomic subtype of uveitis (anterior, intermediate, posterior, and panuveitis.) Results: Across all anatomic subtypes at 24 weeks, patients receiving CLS-TA at baseline and week 12 demonstrated mean increases in BCVA ranging from +12.1 to +15.9 letters, mean central subfield thickness (CST) improvement ranging from −120.1 µm to −189.0 µm, and IOP changes ranging from +0.5 to +3.1 mmHg. Overall, reports of adverse events were similar among subtypes. Conclusions: Irrespective of the uveitic anatomic subtype among patients treated for ME associated with NIU, a clinical benefit in participants treated with CLS-TA was demonstrated, with a comparable safety profile. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Long-acting delivery and therapies for neovascular age-related macular degeneration

Author

Rowe, Lucas W. and Ciulla, Thomas A.

Abstract

ABSTRACTIntroductionNeovascular age-related macular degeneration (nAMD) represents a leading cause of severe visual impairment in individuals over 50 years of age in developed nations. Intravitreal anti-vascular endothelial growth factor (VEGF) injections have become the standard of care for treating nAMD; however, monthly or bimonthly dosing represents significant time and cost burden due to the disease’s chronic nature and limited medication half-life.Areas coveredThis review summarizes innovative therapeutics and delivery methods for nAMD. Emerging methods for extended drug delivery include high molar concentration anti-VEGF drugs, intravitreal sustained-release polymers and devices, reservoirs for intravitreal delivery, suprachoroidal delivery of small molecular suspensions and gene therapy biofactories. In addition to VEGF-A, therapies targeting inhibition of VEGF-C and D, the angiopoetin-2 (Ang-2)/Tie-2 pathway, tyrosine kinases, and integrins are reviewed.Expert opinionThe evolving therapeutic landscape of nAMD is rapidly expanding our toolkit for effective and durable treatment. Recent FDA approvals of faricimab (Vabysmo) and high-dose aflibercept (Eylea HD) for nAMD with potential extension of injection intervals up to four months have been promising developments for patients and providers alike. Further research and innovation, including novel delivery techniques and pharmacologic targets, is necessary to validate the efficacy of developing therapeutics and characterize real-world outcomes, demonstrating promise in expanding treatment durability.

Published
2024
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12. Gene Therapy for Non-Hereditary Retinal Disease: Age-Related Macular Degeneration, Diabetic Retinopathy, and Beyond.

Author

Rowe, Lucas W. and Ciulla, Thomas A.

Subjects
*MACULAR degeneration, *DIABETIC retinopathy, *GENE therapy, *RETINAL diseases, *ENDOTHELIAL growth factors, *MACULAR edema
Abstract

Gene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), aiming to address the challenges of frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. This manuscript reviews ongoing gene therapy clinical trials for these disorders, including ABBV-RGX-314, ixoberogene soroparvovec (ixo-vec), and 4D-150. ABBV-RGX-314 utilizes an adeno-associated virus (AAV) vector to deliver a transgene encoding a ranibizumab-like anti-VEGF antibody fragment, demonstrating promising results in Phase 1/2a and ongoing Phase 2b/3 trials. Ixo-vec employs an AAV2.7m8 capsid for intravitreal delivery of a transgene expressing aflibercept, showing encouraging outcomes in Phase 1 and ongoing Phase 2 trials. 4D-150 utilizes an evolved vector to express both aflibercept and a VEGF-C inhibitory RNAi, exhibiting positive interim results in Phase 1/2 studies. Other therapies reviewed include EXG102-031, FT-003, KH631, OLX10212, JNJ-1887, 4D-175, and OCU410. These therapies offer potential advantages of reduced treatment frequency and enhanced safety profiles, representing a paradigm shift in management towards durable and efficacious cellular-based biofactories. These advancements in gene therapy hold promise for improving outcomes in AMD and addressing the complex challenges of DME and DR, providing new avenues for the treatment of diabetic eye diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Vitreous Pathology

Author

Bracha, Peter, Giuliari, Gian Paolo, Ciulla, Thomas A., Bellomo, Nicola, Series Editor, Tezduyar, Tayfun E., Series Editor, Aoki, Kazuo, Editorial Board Member, Bazilevs, Yuri, Editorial Board Member, Chaplain, Mark, Editorial Board Member, Degond, Pierre, Editorial Board Member, Deutsch, Andreas, Editorial Board Member, Gibelli, Livio, Editorial Board Member, Herrero, Miguel Ángel, Editorial Board Member, Hughes, Thomas J.R., Editorial Board Member, Koumoutsakos, Petros, Editorial Board Member, Prosperetti, Andrea, Editorial Board Member, Rajagopal, K.R., Editorial Board Member, Takizawa, Kenji, Editorial Board Member, Tao, Youshan, Editorial Board Member, van Brummelen, Harald, Editorial Board Member, Guidoboni, Giovanna, editor, Harris, Alon, editor, and Sacco, Riccardo, editor

Published
2019
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14. Vitreous Physiology

Author

Giuliari, Gian Paolo, Bracha, Peter, Sperry, A. Bailey, Ciulla, Thomas, Bellomo, Nicola, Series Editor, Tezduyar, Tayfun E., Series Editor, Aoki, Kazuo, Editorial Board Member, Bazilevs, Yuri, Editorial Board Member, Chaplain, Mark, Editorial Board Member, Degond, Pierre, Editorial Board Member, Deutsch, Andreas, Editorial Board Member, Gibelli, Livio, Editorial Board Member, Herrero, Miguel Ángel, Editorial Board Member, Hughes, Thomas J.R., Editorial Board Member, Koumoutsakos, Petros, Editorial Board Member, Prosperetti, Andrea, Editorial Board Member, Rajagopal, K.R., Editorial Board Member, Takizawa, Kenji, Editorial Board Member, Tao, Youshan, Editorial Board Member, van Brummelen, Harald, Editorial Board Member, Guidoboni, Giovanna, editor, Harris, Alon, editor, and Sacco, Riccardo, editor

Published
2019
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17. Suprachoroidal Drug Delivery for Macular Edema Associated With Noninfectious Uveitis

Author

Huang, Ye, Choo, Charlene, Hancock, Shelley, Ciulla, Thomas A., Wykoff, Charles C., Shantha, Jessica G., and Yeh, Steven

Abstract

Purpose:To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods:A synthesis of the literature was performed. Results:In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions:The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies.

Published
2024
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22. Update: Gene therapy clinical trials in neovascular age-related macular degeneration: Companies are attacking the disease from multiple angles.

Author

Rowe, Lucas W. and Ciulla, Thomas A.

Subjects
VASCULAR endothelial growth factor antagonists, THERAPEUTIC use of monoclonal antibodies, GENE therapy, ADRENOCORTICAL hormones, DRUG side effects, RETINAL degeneration, CLINICAL trials, INTRAVITREAL injections, AGE distribution, TREATMENT effectiveness, MONOCLONAL antibodies, PATHOLOGIC neovascularization, INFLAMMATION
Published
2024

24. Vitreous Physiology

Author

Giuliari, Gian Paolo, primary, Bracha, Peter, additional, Sperry, A. Bailey, additional, and Ciulla, Thomas, additional

Published
2019
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26. Suprachoroidal CLS-TA with and without Systemic Corticosteroid and/or Steroid-Sparing Therapy: A Post-Hoc Analysis of the Phase 3 PEACHTREE Clinical Trial.

Author

Merrill, Pauline T., Henry, Christopher R., Nguyen, Quan Dong, Reddy, Ashvini, Kapik, Barry, and Ciulla, Thomas A.

Subjects
OPTICAL coherence tomography, CLINICAL trials, MACULAR edema, TRIAMCINOLONE acetonide, IRIDOCYCLITIS, CORTICOSTEROIDS
Abstract

To study the efficacy and safety of suprachoroidal CLS-TA (proprietary suspension of triamcinolone acetonide) in uveitic macular edema (UME) with and without concurrent systemic corticosteroid or steroid-sparing therapy (ST). Post hoc analysis of the PEACHTREE phase 3 randomized trial. Among UME patients receiving no ST, at week 24, mean BCVA change was +15.6 letters in 68 CLS-TA patients versus +4.9 letters in 49 sham-control patients (p <.001), while mean CST change was −169.8 µm versus −10.3 µm, respectively (p <.001). Among patients receiving ST, at week 24, mean BCVA change was +9.4 letters in 28 CLS-TA patients versus −3.2 letters in 15 sham-control patients (p =.019), while mean CST change was −108.3 µm versus −43.5 µm, respectively (p =.190). No SAEs related to treatment were reported. A clinically meaningful benefit of CLS-TA was noted in UME patients, regardless of concurrent ST usage. Abbreviation and Acronyms CST = central subfield thickness; BCVA = best corrected visual acuity; ME = macular edemaI; IVT = intravitreal; AE = adverse event; FA = fluocinolone acetonide; SD-OCT = spectral-domain optical coherence tomography; NIU = noninfectious uveitis; SAE = serious adverse event; TEAE = treatment emergent adverse event; ITT = intent to treat; CI = confidence interval [ABSTRACT FROM AUTHOR]

Published
2023
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27. Aging Effects on Optic Nerve Neurodegeneration

Author

Coleman-Belin, Janet, primary, Harris, Alon, additional, Chen, Bo, additional, Zhou, Jing, additional, Ciulla, Thomas, additional, Verticchio, Alice, additional, Antman, Gal, additional, Chang, Michael, additional, and Siesky, Brent, additional

Published
2023
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36. A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration

Author

Poor, Stephen H., primary, Weissgerber, Georges, additional, Adams, Christopher M., additional, Bhatt, Harit, additional, Browning, David J., additional, Chastain, James, additional, Ciulla, Thomas A., additional, Ferriere, Michael, additional, Gedif, Kinfemichael, additional, Glazer, Louis C., additional, Joondeph, Brian C., additional, Normand, Guillaume, additional, Sheth, Veeral, additional, Watters, Christie, additional, and Grosskreutz, Cynthia L., additional

Published
2022
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38. Biosimilars and generic medications in ophthalmology

Author

Harris, Alon, Wirostko, Barbara, Rowe-Rendleman, Cheryl L., Siesky, Brent, Verticchio Vercellin, Alice C., Ciulla, Thomas A., Wentz, Scott, Finnen, Neil P., Kolko, Miriam, Januleviciene, Ingrida, Harris, Alon, Wirostko, Barbara, Rowe-Rendleman, Cheryl L., Siesky, Brent, Verticchio Vercellin, Alice C., Ciulla, Thomas A., Wentz, Scott, Finnen, Neil P., Kolko, Miriam, and Januleviciene, Ingrida

Abstract

Introduction. Generic drugs are currently being promoted globally as substitutes for brand-name drugs. The substitution may be generated from the medical provider, the patient, the pharmacist, and/or the third-party payer. The appeal for the substitution is generally the cost. Generic drugs are often substantially cheaper than their brand-name counterparts, thus imparting cost savings to the payer, patient, and the healthcare system. In addition to decreased cost, markers of generic drugs help to increase access. After the patent of an innovative or branded drug has expired, manufacturers are free to provide the market with various competitive genetic formulations of that drug. Although generic and brand-name medicines share the same active ingredient, other characteristics, such as colors and certain excipients, that do not affect the performance, safety, or efficacy of the generic medicine, may be different. This substitution can aften occur unbeknownst to the health-care provider or the patient. Given that the understanding and knowledge base differs by each party involved, whether it is the prescriber, payer, and/or patient, the perceived benefits and risks may also differ. [...]. In this book, we present this history of generic drug development, FDA and European Medicines Agency (EMA) requirements for genetic drug entry, a comparison of generic and brandedf drugs, concerns around generic ophthalmic drugs, the issues of costs of generics and branded drugs, and issues as well as perceptionsregarding the clinical use and acceptance of generic drugs among the patients, prescribers, and pharmacists. In addition to the previous edition, a chapter has been added about biosimilars

Published
2022

39. Suprachoroidal Triamcinolone Acetonide Injectable Suspension for Macular Edema Associated With Noninfectious Uveitis: An In-Depth Look at Efficacy and Safety.

Author

Yeh, Steven and Ciulla, Thomas

Subjects
*TRIAMCINOLONE, *MACULAR edema, *CLINICAL trials, *UVEITIS, *TREATMENT effectiveness, *QUALITY of life, *KAPLAN-Meier estimator, *DECISION making, *NEEDS assessment
Abstract

Patients with macular edema (ME) associated with uveitis (UME) are at risk for vision loss and decreased quality of life, and they often experience high health care costs and rates of workforce absenteeism. Systemically or locally delivered corticosteroids are the mainstay of treatment for UME. Although traditional corticosteroid treatments may demonstrate high levels of efficacy, systemic delivery carries the risk of potentially serious systemic adverse effects (AEs), and standard local modes of delivery may be associated with low bioavailability in posterior ocular tissues and steroid-associated AEs due to anterior ocular tissue exposure. Drug injection into the suprachoroidal space (SCS) allows for targeted delivery to chorioretinal tissues with high bioavailability in the posterior segment, as well as for inherent drug sequestration away from the anterior segment, which may lower the risk of AEs associated with anterior tissue exposure to steroids. A novel triamcinolone acetonide (TA) injectable suspension formulated for administration to the SCS, SCS-TA (Xipere®; Bausch + Lomb), received FDA approval in 2021 for the treatment of UME. It is administered via the SCS Microinjector® (Clearside Biomedical, Inc), a device specifically designed for SCS delivery of ocular therapeutics. This approval was based on results from the phase 3 PEACHTREE clinical trial (NCT02595398) that demonstrated the clinical efficacy--including significantly increased visual acuity and decreased central subfield thickness--and safety of SCS-TA in patients with UME. Results from this trial, as well as from its long-term observational extension (MAGNOLIA; NCT02952001) and an open-label safety study (AZALEA; NCT03097315), support the possibility that treatment with SCS-TA may address the burden of disease in patients with UME. [ABSTRACT FROM AUTHOR]

Published
2023

45. Microinjection via the Suprachoroidal Space: A Review of a Novel Mode of Administration.

Author

Ciulla, Thomas and Yeh, Steven

Subjects
*NON-communicable diseases, *DRUG delivery systems, *MACULAR edema, *ADRENOCORTICAL hormones, *INJECTIONS, *INTRAOCULAR pressure, *TRIAMCINOLONE, *COMBINATION drug therapy, *BIOAVAILABILITY, *SCLERA, *UVEITIS, *HYPODERMIC needles, *OPHTHALMIC drugs, *DIABETIC retinopathy, *UVEAL diseases
Abstract

Standard ocular drug delivery methods generally are safe and effective for treating diseases of the eye. However, many routes of administration carry the risk of adverse effects due to drug exposure to anterior ocular tissues. Additionally, these delivery methods may not result in high and consistent levels of a therapeutic agent delivered to target tissues for diseases affecting the posterior segment of the eye. Injection into the suprachoroidal space (SCS) represents an alternative method of ocular drug delivery to the posterior segment. SCS injection facilitates targeted distribution to affected chorioretinal tissues for potential efficacy benefits, compartmentalization away from unaffected anterior segment tissues for potential safety benefits, and a high degree of bioavailability. Furthermore, the SCS may serve as a drug depot for long-acting drug delivery of small-molecule suspensions. Until recently, drug delivery to the SCS could be achieved only in the operating room setting with anesthetic immobilization of the eye and surgical dissection through the sclera. A novel microneedle device, the SCS Microinjector® (Clearside Biomedical, Inc) was developed to permit physicians to administer therapies safely and reliably into the SCS in the office setting. Successful use of SCS injection has been demonstrated with triamcinolone acetonide injectable suspension (Xipere®, Bausch + Lomb), a novel formulation optimized for use with the SCS Microinjector®. FDA approval of this combination drug and device for the treatment of macular edema associated with uveitis (UME) was based on outcomes from the phase 3 PEACHTREE study (NCT02595398); other important studies included its long-term observational extension (MAGNOLIA; NCT02952001) and an open-label safety study (AZALEA; NCT03097315). The SCS Microinjector® together with triamcinolone acetonide injectable suspension for use in the SCS presents an opportunity for safe and effective drug delivery for the treatment of UME and, potentially, for broader use with alternate medications to treat other ocular diseases that impact chorioretinal tissues (eg, age-related macular degeneration, diabetic retinopathy, choroidal melanoma). [ABSTRACT FROM AUTHOR]

Published
2022
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46. Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment

Author

Leley,Sameer P, Ciulla,Thomas A, and Bhatwadekar,Ashay

Subjects
Clinical Interventions in Aging
Abstract

Sameer P Leley,1 Thomas A Ciulla,2– 4 Ashay D Bhatwadekar2 1Indiana University School of Medicine, Indianapolis, IN, USA; 2Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University, Indianapolis, IN, USA; 3Clearside Biomedical, Inc., Alpharetta, GA, USA; 4Midwest Eye Institute, Indianapolis, IN, USACorrespondence: Ashay D BhatwadekarDepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, 1160 W. Michigan Street, GK-305P, Indianapolis, IN, 46202, USATel +1 317-278-5075Fax +1 317-274-2277Email abhatwad@iupui.eduAbstract: The elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.Keywords: diabetic retinopathy, aging, vascular endothelial growth factor, adherence, pharmacodynamic, pharmacokinetic

Published
2021

49. Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA).

Author

Khurana, Rahul N., Merrill, Pauline, Yeh, Steven, Suhler, Eric, Barakat, Mark R., Uchiyama, Eduardo, Henry, Christopher Ryan, Shah, Milan, Wang, Robert C., Kapik, Barry, and Ciulla, Thomas

Abstract

Purpose To assess the extended efficacy and safety of suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) among patients with macular oedema (ME) secondary to non-infectious uveitis (NIU). Methods Patients with uveitic ME were treated with suprachoroidal CLS-TA at baseline and week 12 of the Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial (PEACHTREE) study. Time to rescue was evaluated over 24 additional weeks for MAGNOLIA. Safety data, visual acuity and retinal central subfield thickness (CST) reduction were also evaluated. Of the 53 eligible patients (46 CLS-TA and 7 control), 33 patients were enrolled (28 CLS-TA and 5 control). Results Over the entire 48-week period for PEACHTREE and MAGNOLIA, the median time to rescue therapy was 257 days versus 55.5 days for the CLS-TA and sham-control arms, respectively. Of 28 CLS-TA treated patients who participated in MAGNOLIA, 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. Among CLS-TA patients not requiring rescue, there was a mean gain of 12.1 letters and mean CST reduction of 174.5 µm at week 48. No serious adverse events related to study treatment were observed. Conclusion Approximately 50% of patients did not require additional treatment for up to 9 months following the last CLS-TA administration. [ABSTRACT FROM AUTHOR]

Published
2022
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