Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration
Edited by Xiaodong Wang, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 8, 2011 (received for review December 17, 2010)
Abstract
There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.
Acknowledgments
We thank the patients who participated in this study, their families, and the research team at each site; the members of the data safety monitoring committee: Donald J. D'Amico, MD (chair); Thomas R. Friberg, MD; Alan M. Laties, MD; Raymond Iezzi, MD, MS; and David C. Musch, PhD.; the members of Duke University Optical Coherence Tomography Reading Center, the members of RADIARC Reading Center, Janet Sunness for GA lesion area grading, and the members of Neurotech clinical research team for their invaluable assistance in the conduct of this study. Original design for this study protocol was developed through a Clinical Trials Agreement (612) between Neurotech USA, Inc. and the National Eye Institute (NEI), National Institutes of Health (NIH). The protocol was designed by Ronald A. Bush, PhD, NEI; Rafael Caruso, MD, NEI; Emily Y. Chew, MD, NEI; Frederick L. Ferris III, MD, NEI; Paul A. Sieving, MD, PhD, NEI; W.T., MD, PhD, Neurotech USA, Inc.; and Santa J. Tumminia, PhD, NEI. K.Z. is the chair of this study. The following investigators are members of the CNTF2 GA study group: Rand Spencer, MD, David Boyer, MD; Roger Novack, MD; Firas Rahhal, MD; Thomas Chu, MD; Albert Vitale, MD; Paul Bernstein, MD; Mike Teske, MD; and Bruce Garretson, MD K.Z. is supported by grants from Chinese National 985 Project to Sichuan University and West China Hospital, NEI/NIH, the Macula Vision Research Foundation, Research to Prevent Blindness (RPB), Burroughs Wellcome Fund Clinician Translational Award, and RPB Lew Wasserman Merit Award. Dr. Zhang is a RPB Senior Investigator.
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Cover image: Pictured are mouse mammary gland epithelial cells displaying the signaling protein β-catenin (red), the cytoskeletal protein actin (green), and nuclei (blue). Aberrant signaling through β-catenin can lead to a range of cancers by deregulating genes involved in cell motility and growth control. However, therapeutic strategies to block β-catenin have remained elusive because the protein plays a pivotal role in stabilizing junctions between cells. Foster C. Gonsalves et al. report that small chemical compounds dubbed “inhibitors of catenin responsive transcription,” or iCRTs, selectively block β-catenin signaling without affecting the protein’s function at cell junctions, thus helping restore normal morphology to mouse cells that had been experimentally rendered cancerous. See the Feature Article by Gonsalves et al. on pages 5954–5963. Image courtesy of Foster C. Gonsalves.
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Published online: March 28, 2011
Published in issue: April 12, 2011
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Acknowledgments
We thank the patients who participated in this study, their families, and the research team at each site; the members of the data safety monitoring committee: Donald J. D'Amico, MD (chair); Thomas R. Friberg, MD; Alan M. Laties, MD; Raymond Iezzi, MD, MS; and David C. Musch, PhD.; the members of Duke University Optical Coherence Tomography Reading Center, the members of RADIARC Reading Center, Janet Sunness for GA lesion area grading, and the members of Neurotech clinical research team for their invaluable assistance in the conduct of this study. Original design for this study protocol was developed through a Clinical Trials Agreement (612) between Neurotech USA, Inc. and the National Eye Institute (NEI), National Institutes of Health (NIH). The protocol was designed by Ronald A. Bush, PhD, NEI; Rafael Caruso, MD, NEI; Emily Y. Chew, MD, NEI; Frederick L. Ferris III, MD, NEI; Paul A. Sieving, MD, PhD, NEI; W.T., MD, PhD, Neurotech USA, Inc.; and Santa J. Tumminia, PhD, NEI. K.Z. is the chair of this study. The following investigators are members of the CNTF2 GA study group: Rand Spencer, MD, David Boyer, MD; Roger Novack, MD; Firas Rahhal, MD; Thomas Chu, MD; Albert Vitale, MD; Paul Bernstein, MD; Mike Teske, MD; and Bruce Garretson, MD K.Z. is supported by grants from Chinese National 985 Project to Sichuan University and West China Hospital, NEI/NIH, the Macula Vision Research Foundation, Research to Prevent Blindness (RPB), Burroughs Wellcome Fund Clinician Translational Award, and RPB Lew Wasserman Merit Award. Dr. Zhang is a RPB Senior Investigator.
Notes
*This Direct Submission article had a prearranged editor.
Authors
Competing Interests
Conflict of interest statement: W.T. is an employee of Neurotech.
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