Post by David Feder on Apr 18, 2009 8:28:26 GMT -5
LGMD 2D gene therapy restores alpha-sarcoglycan and associated proteins
Jerry R. Mendell, M.D. 1 2 4 *, Louise R. Rodino-Klapac, Ph.D. 1 4, Xiomara Rosales-Quintero, M.D. 1 4, Janaiah Kota, Ph.D. 1 4, Brian D. Coley, M.D. 3, Gloria Galloway, M.D. 1 4, Josepha M. Craenen, M.D. 1, Sarah Lewis 4, Vinod Malik, Ph.D. 4, Christopher Shilling, MS 1 4, Barry J. Byrne, M.D, Ph.D. 6, Thomas Conlon, Ph.D. 6, Katherine J Campbell 5, William G. Bremer 5, Laurence Viollet, Ph.D. 4, Christopher M. Walker, Ph.D. 1 5, Zarife Sahenk, M.D., Ph.D. 1 2 4, K. Reed Clark, Ph.D. 1 4
1Departments of Pediatrics, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
2Neurology, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
3Radiology, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
4Centers for Gene Therapy, at The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205
5Vaccines and Immunity at The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205
6Department of Pediatrics, University of Florida College of Medicine, and the Powell Gene Therapy Center. Gainesville, FL
email: Jerry R. Mendell (Jerry.Mendell@nationwidechildrens.org)
*Correspondence to Jerry R. Mendell, Research Institute at Nationwide Childrens Hospital, 700 Children's Dr. Room WA3011, Columbus OH 43235
Ph: 614-722-5615; Fax: 614-722-3273
Funded by:
NIAMS
NIH; Grant Number: 1U54NS055958
Muscular Dystrophy Association and performed; Grant Number: FDA IND #, FDA IND #
Abstract
Objectives:
Alpha-sarcoglycan deficiency is a severe form of muscular dystrophy (LGMD2D) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy, and persistence of gene expression.
Methods:
A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis (EDB) muscle was conducted. Control sides received saline. A three-day course of methylprednisolone accompanied gene transfer without further immune suppression.
Results:
No adverse events were encountered. SGCA gene expression increased 4-5 fold over control sides when examined at 6 weeks (two subjects) and 3 months (one subject). The full sarcoglycan complex was restored in all subjects and muscle fiber size was increased in the 3-month subject. AAV1 neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found but showed features of programmed cell death. ELISpot showed no IFN- response to -SG or AAV1 capsid peptide pools with the exception of a minimal capsid response in one subject. Restimulation to detect low frequency capsid specific T cells by ELISpot assays was negative. Results of the first three subjects successfully achieved study aims precluding the need for additional enrollment.
Interpretation:
The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials. Ann Neurol 2009
www3.interscience.wiley.com/journal/122325394/abstract
Jerry R. Mendell, M.D. 1 2 4 *, Louise R. Rodino-Klapac, Ph.D. 1 4, Xiomara Rosales-Quintero, M.D. 1 4, Janaiah Kota, Ph.D. 1 4, Brian D. Coley, M.D. 3, Gloria Galloway, M.D. 1 4, Josepha M. Craenen, M.D. 1, Sarah Lewis 4, Vinod Malik, Ph.D. 4, Christopher Shilling, MS 1 4, Barry J. Byrne, M.D, Ph.D. 6, Thomas Conlon, Ph.D. 6, Katherine J Campbell 5, William G. Bremer 5, Laurence Viollet, Ph.D. 4, Christopher M. Walker, Ph.D. 1 5, Zarife Sahenk, M.D., Ph.D. 1 2 4, K. Reed Clark, Ph.D. 1 4
1Departments of Pediatrics, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
2Neurology, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
3Radiology, The Ohio State University, and Nationwide Childrens Hospital, Columbus, OH 43210
4Centers for Gene Therapy, at The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205
5Vaccines and Immunity at The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205
6Department of Pediatrics, University of Florida College of Medicine, and the Powell Gene Therapy Center. Gainesville, FL
email: Jerry R. Mendell (Jerry.Mendell@nationwidechildrens.org)
*Correspondence to Jerry R. Mendell, Research Institute at Nationwide Childrens Hospital, 700 Children's Dr. Room WA3011, Columbus OH 43235
Ph: 614-722-5615; Fax: 614-722-3273
Funded by:
NIAMS
NIH; Grant Number: 1U54NS055958
Muscular Dystrophy Association and performed; Grant Number: FDA IND #, FDA IND #
Abstract
Objectives:
Alpha-sarcoglycan deficiency is a severe form of muscular dystrophy (LGMD2D) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy, and persistence of gene expression.
Methods:
A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis (EDB) muscle was conducted. Control sides received saline. A three-day course of methylprednisolone accompanied gene transfer without further immune suppression.
Results:
No adverse events were encountered. SGCA gene expression increased 4-5 fold over control sides when examined at 6 weeks (two subjects) and 3 months (one subject). The full sarcoglycan complex was restored in all subjects and muscle fiber size was increased in the 3-month subject. AAV1 neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found but showed features of programmed cell death. ELISpot showed no IFN- response to -SG or AAV1 capsid peptide pools with the exception of a minimal capsid response in one subject. Restimulation to detect low frequency capsid specific T cells by ELISpot assays was negative. Results of the first three subjects successfully achieved study aims precluding the need for additional enrollment.
Interpretation:
The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials. Ann Neurol 2009
www3.interscience.wiley.com/journal/122325394/abstract