Potential conflict of interest: Nothing to report.
Article first published online: 16 APR 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 66, Issue 3, pages 290–297, September 2009
How to Cite
Mendell, J. R., Rodino-Klapac, L. R., Rosales-Quintero, X., Kota, J., Coley, B. D., Galloway, G., Craenen, J. M., Lewis, S., Malik, V., Shilling, C., Byrne, B. J., Conlon, T., Campbell, K. J., Bremer, W. G., Viollet, L., Walker, C. M., Sahenk, Z. and Clark, K. R. (2009), Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. Ann Neurol., 66: 290–297. doi: 10.1002/ana.21732
This study has been registered at Clinicaltrials.gov NCT00494195.
- Issue published online: 1 OCT 2009
- Article first published online: 16 APR 2009
- Accepted manuscript online: 16 APR 2009 12:00AM EST
- Manuscript Accepted: 25 MAR 2009
- Manuscript Revised: 19 MAR 2009
- Manuscript Received: 6 MAR 2009
- National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health. Grant Number: 1U54NS055958
- Muscular Dystrophy Association
α-Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb-girdle muscular dystrophy type 2D [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.
A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis muscle was conducted. Control sides received saline. A 3-day course of methylprednisolone accompanied gene transfer without further immune suppression.
No adverse events were encountered. SGCA gene expression increased 4–5-fold over control sides when examined at 6 weeks (2 subjects) and 3 months (1 subject). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in the 3-month subject. Adeno-associated virus serotype 1 (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. Enzyme-linked immunospot (ELISpot) showed no interferon-γ response to α-SG or AAV1 capsid peptide pools, with the exception of a minimal capsid response in 1 subject. Restimulation to detect low-frequency capsid-specific T cells by ELISpot assays was negative. Results of the first 3 subjects successfully achieved study aims, precluding the need for additional enrollment.
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;66:290–297