Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins

Jerry R. Mendell, Louise R. Rodino-Klapac, Xiomara Rosales-Quintero, Janaiah Kota, Brian D. Coley, Gloria Galloway, Josepha M. Craenen, Sarah Lewis, Vinod Malik, Christopher Shilling, Barry J. Byrne, Thomas Conlon, Katherine J. Campbell, William G. Bremer, Laurence Viollet, Christopher M. Walker, Zarife Sahenk, K. Reed Clark

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Objective: 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. Methods: 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. Results: 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 lowfrequency 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. 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.

Original languageEnglish (US)
Pages (from-to)290-297
Number of pages8
JournalAnnals of Neurology
Volume66
Issue number3
DOIs
StatePublished - 2009
Externally publishedYes

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Sarcoglycanopathies
Sarcoglycans
Capsid
Genetic Therapy
Dependovirus
Muscular Dystrophies
Gene Expression
Immunotherapy
Genes
Enzyme-Linked Immunospot Assay
Muscles
Proteins
Methylprednisolone
Neutralizing Antibodies
Double-Blind Method
Interferons
Blood Vessels
Cell Death
Randomized Controlled Trials
Clinical Trials

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Mendell, J. R., Rodino-Klapac, L. R., Rosales-Quintero, X., Kota, J., Coley, B. D., Galloway, G., ... Reed Clark, K. (2009). Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. Annals of Neurology, 66(3), 290-297. https://doi.org/10.1002/ana.21732

Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. / Mendell, Jerry R.; Rodino-Klapac, Louise R.; Rosales-Quintero, Xiomara; Kota, Janaiah; Coley, Brian D.; Galloway, Gloria; Craenen, Josepha M.; Lewis, Sarah; Malik, Vinod; Shilling, Christopher; Byrne, Barry J.; Conlon, Thomas; Campbell, Katherine J.; Bremer, William G.; Viollet, Laurence; Walker, Christopher M.; Sahenk, Zarife; Reed Clark, K.

In: Annals of Neurology, Vol. 66, No. 3, 2009, p. 290-297.

Research output: Contribution to journalArticle

Mendell, JR, Rodino-Klapac, LR, Rosales-Quintero, X, Kota, J, Coley, BD, Galloway, G, Craenen, JM, Lewis, S, Malik, V, Shilling, C, Byrne, BJ, Conlon, T, Campbell, KJ, Bremer, WG, Viollet, L, Walker, CM, Sahenk, Z & Reed Clark, K 2009, 'Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins', Annals of Neurology, vol. 66, no. 3, pp. 290-297. https://doi.org/10.1002/ana.21732
Mendell, Jerry R. ; Rodino-Klapac, Louise R. ; Rosales-Quintero, Xiomara ; Kota, Janaiah ; Coley, Brian D. ; Galloway, Gloria ; Craenen, Josepha M. ; Lewis, Sarah ; Malik, Vinod ; Shilling, Christopher ; Byrne, Barry J. ; Conlon, Thomas ; Campbell, Katherine J. ; Bremer, William G. ; Viollet, Laurence ; Walker, Christopher M. ; Sahenk, Zarife ; Reed Clark, K. / Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. In: Annals of Neurology. 2009 ; Vol. 66, No. 3. pp. 290-297.
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abstract = "Objective: 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. Methods: 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. Results: 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 lowfrequency 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. 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.",
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AU - Kota, Janaiah

AU - Coley, Brian D.

AU - Galloway, Gloria

AU - Craenen, Josepha M.

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