Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer
Authors
Grose, William E.Clark, K. Reed
Griffin, Danielle
Malik, Vinod
Shontz, Kimberly M.
Montgomery, Chrystal L.
Lewis, Sarah
Brown, Robert H.
Janssen, Paul M. L.
Mendell, Jerry R.
Rodino-Klapac, Louise R.
Issue Date
2012-06-15
Metadata
Show full item recordAbstract
The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes.Citation
PLoS One. 2012 Jun 15; 7(6):e39233ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0039233
Scopus Count
Related articles
- Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer.
- Authors: Lostal W, Bartoli M, Bourg N, Roudaut C, Bentaïb A, Miyake K, Guerchet N, Fougerousse F, McNeil P, Richard I
- Issue date: 2010 May 15
- The phenotype of dysferlin-deficient mice is not rescued by adeno-associated virus-mediated transfer of anoctamin 5.
- Authors: Monjaret F, Suel-Petat L, Bourg-Alibert N, Vihola A, Marchand S, Roudaut C, Gicquel E, Udd B, Richard I, Charton K
- Issue date: 2013 Jun
- Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
- Authors: Lostal W, Bartoli M, Roudaut C, Bourg N, Krahn M, Pryadkina M, Borel P, Suel L, Roche JA, Stockholm D, Bloch RJ, Levy N, Bashir R, Richard I
- Issue date: 2012
- Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy.
- Authors: Potter RA, Griffin DA, Sondergaard PC, Johnson RW, Pozsgai ER, Heller KN, Peterson EL, Lehtimäki KK, Windish HP, Mittal PJ, Albrecht DE, Mendell JR, Rodino-Klapac LR
- Issue date: 2018 Jul
- Structure-Based Designed Nano-Dysferlin Significantly Improves Dysferlinopathy in BLA/J Mice.
- Authors: Llanga T, Nagy N, Conatser L, Dial C, Sutton RB, Hirsch ML
- Issue date: 2017 Sep 6