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- Title
Adeno-associated Virus-mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis.
- Authors
Patel, Priyanka; Kriz, Jasna; Gravel, Mathieu; Soucy, Geneviève; Bareil, Christine; Gravel, Claude; Julien, Jean-Pierre
- Abstract
There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1G93A mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1G93A mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations.
- Subjects
SUPEROXIDE dismutase; AMYOTROPHIC lateral sclerosis treatment; ADENO-associated virus; MONOCLONAL antibodies; SPINAL cord; DNA; TITERS
- Publication
Molecular Therapy, 2014, Vol 22, Issue 3, p498
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2013.239