Abstract
The process of misfolding of proteins that can trigger a pathogenic cascade leading to neurodegenerative diseases largely originates intracellularly. It is possible to harness the specificity and affinity of antibodies to counteract either protein misfolding itself, or the aberrant interactions and excess stressors immediately downstream of the primary insult. This review covers the emerging field of engineering intracellular antibody fragments, intrabodies and nanobodies, in neurodegeneration. Huntington's disease has provided the clearest proof of concept for this approach. The model systems and readouts for this disorder power the studies, and the potential to intervene therapeutically at early stages in known carriers with projected ages of onset increases the chances of meaningful clinical trials. Both single-chain Fv and single-domain nanobodies have been identified against specific targets; data have allowed feedback for rational design of bifunctional constructs, as well as target validation. Intrabodies that can modulate the primary accumulating protein in Parkinson's disease, alpha-synuclein, are also reviewed, covering a range of domains and conformers. Recombinant antibody technology has become a major player in the therapeutic pipeline for cancer, infectious diseases, and autoimmunity. There is also tremendous potential for applying this powerful biotechnology to neurological diseases.
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Acknowledgments
We thank members of the Messer laboratory group, especially Drs David Butler and Abigail Snyder-Keller, and Kevin Manley for helpful discussions of the manuscript. Work in the Messer laboratory was supported, in part, by grants from NIH/NINDS NS053912 and NS061257, and NSF REU #DBI1062963; Hereditary Disease Foundation, High Q Foundation/ CHDI, Huntington’s Disease Society of America, and the Michael J. Fox Foundation. Full conflict of interest disclosure is available in the electronic supplementary material for this article.
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Messer, A., Joshi, S.N. Intrabodies as Neuroprotective Therapeutics. Neurotherapeutics 10, 447–458 (2013). https://doi.org/10.1007/s13311-013-0193-6
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DOI: https://doi.org/10.1007/s13311-013-0193-6