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Immunotherapy on Experimental Models for Huntington’s Disease

  • Anne MesserEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

The misfolding mutant Huntingtin protein (HTT) has been identified as the primary trigger of dysregulation and degeneration in Huntington’s disease (HD). In order to counteract the abnormal protein–protein interactions and aggregation that characterize this and related protein misfolding diseases, antibody fragments that bind near the pathogenic region have been identified and characterized, and then engineered for improved affinity, intracellular solubility, and bispecific function. HD is a paradigm disease for misfolding proteins, since the readouts are exceptionally robust in cell and animal models. Candidate antibody fragments include single-chain Fv (scFv) and single domain antibodies (dAb, VL, VH). They have been selected from phage display libraries, or cloned from monoclonal antibodies of known specificity for the HTT Exon1 targets.

Preclinical immunotherapies have been tested with gene delivery via transgenes, or delivered using AAV or lentiviral gene therapy vectors. These intrabodies can strongly affect the HD phenotype across a range of epitopes and model systems. Given that individuals with HD can be identified genetically in a premanifest stage of disease, the potential for immunotherapeutic interventions is very promising.

Key words

Trinucleotide repeats Polyglutamine expansion Fibrillar aggregates Single-chain Fv (scFv) 

Notes

Acknowledgments

We thank members of the Messer lab group, especially Drs. David Butler and Abigail Snyder-Keller, and Kevin Manley for helpful discussions of the manuscript. Work in the Messer lab 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.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Neural Stem Cell InstituteRensselaerUSA

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