Recombinant Intrabodies as Molecular Tools and Potential Therapeutics for Huntington's Disease

Abstract

The therapeutic potential of intracellularly expressed, recombinant, or single-chain fragment variable (scFv) antibodies (intrabodies) is being explored for several diseases, including cancer, HIV, and neurodegenerative disorders. Intrabodies can bind and inactivate toxic intracellular proteins, prevent misfolding, promote degradation, and block aberrant protein–protein interactions with extreme molecular specificity. Neurodegenerative disorders are particularly attractive candidates for these reagents because many of these diseases involve protein misfolding, oligomerization, and aggregation [1]. In particular, intrabodies have shown efficacy in blocking the toxicity of the amyloidogenic protein fragment Aβ in cell culture and mouse models of Alzheimer's disease (AD), paving the way for clinical trials of these reagents in brain disorders [2]. In addition to their therapeutic potential, intrabodies are also useful molecular tools to identify the pathogenic epitopes in toxic proteins, which can be targets for other types of therapy. In this chapter, we will review the strategies that have been used to develop intrabodies specific for the huntingtin (htt) protein, and describe their testing in models of Huntington's disease (HD) and their development as potential therapeutic agents for clinical use in HD.

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