Gene-Based Antibody Strategies for Prion Diseases

Prion diseases or transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative and infectious disorders characterized by the conversion of a normal cellular protein PrPC into a pathological abnormally folded form, termed PrPSc. There are neither available therapies nor diagnostic tools for an early identification of individuals affected by these diseases. New gene-based antibody strategies are emerging as valuable therapeutic tools. Among these, intrabodies are chimeric molecules composed by recombinant antibody fragments fused to intracellular trafficking sequences, aimed at inhibiting, in vivo, the function of specific therapeutic targets. The advantage of intrabodies is that they can be selected against a precise epitope of target proteins, including protein-protein interaction sites and cytotoxic conformers (i.e., oligomeric and fibrillar assemblies). Herein, we address and discuss in vitro and in vivo applications of intrabodies in prion diseases, focussing on their therapeutic potential. 1. Introduction Prion diseases or transmissible spongiform encephalopathies (TSE) are a group of fatal neurodegenerative disorders comprising Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, chronic wasting disease in cervids, bovine spongiform encephalopathy in cattle, and scrapie in sheep [1]. Prion diseases together with others, as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD), are also termed conformational or misfolding diseases, because they are characterized by protein misfolding and accumulation of intracellular and/or extracellular aggregates [2]. In the case of TSE, experimental evidence points to the conversion of the normal cellular prion protein (PrPC), into the misfolded and pathogenic form (PrPSc), as the key event in the pathogenesis [3, 4]. A template-based self-propagating process underlines the generation of infectious prions. Therefore, molecules that interfere with PrPC/PrPSc conversion and/or neutralization serve as potential therapeutic candidates for prion diseases. Moreover, cellular cofactors, as nonproteinaceous chaperones or RNA, may play a crucial role in the generation of infectious prions and could be considered as additional therapeutic targets [5]. There are as yet no effective treatments for TSE, and immunobased approaches are emerging as important therapeutic strategies against these pathologies [6, 7]. A distinguishing feature of antibodies is that they can be specifically selected against conformational protein