Immunotherapy for Conformational Diseases

Abstract

The seminal finding that immunization with amyloid-beta 1-42 in Alzheimer's disease (AD) mouse model prevented formation of and/or cleared amyloid plaques has led to numerous studies exploring related approaches for AD and other conformational degenerative disorders. While clinical trials in AD patients were discouraging because of serious side effects, this approach remains promising in light of recent findings in animal models, in which refinements aimed at reducing potential adverse reactions continue to lead to cognitive improvements. In addition to AD and its models, this type of therapy has primarily been assessed in prion disease with positive results, further supporting the potential of immunotherapy for a variety of protein-related diseases in which clearance of the pathogenic agent is likely to alleviate symptoms.

Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements

“…These findings emphasize the need for therapy targeting pathological tau conformers. As we and others have observed in A␤ plaque mouse models, it may not be necessary to clear plaques to observe a cognitive benefit (Sigurdsson, 2006). This concept may also apply to tau pathology, because suppression of transgenic tau in a different P301L mouse model has been shown to improve memory although neurofibrillary tangles remained (Santacruz et al, 2005).…”

Anti‐Misfolding and Anti‐Fibrillization Therapies for Protein Misfolding Disorders

“…They also immunized 11-month-old mice, and the results showed a reduction in the extent and progression of the pathology [38]. This pioneer study was then repeated and confirmed by many groups, showing that immunization also prevents memory deficits in transgenic mice [39,40]. Passive immunization has also been done by intraperitoneal injection of antibodies against Ab, which reduced pathology in the brain [41].…”

“…The promising results with immunotherapy in AD prompted investigators to apply similar strategies for other PMDs. Indeed, positive results with diverse passive or active immunization paradigms have been reported in diverse diseases, including PD, prion diseases, and systemic amyloidosis [40]. The immunization approach showed such great promise that it moved quickly to human clinical trials.…”

“…Immunotherapy is currently regarded as one of the most promising strategies for treatment if research can reduce side effects maintaining efficacy. Several modifications are currently under development, including the use of shorter or modified peptides as immunogens and DNA immunization among others [39,40].…”

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

“…It is particularly in these early phases of disease, prior to irreversible damage, that a diagnosis is most difficult to make while having potentially greatest value. Treatment initiated at this early stage will likely have the most dramatic effects on the subsequent amyloid burden, as suggested by therapeutic interventions in AD model animals (Sigurdsson, 2006;Wisniewski and Frangione, 2005) Amyloid plaque deposition tends to follow a stereotypic pattern with AD pathology progression in terms of regional distribution and density of plaque burden, while at the same time it is common for elderly individuals to have some degree of plaque burden, but to remain clinically asymptomatic (Braak and Braak, 1997;Price and Morris, 1999;Thal et al, 2000). Magnetic resonance imaging (MRI) based plaque detection methods coupled with more accurate amyloid quantitation, may be superior to PET based methods at differentiating degrees of amyloid burden that are associated with early AD versus clinically normal aging.…”