CNS Delivery of Vectored Prion-specific Single-chain Antibodies Delays Disease Onset

• Published in: Molecular therapy Vol. 16; no. 3; pp. 481 - 486
• Main Authors: Wuertzer, Charles A, Sullivan, Mark A, Qiu, Xing, Federoff, Howard J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2008; Elsevier Limited
• Subjects: Amino Acid Sequence; Amino acids; Animals; Antibodies; Antibodies - genetics; Antibodies - immunology; Antigens; Blotting, Western; Cell culture; Cell Line; Central Nervous System - metabolism; Cytomegalovirus; Densitometry; Dentistry; Dependovirus - genetics; Disease; Endopeptidase K - metabolism; Enzyme-Linked Immunosorbent Assay; Enzymes; Gene therapy; Genetic Vectors - genetics; Humans; Immunization; Immunoblotting; Immunoglobulins; Immunohistochemistry; Immunoprecipitation; Libraries; Medicine; Mice; Molecular Sequence Data; Pathogenesis; Prion Diseases - prevention & control; Prion Diseases - therapy; Prions; Proteins; PrPC Proteins - immunology; Sequence Homology, Amino Acid; Surface Plasmon Resonance; Transduction, Genetic; New York; United States > US
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/sj.mt.6300387

A unifying characteristic of prion diseases is the conversion of a normal cellular protein (PrPc) to an abnormal pathogenic conformation, designated PrPsc. Antibodies directed against PrPc, when added to scrapie-infected cell cultures or passively administered in vivo, can result in elimination of PrPsc or prevent its replication, respectively. In our efforts to develop an approach with potential prophylactic utility we employed a recombinant adeno-associated vector type 2 (rAAV2) viral vector platform to express PrPc-specific single-chain fragment variable (scFv) antibodies within the central nervous system (CNS) of susceptible mice that were subsequently inoculated peripherally with infectious prions. Vector expressed scFvs delayed onset of prion pathogenesis as evidenced by improvements in clinical signs and rotarod performance, in extended incubation periods, and in decreased PrPsc burden in the CNS. This novel antibody delivery platform enables the in vivo translation of prion prophylactics to other species afflicted by transmissible spongiform encephalopathies (TSEs) and which also has relevance to the development of therapeutics for other protein-misfolding diseases such as Alzheimer's or Parkinson's disease.