Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

Abstract

(2012) Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice, Prion, 6:4,[383][384][385][386][387][388][389][390]

Advances in the development of antibody-based immunotherapy against prion disease

“…Recently, passive immunization has been extensively investigated ( Figure 1). 63,68,96,[108][109][110][111][112][113] Transgenic expression of the µ heavy chain of anti-PrP antibody 6H4 in PRNP -/-mice was found to completely prevent prion infection after intraperitoneal PrP Sc administration. 68 The most common way of administering anti-prion antibodies to prion-infected mice is peripherally.…”

“…Novel scFv variants with improved stability can be selected from large randomly mutated phage-displayed libraries with a specific antigen, [120][121][122] and phage display has been successfully used in engineering anti-prion antibodies. 110,123 An scFv version of a PrP-specific full-length antibody (6H4) has been demonstrated therapeutic 63,68 and to increase PrP Sc clearance when secreted from stably transfected and cultured cells. 117 Serotype 2 of AAV (AAV2) is one of the most commonly used vectors for brain delivery.…”

“…129 Moda et al engineered the single-chain variable fragment antibody D18 (scFvD18), specifically recognizing residues 132-156 of PrP, into the AAV9 vector (AAV9-scFvD18). 110 Mice were then intracerebrally inoculated with this before being intraperitoneally injected with the RML prion strain. The treatment efficiently reduced the accumulation of proteaseresistant PrP and significantly delayed the onset of disease in mice.…”

“…Moreover, the treatment was found to be safe. 110 To treat prion disease efficiently, anti-prion antibodies that can cross the BBB have also been investigated. Jones et al raised a camelid anti-prion antibody, known as PrioV3, capable of crossing the BBB in vitro and in vivo via receptormediated transport that did not display any neurotoxic effects in a scrapie-susceptible neuroblastoma N2a cell line.…”

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

“…The advantage of VHs and scFvs is the single polypeptide sequence used for the gene transfer-based passive immunisation. Studies conducted by Moda et al [124] and Wuertzer et al [125] investigated vectors for antibody gene delivery to both periphery and brain areas and highlighted two: AAV2 and AAV9 showing a promising delay in the onset of clinical signs of the disease, prolonged survival time, milder neuropathological changes, reduced PrP SC in brain and more importantly, no inflammation and neurotoxicity. An additional benefit of intrabodies is the ability to design them to target a specific cellular compartment.…”