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Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody.

ABSTRACT: The microtubule-associated protein tau is an attractive therapeutic target for the treatment of Alzheimer's disease and related tauopathies as its aggregation strongly correlates with disease progression and is considered a key mediator of neuronal toxicity. Delivery of most therapeutics to the brain is, however, inefficient, due to their limited ability to cross the blood-brain barrier (BBB). Therapeutic ultrasound is an emerging non-invasive technology which transiently opens the BBB in a focused manner to allow peripherally delivered molecules to effectively enter the brain. In order to open a large area of the BBB, we developed a scanning ultrasound (SUS) approach by which ultrasound is applied in a sequential pattern across the whole brain. We have previously shown that delivery of an anti-tau antibody in a single-chain variable fragment (scFv) format to the brain is increased with SUS allowing for an enhanced therapeutic effect. Here we compared the delivery of an anti-tau antibody, RN2N, in an scFv, fragment antigen-binding (Fab) and full-sized immunoglobulin G (IgG) format, with and without sonication, into the brain of pR5 tau transgenic mice, a model of tauopathy. Our results revealed that the full-sized IgG reaches a higher concentration in the brain compared with the smaller formats by bypassing renal excretion. No differences in either the ultrasound-mediated uptake or distribution in the brain from the sonication site was observed across the different antibody formats, suggesting that ultrasound can be used to successfully increase the delivery of therapeutic molecules of various sizes into the brain for the treatment of neurological diseases.

SUBMITTER: Janowicz PW

PROVIDER: S-EPMC6592925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: The blood-brain barrier (BBB) while functioning as a gatekeeper of the brain, impedes cerebral drug delivery. An emerging technology to overcome this limitation is focused ultrasound (FUS). When FUS interacts with intravenously injected microbubbles (FUS+MB), the BBB opens, transiently allowing the access of therapeutic agents into the brain. However, the ultrasound parameters need to be tightly tuned: when the acoustic pressure is too low there is no opening, and when it is too high, tissue damage can occur. We therefore asked whether barrier permeability can be increased by combining FUS+MB with a second modality such that in a clinical setting lower acoustic pressures could be used. Methods: Given that FUS+MB achieves BBB opening in part by disruption of tight junction (TJ) proteins such as claudin-5 of brain endothelial cells, we generated a stable MDCK (Madin-Darby Canine Kidney) II cell line (eGFP-hCldn5-MDCK II) that expresses fluorescently tagged human claudin-5. Two claudin-5 binders, the peptide mC5C2 and cCPEm (truncated form of an enterotoxin), reported previously to weaken the barrier, were synthesized and assessed for their abilities to enhance the permeability of cellular monolayers. We then performed a comparative analysis of single and combination treatments, measuring transendothelial electrical resistance (TEER) and cargo leakage, combined with confocal image analysis. Results: We successfully generated a novel cell line that formed functional monolayers as validated by an increased TEER reading and a low (< 0.2%) permeability to sodium fluorescein (376 Da). We found that the binders exerted a time- and concentration-dependent effect on barrier opening when incubated over an extended period, whereas FUS+MB caused a rapid opening followed by recovery after 12 hours within the tested pressure range. Importantly, preincubation with cCPEm prior to FUS+MB treatment resulted in greater barrier opening compared to either FUS+MB or cCPEm alone as measured by reduced TEER values and an increased permeability to fluorescently labelled 40 kDa dextran (FD40). Conclusion: The data suggest that pre incubation with clinically suitable binders to TJ proteins may be a general strategy to facilitate safer and more effective ultrasound-mediated BBB opening in cellular and animal systems and potentially also for the treatment of human diseases of the brain.

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Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody.

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