The first hurtle for a tau therapeutic in clinical trials is pharmacokinetics. For neurodegenerative diseases, the blood brain barrier (BBB) presents a formidable obstacle to ensuring adequate drug reaches its intended target in the CNS, and while intrathecal approaches such as ASOs circumvent the BBB, the cost of administration is a necessary consideration given the prevalence of neurodegeneration. However, the BBB provides a major limitation to antibody therapies as only very low levels, approximately 0.1-0.2%, distribute to the brain from the systemic circulation after passive immunization. [104] Thus, in order to achieve efficacy, antibodies need to have extremely high affinity to tau. Very high doses need to be used to achieve proper target coverage and antibody production becomes exceptionally expensive.
