I think what we have found in the past is that tau presents as a more challenging drug target as compared to amyloid. And I think a key difference is that amyloid is in the extracellular space, so it’s basically accessible for any therapeutic agent. It’s more easily accessible once a drug is in the brain. Tau is a much harder target because tau is largely intraneuronal, which means that a therapeutic does not only need to enter the brain, but it also needs, on top of that, to enter a neuron...
I think what we have found in the past is that tau presents as a more challenging drug target as compared to amyloid. And I think a key difference is that amyloid is in the extracellular space, so it’s basically accessible for any therapeutic agent. It’s more easily accessible once a drug is in the brain. Tau is a much harder target because tau is largely intraneuronal, which means that a therapeutic does not only need to enter the brain, but it also needs, on top of that, to enter a neuron. And we know that with ultrasound, we can increase the uptake of therapeutic agents. We also know that, for example, companies such as Roche or Denali, they use brain shuttles in order to achieve a better uptake of therapeutic antibodies by the brain. But this still leaves the challenge for tau as a target because tau is largely intraneuronal but these therapeutic agents don’t enter the brain. So we believe that this needs an additional step and in our lab we use cell-penetrating peptides so we modulate or we modify the antibody, anti-tau antibody by adding a cell-penetrating peptide. Now, normally, approximately 0.1% of an antibody enters the brain. However, when we use ultrasound, we can increase the brain uptake by a factor of up to 20-fold. But this still leaves the challenge that the therapeutic antibody needs to enter a neuron. And I think this is a major challenge for a lot of the current therapeutic approaches that while a drug such as an anti-tau antibody may enrich in the brain, the challenge really is to get it into neurons. And one approach, I think, which would allow to achieve that is by using a cell-penetrating peptide. I think the jury is still out as to what the contribution is of extra versus intracellular tau. And my lab also works on exosomal tau. And the challenge is, from a point of therapeutic intervention, is when one has, for example, an anti-tau antibody, that this anti-tau antibody may interact with extracellular tau, which is, for example, being secreted. However, when the tau is enclosed in an extracellular vesicle, such as an exosome, it’s obviously not visible to an anti-tau antibody. So I believe that adds an additional challenge to developing anti-tau therapeutics because some of the extracellular tau is enclosed in vesicles and thereby it’s shielded from therapeutic agents. So there are two challenges, to get an antibody effectively into the brain, but then once the therapeutic is in the brain, the challenge is to get the tau, whether it’s intraneuronal or extracellular, to be exposed to the tau. And I think another challenge is, even with intraneuronal approaches, is that tau has been shown to be toxic for the proteasome. It’s inhibiting proteasome functions. So we don’t want to target tau to the proteasome. We want to target it for autophagic degradation.
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