Benn J, Cheng S, Keeling S, Smith AE, Vaysburd MJ, Böken D, Miller LV, Katsinelos T, Franco C, Dupré E, Danis C, Landrieu I, Buée L, Klenerman D, James LC, McEwan WA. Aggregate-selective removal of pathological tau by clustering-activated degraders. Science. 2024 Aug 30;385(6712):1009-1016. Epub 2024 Aug 29 PubMed.

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Comments

  1. I think these are very promising and exciting strategies, especially the nanobody-based approach. This provides true specificity of binding/degradation. The protein fragment-based strategy could work, but could also conceivably have off-target binding, or be limited in the types of aggregates it could target.

    The major challenge to this as a therapeutic strategy is delivery of the degrader. Given that tauopathy affects a large amount of brain volume, it would be hard to transduce sufficient amounts of brain tissue to get a therapeutic effect, and additionally we don’t really know how well these therapies would be tolerated in the complex milieu of the human brain. Obviously, a mouse can’t tell you if it is not thinking clearly!

    I think the best potential for AAV-based therapies, so far, has been for spinal cord or retinal delivery. The use of mice to validate AAV for brain delivery is difficult to translate to humans.

    View all comments by Marc Diamond

  2. These two articles by the groups of William A. McEwan and Leo C. James are very interesting and show two different but related therapeutic approaches to clear pathological tau. Both rely on the RING-domain of TRIM21, with one using a single-domain antibody (sdAb, VHH, nanobody) as the tau binder, whereas the other one uses mutated tau itself as the binder. Both of these potential therapies are successful in clearing pathological tau and it would have been interesting to see how they compare under identical conditions. The antibody approach would seem to be safer because of better specificity and because in the tau approach the RING-domain could possibly be cleaved to some extent from the mutant tau, which could then become pathological. That would be of particular concern with gene therapy because of its irreversible nature.

    Focusing on the in vivo experiments, both take advantage of AAV technology, which would be particularly suitable for treating familial tauopathies, and we are performing similar studies with our sdAbs. In a related approach, we recently reported that an unmodified anti-tau sdAb expressed transgenically in tauopathy flies clears pathological tau and attenuates its toxicity and related functional deficits (Nair et al., 2024). Intriguingly, sdAb efficacy can vary substantially depending on its construct and some can even render the sdAb toxic (Congdon et al., 2022). With that in mind, and given the irreversibility of the AAV approach, it would be interesting to determine if direct administration of the RING-sdAb or RING-tau constructs would be effective. That would be more likely for the RING-sdAb, considering that we recently reported that three intravenous injections of a rather low dose of an anti-α-synuclein sdAb, or its proteolysis targeting chimera derivative (3 mg/kg), cleared α-synuclein from the brain of synucleinopathy mice, with the PROTAC derivative being more effective (Jiang et al., 2024). 

    We had previously reported the potential of anti-α-synuclein and anti-tau sdAbs for diagnostic brain imaging, showing that those sdAbs readily enter the brain and bind to their pathological target within the endosomal-lysosomal system following their intravenous injection (Jiang et al., 2023). That study also supports the feasibility of direct sdAb administration, and sdAb engineering to enhance lysosomal clearance of the pathological protein. As we have reported over the years, the extent of antibody uptake into neurons varies between different antibodies and it appears to be charge-dependent (Congdon et al., 2019). Nonetheless, if direct administration would be effective with their constructs, it would be safer because of its reversibility in light of any adverse effects.

    References:

    Nair S, Jiang Y, Marchal IS, Chernobelsky E, Huang HW, Suh S, Pan R, Kong XP, Ryoo HD, Sigurdsson EM. Anti-tau single domain antibodies clear pathological tau and attenuate its toxicity and related functional defects. Cell Death Dis. 2024 Jul 30;15(7):543. PubMed.

    Congdon EE, Pan R, Jiang Y, Sandusky-Beltran LA, Dodge A, Lin Y, Liu M, Kuo MH, Kong XP, Sigurdsson EM. Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity. EBioMedicine. 2022 Oct;84:104249. Epub 2022 Sep 10 PubMed.

    Jiang Y, Lin Y, Tetlow AM, Pan R, Ji C, Kong XP, Congdon EE, Sigurdsson EM. Single-domain antibody-based protein degrader for synucleinopathies. Mol Neurodegener. 2024 May 31;19(1):44. PubMed.

    Jiang Y, Lin Y, Krishnaswamy S, Pan R, Wu Q, Sandusky-Beltran LA, Liu M, Kuo MH, Kong XP, Congdon EE, Sigurdsson EM. Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology. Sci Adv. 2023 May 10;9(19):eadf3775. PubMed.

    Congdon EE, Chukwu JE, Shamir DB, Deng J, Ujla D, Sait HB, Neubert TA, Kong XP, Sigurdsson EM. Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy. EBioMedicine. 2019 Apr;42:157-173. Epub 2019 Mar 22 PubMed.

    View all comments by Erin Congdon

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  1. Put a RING on It: Targeting Intracellular Tau Aggregates for Destruction