William McEwan, Ph.D., spent years unraveling how an antiviral protein, tripartite motif-containing 21 (TRIM21), protects our cells from infection. Working in the lab of Leo James, Ph.D., McEwan and collaborators realized that TRIM21 marks viruses to be destroyed by the cell’s waste disposal system—but only activates when enough of the proteins cluster together.
McEwan and James have now taken advantage of TRIM21’s cluster activation by turning it against another protein with a penchant for aggregation: the misfolded tau protein that causes Alzheimer’s and other neurodegenerative diseases. In two new papers, they demonstrate how two TRIM21-based techniques can remove tau tangles inside of mouse neurons while leaving healthy tau alone and improve mobility in a mouse model of Alzheimer’s disease.
“These two articles by the groups of William McEwan and Leo James are very interesting,” Einar Sigurdsson, Ph.D., a neuroscientist at NYU Grossman School of Medicine, and colleagues wrote in a forthcoming commentary that Sigurdsson shared in advance with Fierce Biotech. “Both of these potential therapies are successful in clearing pathological tau.”
Our cells normally use TRIM21 as a last line of defense against viruses that manage to breach the cell membrane. Once McEwan, now at the UK Dementia Research Institute at the University of Cambridge, understood how TRIM21 is activated by bunching together, he saw its potential to go after tau aggregates right away.
“It's only when it's forced to cluster on the surface of a virus that it becomes activated,” McEwan told Fierce in an interview. “We asked whether this could therefore allow us to encode specificity for aggregates.” In a 2017 study, he found that TRIM21, combined with antibodies that target tau, could effectively destroy tangles of misfolded tau protein in human cells.
To turn TRIM21 into a treatment, McEwan and James, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, needed to make the molecule smaller and simpler. They first isolated the part of the protein that does the antiviral dirty work, called the RING domain, and then linked it to two different tau-targeting molecules: a miniature antibody (nanobody) called F8-2 and tau protein itself.
The team engineered genes to code for the RING constructs and delivered them to mice using an adenovirus vector, commonly used in gene therapy. Injecting the RING-nanobody gene into mice with pathogenic tau, either directly into their brains or in their tails (depending on the vector), successfully cleared the aggregated proteins from their brains while not decreasing overall tau levels. The results were published in Science on Aug. 29.
In the other study, the team used tau protein itself as bait, because the misfolded tau seen in Alzheimer’s stick together and turn healthy tau pathological. This RING-Bait gene therapy also cleared tau tangles in mouse brains, and treated mice were able to walk more quickly and with more coordination. These results appeared in Cell on Sept. 13.
“It would have been interesting to see how [the two techniques] compare under identical conditions,” Sigurdsson and colleagues said in their commentary. “The antibody approach would seem to be safer because of better specificity and the RING-domain could possibly be cleaved to some extent from the mutant tau, which could then become pathological.”
“It's a hypothetical possibility” that the tau bait could separate from RING, McEwan said. “We didn't see evidence of that in our study, but it's definitely something you would want to keep an eye out for.”
Recent years have seen a boom in therapies that go after tau, which is a tougher target than the other main neurodegenerative protein—amyloid beta—because it mostly sits inside of brain cells rather than outside of them. Sigurdsson recently published a paper on a gene therapy that produces tau-targeting antibodies, and, in July, AC Immune presented preclinical data on a new class of antibody-drug conjugates that the biotech thinks has “landmark” potential.
McEwan said he’s looking to set up a company to develop other TRIM21-based degrader molecules. He also plans to continue using the new RING techniques to study the basic biology of tau in neurodegenerative disease.
“What really pays is the molecular understanding of the pathogenesis of the disease and the molecular pathways that could be applied to treat it,” McEwan said. “The investment that charities and governmental bodies have put into basic research is beginning to come to fruition.”