This research is promising, but is still in a very preliminary stage. The Florey team previously tested RNJ1 in a mouse model but hasn’t yet tried out the intrabody version beyond these initial cell culture studies. While the potential of an mRNA vaccine against aberrant tau is exciting, several hurdles remain to be overcome.
The first of these is access to the brain. As we noted earlier, scientists have to package therapeutic mRNA up into protective lipid nanoparticles to keep it from being degraded as it travels the body. However, the brain is in a kind of biological Fortress of Solitude, protected against foreign materials by a layer of cells that are tightly wedged together in the lining of the blood vessels that feed it. As a result, no one has yet figured out how to get lipid nanoparticles into the brain after a simple injection. However, there’s a lot of excitement about using mRNA to target cancers and other health problems in the brain, so hopefully someone will develop a working delivery system soon — perhaps by changing the composition of fats in the nanoparticles, or by developing a way to let them port in via one of the many transport systems that allow essential biological molecules to get inside the cerebral bunker.
Another area where more work is needed is the underlying antibody from which the intrabody is made. To be frank, RNJ1 is not a particularly promising place to start. As we noted earlier, RNJ1’s effects in a mouse model were quite limited, both in terms of how much it lowered abnormal tau and in terms of improving the function of the mice. Part of the reason may be that it grabs onto the same region inside the tau protein as did three other antibodies that failed in human clinical trials.
But a more important reason, also shared by most of those antibodies, is that it goes after tau in an indiscriminate way: it not only binds to some kinds of abnormal tau, but also to normal, undamaged tau protein. This may actually be part of how it works: by binding up normal, unaggregated tau, less tau is available for the “seeds” of aggregated tau to twist into new aggregates, which then reduces the number of new tau aggregates that get seeded in the brain.
That would explain the results of a recent mouse study in which scientists treated mice that harbor a human tau mutation with a conventional antibody that exclusively targets normal tau. Mice that received the antibody went on to suffer fewer tau aggregates and lost fewer neurons going forward than the control mice. Yet, the antibody didn’t protect them against the degenerative motion disorder that the mutation causes.
Developing a true damage-repair intrabody that targeted aberrant tau exclusively and removed pre-existing aggregates would be a much more powerful strategy. It would also reduce the risk of side-effects related to robbing the cell of normal tau, which the cell needs as a scaffolding protein that also helps shuttle proteins along its length like a monorail. There are several strong conventional antibody AmyloSENS candidates that target aberrant tau and might be tweaked into intrabodies instead, such as tau oligomer-specific monoclonal antibody (TOMA) (which targets tau oligomers) and two antibodies that target ptau-217, a specific form of abnormal tau that looks promising as both a biomarker for tau-based molecular damage and also as a target for damage-repair longevity therapeutics. One of these antibodies, Janssen’s JNJ-63733657, is currently in a Phase III human clinical trial, and another recently showed promising results in a mouse model.
And having bound to aberrant tau inside the neuron — well, what then? As we noted above, in the few cases where regular tau-targeting antibodies do get inside neurons and manage to break out of their entry bubbles and bind to aberrant tau in the neuron, their ability to clear out tau is limited, and it’s not entirely clear how they are able to do what they do. Likely, most of them keep tau from assembling into aggregates, or even break early aggregates up, and some of them may help the cell’s protein-degrading machinery tear them apart.
A more powerful approach, which SENS Research Foundation scientists have worked to develop with the novel delivery system we mentioned earlier, is catalytic antibodies (catabodies) to chop pathological aggregates into harmless debris that the cell could then mop up on its own. Our scientists were endeavoring to shuttle tau-targeting catabodies into the cell, but this study suggests that promising catabodies could instead be encoded in mRNA and produced on-site inside the neuron.
The good news, again, is that there is enormous enthusiasm amongst researchers and biotech companies in harnessing mRNA as a delivery system to deliver therapies for a wide range of unrelated diseases, from congenital genetic disorders to cancer. Because mRNA is a platform for delivering therapies rather than a disease-specific or target-specific therapeutic approach, solutions for the challenges that face scientists working to use mRNA for one use case are likely to quickly spill over into other uses, including tau-targeting intrabodies or catabodies. In fact, this pilot study in using mRNA to deliver intrabodies targeting tau is not even the first case of mRNA being used to deliver a longevity therapeutic: we are aware of a biotech company working to use this platform to deliver a LysoSENS therapy targeting a completely unrelated intracellular aggregate on damage-repair principles, and other longevity biotech companies are likely to come up with good use-cases for targeting other forms of cellular and molecular aging damage.
We’ve already seen evidence that people enjoy greater benefits from AmyloSENS therapies like lecanemab and donanemab when their burden of aberrant tau is lower rather than higher. The clear implication is that they would get even more benefit if their existing burden of aberrant tau were cleaned out — perhaps before receiving amyloid-clearing therapies, perhaps after starting on them. Using mRNA to deliver antibodies designed for damaged proteins inside cells is another key piece in the puzzle of keeping our minds clear and sharp and holding onto our memories and identities into an indefinite future.
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- Source: https://www.sens.org/get-the-message-mrna-to-target-intracellular-aggregates/