Fight Aging!

Here find a SENS Research Foundation article covering some of the specifics of progress towards messenger RNA (mRNA) therapies capable of breaking down harmful age-related intracellular protein aggregates, with a focus on those involved in neurodegenerative conditions. Delivery of synthetic mRNA into cells by lipid nanoparticle is an active area of gene therapy development. Once inside cells, mRNA molecules are processed by ribosomes to produce proteins for a short period of time. A range of biochemical problems in the cells of aged tissues can only be solved by expressing suitable proteins inside those cells, such as clearance of protein aggregates. This sort of repair task is well suited to mRNA gene therapies that produce only short-term expression of therapeutic proteins. When damage accumulates slowly, only intermittent and short periods of treatment are needed.

Rejuvenation biotechnologies targeting aberrant tau are in development, ranging from the earliest cell studies all the way up to Phase III clinical trials. In part, this ambition to clear out tau started off as a hedge against the unfounded skepticism about the role of beta-amyloid in Alzheimer's disease. Although biotech companies were forced to abandon many of their first attempts to target tau (often because they interfered with the physiological function of the healthy, non-aggregated tau protein), clinical trials are presently testing numerous therapies targeting tau. Most of these potential therapies are in Phase II.

An important limitation of these candidate therapies is that most of them only clear tau aggregates located outside of cells - in the spaces where neurons interact with one another or in the wider fluid that bathes the brain. Such therapies should do some good, most notably by slowing down the rate at which "seeds" of aberrant tau "infect" other neurons in their network. But they would do nothing to clear existing aberrant tau in the location where those seeds form and where they inflict most of their harm: inside of neurons.

In recent years, scientists began targeting tau inside neurons using functional fragments of antibodies with key subunits that target different segments of the tau protein. When they treated animals that carry forms of mutated human tau that aggregate and drive neurodegenerative disease in humans, these antibody fragments lowered the burden of soluble aberrant tau in these animals' brains - and the effect was almost entirely the result of clearing it from inside the neurons. Scientists then pitted different tau-targeting antibody fragments against each other, and also against the same fragments after further modifying them to turn them into intrabodies. Intrabodies are antibody fragments that have been engineered to remain within and function inside cells, sometimes including targeting them to specific locations within the cell.

But how would we deliver these intrabodies to aging humans? Researchers have seized on the recent revolution of mRNA technology. Researchers realized that they could use mRNA to deliver the instructions for tau-targeting intrabodies into neurons. The cells would then produce free, active antibodies inside of themselves from scratch, avoiding the entire fraught journey required for conventional antibody infusions to reach and become active in the cell without requiring gene therapy. This research is promising, but is still in a very preliminary stage. While the potential of an mRNA vaccine against aberrant tau is exciting, hurdles remain to be overcome.

Link: https://www.sens.org/get-the-message-mrna-to-target-intracellular-aggregates/