Study: mRNA Technology Holds Potential for Delivery of Tau-Targeting Antibodies

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Investigators found that mRNA technology for the delivery of antibody therapeutics were used to target tau in Alzheimer disease and can be applied to other tau targets.

Investigators have developed mRNA technology for the delivery of antibody therapeutics used to target tau in Alzheimer disease (AD), according to results in Brain Communications. Currently, mRNA has been predominately used in vaccines, according to a press release, which included the vaccines for COVID-19.1,2

Human brain digital illustration. Electrical activity, flashes and lightning on a blue background. | Image Credit: Siarhei - stock.adobe.com

Image Credit: Siarhei - stock.adobe.com

“This is the first time mRNA has been explored for use in Alzheimer disease,” said Rebecca Nisbet, PhD, lab head of the Florey Institute of Neuroscience and Mental Health, in the press release. “Our work in cell models demonstrates that this technology can serve purposes other than vaccine development.”1

In the study, authors said that anti-amyloid monoclonal antibodies are expensive and time consuming to create as well as require frequent dosing regimens to be effective. According to the study authors, they used a synthetic in vitro transcribed mRNA coding antibody specifically for tau, which was a full-sized immunoglobulin and was created as a single chain variable fragment.2

Investigators used the in vitro transfection of human neuroblastoma SH-SY5Y cells, showing that the synthetic mRNA had the ability to be translated into a functional tau-specific antibody, according to the study authors. The mRNA encoded RNJ1, a tau specific antibody that bound with amino acids 1 through 22 of tau.2

The study authors added that the mRNA in the study was generated from synthetic double-stranded DNA, instead of linearized plasmid, which they said could overcome the time and expensive barriers for these treatment options.2

“Our technique can be applied to any therapeutic antibody, and we envision that this strategy, when combined with nanoparticle packaging, will enhance targeting of toxic molecules in the brain and improve patient outcomes compared to conventional strategies,” Patricia Wongsodirdjo, a PhD student, said in the press release.1

Furthermore, the investigators noted that the translation of the single-chain variable fragment also demonstrated specific engagement of intracellular tau. The study authors said this highlights the utility of mRNA for the delivery of antibody therapeutics, which included intrabodies, according to the study results.2

Key Takeaways

  1. Researchers are exploring using mRNA technology, known for vaccines, to deliver antibody treatments for Alzheimer's disease (AD), specifically targeting the tau protein.
  2. This method could address limitations of current treatments like high cost, complex manufacturing, and difficulty targeting tau within brain cells.
  3. The study used cell models and highlights the potential of mRNA delivery, but further research is needed to address limitations like immunogenicity and degradation.

The study authors added that although intracellular tau were better targets for therapeutic strategy of AD, the full-sized immunoglobulin G were ideal for the extracellular proteins. They said that the protocol developed by the study could be applied to the development of future generations of the amyloid-b-specific therapies.2

“With conventional antibodies, such as lecanemab, the small amount of antibody that does enter the brain can remove some harmful plaque that lies outside our brain cells but can’t access toxic proteins such as tau, which is located in our brain cells,” Nisbet said in the press release.1

Investigators noted that synthetic mRNA does have limitations, including with immunogenicity and propensity, which can be rapidly degraded, according to the study authors. They said the results of the study do not have to be limited to RNJ1 but can be applied to the delivery of author tau antibodies that have shown therapeutic potential. The authors also said that this study is the first to their knowledge to document evidence of a direct interaction between tau antibody and tau within a cell.2

References
  1. Florey researchers unlock how to use mRNA to target Alzheimer’s disease. News release. The Florey. March 29, 2024. Accessed March 29, 2024. https://florey.edu.au/news/2024/03/florey-researchers-unlock-how-to-use-mrna-to-target-alzheimers-disease/
  2. Wongsodirdjo P, Caruso AC, Yong AK, Lester MA, et al. mRNA encoded antibody approach for targeting extracellular and intracellular tau. 2024. doi:https://doi.org/10.1093/braincomms/fcae100
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