A way of sneaking messenger RNA molecules into the brain could help us treat neurodegenerative conditions and brain tumours.
Illnesses that affect the brain can be difficult to medicate because the blood-brain barrier, which prevents pathogens in our bloodstream reaching our brain, also stops large potentially therapeutic molecules such as mRNAs getting across.
Now, at Cornell University in New York and her colleagues have developed a method that is based on innate, virus-like particles recently discovered in our brains. 鈥淲e take advantage of them,鈥� says Gu. 鈥淭hey naturally function in our brain to deliver mRNAs between neurons.鈥�
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Many of our most effective drugs are essentially proteins, but these can be difficult and expensive to make. Giving people mRNAs, which provide the body with the genetic code for making proteins, should be much cheaper. Such mRNAs have already been used in covid-19 vaccines and their potential goes way beyond that.
However, getting enough mRNAs into the right cells remains a formidable challenge, especially when it comes to the brain.
One problem with many existing methods, such as using harmless viruses to deliver therapeutic molecules to cells, is that the immune system spots and then targets the delivery vehicle. This means people can鈥檛 be given repeated doses.
So, many groups around the world have been trying to take advantage of a natural transport system called extracellular vesicles. These are little 鈥渂ags鈥� of molecules that bud off from cells in the body and fuse with other cells, delivering their contents.
In 2018, at the University of Utah and his colleagues showed that in the nerve cells of mammals, mRNAs with sequences that include a specific bit of extra genetic code get . These so-called Arc particles are then released in extracellular vesicles and transfer this mRNA to other neurons.
Gu and her colleagues have now shown that any cell type can produce extracellular vesicles containing specific mRNAs, as long as you add to the cells the genes for the Arc proteins and the extra code for the mRNAs you want.
鈥淭he beauty of this system is that they can be produced from any donor cell, and each different type of donor cell will have the capacity of targeting a different location,鈥� she says.
To target the brain, the researchers used immune cells called leucocytes to produce the vesicles. These cells have molecules on their surface that enable them to get through the blood-brain barrier if any inflammation is present, so extracellular vesicles that bud off leucocytes also have these surface features and can get through the barrier too.听
After the extracellular vesicles were injected into the blood of mice, neurons in the brains of the animals produced proteins encoded by packaged mRNAs, as long as there was some inflammation in the brain, the team showed.
鈥淭his will limit the applications, but of course many neurodegenerative conditions have a degree of blood-brain barrier inflammation,鈥� says at the UCL Great Ormond Street Institute of Child Health in London.
The characteristic could also be seen as an advantage, says Gu, because it means delivery of the therapeutic protein would be concentrated in regions of the brain that need treating. 鈥淲e actually like this feature,鈥� she says.
Another issue is that the extracellular vesicles would have to be derived from an individual鈥檚 own cells to avoid being rejected by the body鈥檚 immune system. But it should be possible to create universal ones that could be used to treat anyone, says team member at Cornell.
Applications of this drug-delivery method could include treating Parkinson鈥檚, 础濒锄丑别颈尘别谤鈥檚, ageing, depression and brain cancers, says Jiang. Collaboration has begun with other groups at Cornell that work in these areas.
鈥淲e are getting lots of good results,鈥� says Jiang. 鈥淏ut we are not ready to discuss them yet.鈥�
Reference: bioRxiv, DOI:
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