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New mRNA delivery system effectively protects neurons in rats from ischemia 

Researchers have shown that an mRNA delivery system can be used to produce the BDNF protein in rats to protect neurons from ischemia. 

Rat and mRNA system

Researchers from Tokyo Medical and Dental University (TMDU), Japan, have demonstrated that a messenger RNA (mRNA) delivery system can effectively produce the brain-derived neurotrophic factor (BDNF) protein in rat brains to protect neurons from ischemia. 

According to the researchers, a lack of oxygen to brain tissue – known as ischemia – leads to the death of neurons, which results in stroke. Despite considerable research, there are currently no treatments that successfully prevent neuronal death. In their new study, the team have reported a way of delivering mRNA to produce BDNF, a therapeutic protein that protects neurons. 

The BDNF molecule is too large to cross the brain’s protective barrier and is rapidly removed from the central nervous system (CNS), making it difficult for the protein to make its mark as a treatment. The researchers therefore devised a way of producing BDNF where it is needed most.

They designed a delivery system containing BDNF mRNA. When the mRNA gets inside a cell, it can be used as a blueprint to make the protein.

The system – known as an mRNA nanomicelle – is a tiny ball-like parcel of mRNA surrounded by polymer strands. The polymer protects the mRNA from molecules that might break it down and helps to disguise it from the immune system.

Rat brains

Brain-derived neurotrophic factor (BDNF) serves as a potential candidate neuroprotective agent, but there are almost no successful clinical trials due to high hurdle in brain access and short half-life. Fukushima et al. show intraventriclarly administered BDNF mRNA using polyplex nanomicelle exerted a prominent effect to prevent neuronal death with the unique mechanism of action. BDNF mRNA was extensively introduced into the astrocytes to generate a higher level BDNF protein in ischemic lesion [credit: Department of Biofunction Research, TMDU].

“As well as protecting the mRNA by providing containment, the polymer allows the release of the cargo to be controlled,” said study first author Yuta Fukushima. “By selecting polymers with particular properties, we can ensure the mRNA is released when and where it is needed.”

The effectiveness of the mRNA therapy was tested on rats that had experienced brain ischemia. The nanomicelles were found to increase the survival of hippocampal neurons. In particular, the nanomicelles showed better effects when administered two days after the ischemia than when given immediately. This indicates that the nanomicelles extend the opportunity for providing effective treatment.

In addition, long-term therapeutic benefits were observed 20 days after ischemia when the mRNA nanomicelle was administered on both days two and five. Treated rats showed better spatial memory than untreated rats in a maze experiment.

“We are very encouraged by the performance of our system,” said study corresponding author Keiji Itaka. “Our experiments not only demonstrated that the mRNA nanomicelle could prevent neuron death, but also that the potential treatment window could be extended. We expect these findings to have a significant impact on the development of practical clinical treatments.”

The findings are published in Biomaterials.

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