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mRNA pills show promise in animal studies

Messenger RNA (mRNA) technology helps treat and prevent various diseases, including cancerTrusted Source, Zika virusTrusted Source, and COVID-19Trusted Source.

DNA is converted into mRNA that translates to make proteins. mRNA technology works by inserting new mRNA into cells to code for new proteins.

As mRNA vaccines require shorter time frames for development than other vaccine types, they could play an essential role in controlling pandemic diseases.

However, researchTrusted Source shows that patients and clinicians prefer oral medicines — such as pills — over injections. Oral medicines also have the advantage of delivering drugs directly to the gastrointestinal (GI) tract, which can be difficult to achieve with other methods.

As mRNA-based drugs degrade quicklyTrusted Source after ingestion, they are administered intravenously, intramuscularly, or subcutaneously.

Developing a way to deliver mRNA treatments and vaccines via a pill may increase mRNA drug acceptance by both patients and clinicians and enable better targeting of the GI tract.

In a recent study, researchers led by the Massachusetts Institute of Technology (MIT) in Cambridge investigated an oral delivery method for mRNA treatments.

The researchers found that their new delivery method successfully delivered mRNA treatments in animal models.

“When you have systemic delivery through intravenous injection or subcutaneous injection, it’s not very easy to target the stomach,” says Alex Abramson, Ph.D., a postdoctoral fellow at Stanford University and co-lead author of the study. “We see this as a potential way to treat different diseases that are present in the gastrointestinal tract.”

The study appears in the journal MatterTrusted Source.

Drug delivery capsules

The MIT researchers have been developing ways to deliver drugs to the gastrointestinal tract for many years. In 2019Trusted Source, they designed a capsule called ‘self-orienting millimeter-scale applicator’ (SOMA) that, when swallowed, places drugs such as insulin directly into the stomach lining without damaging it.

In 2021Trusted Source, the researchers delivered large molecules such as monoclonal antibodies in liquid form to the GI tract using SOMA.

SOMA’s design was inspired by the leopard tortoise. In a manner similar to how the tortoise reorients itself by rolling onto its back, the capsule first positions itself and then injects its contents into the stomach lining.

In the present study, the researchers set out to determine if the same capsule could also deliver mRNA molecules to the stomach lining.

From previous work, they found that a type of nanoparticles called poly(beta-amino esters) is more effective than other materials at protecting mRNA before reaching its target site. They thus used these polymers to protect mRNA in their experiments.

Animal models

The researchers first tested whether the polymers could protect mRNA from degradation in the stomach. To do so, they injected polymer-encased mRNA for a reporter protein into the stomachs of mice. In this experiment, they did not use SOMA.

They note that the reporter protein was expressed in both the stomachs and the liver of the mice. This meant that the mRNA had been absorbed by other organs and then carried to the liver, which filters the blood.

Afterward, the researchers freeze-dried the mRNA-nanoparticle complexes and put them into their SOMA capsules. Together with scientists at Novo Nordisk, they loaded 50 micrograms of mRNA into each capsule and then delivered three each into the stomachs of pigs.

While the reporter protein was successfully produced in the pig’s stomach cells, the researchers note it did not spread to other organs.

Technical hurdles

To explain the differences between the pig and mouse models, the researchers say that higher doses of their formulation may have been needed to detect the reporter protein in pigs.

When asked why the reporter protein was produced only in the stomach lining among pigs and not in other organs as with mice, Dr. Traverso added that the different results also might be the result of different testing methods used to identify the proteins:

“The key difference between the [pig and mouse] models was that the rodent model has an inbuilt reporter with a green fluorescent protein which is produced for expression. For the pigs, we had to sample tissue and look for expression with immunohistochemical means.”

“Given this, one of the potential explanations is a technical one insofar as it [is] more challenging to test through immunohistochemistry in a large organ. We are exploring other mRNA molecules that can serve as better markers as we continue to develop these technologies,” he added.

Dr. Piotr Kowalski, Ph.D., HRB emerging investigator for health at University College Cork, Cork, Ireland, not involved the study, told MNT, “mRNA nanoparticles contained in SOMA and released via milli-needle injection will facilitate protein production primarily in the cells located close to the injection site, since the relatively large size of the nanoparticles makes it difficult for them to migrate to the systemic circulation through the stomach lining.”

The researchers conclude that SOMA can bypass the degradative enzymes in the GI tract and deliver mRNA medications directly to the stomach lining.

The researchers note some limitations to their research. Firstly, additional large animal models and human trials are needed to understand the clinical safety and efficacy of the method.

Furthermore, nanoparticle-optimization may reduce degradation after injection, and therapeutic mRNA, such as mRNA vaccines, should be tested.

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