Decades after breakthrough, scientists still puzzling over mRNA delivery

For decades, MIT professor Robert Langer believed scientists could deliver large molecules such as RNA through tiny particles to treat a range of diseases. When he told a group of senior scientists about his ideas for drug delivery at a Chinese restaurant in 1979, one of them blew cigar smoke in his face.

“You better start looking for another job,” the scientist said.

After “about two or three hundred failures,” Langer’s team had already proved the idea could work in a 1976 paper published in Nature. Still, he faced a string of rejected grants and skepticism. His research on drug delivery, which led him to co-found Moderna in 2010, went on to prove critical in developing the company’s Covid-19 vaccine. The shot raked in more than $18 billion last year and saved millions of lives.

Langer never thought messenger RNA’s potential was limited to vaccines, and now neither do other scientists and investors. Drugmakers are pursuing a range of disease areas, from cancer to cystic fibrosis, triggering a record $3.2 billion in venture cash in 2021. Another $2 billion followed in 2022, according to DealForma’s Chris Dokomajilar. The large investments solidified mRNA as the next big thing after decades of existing on the fringes.

The realization of mRNA’s potential in other areas, however, means tackling more challenges. It has to get to and express in the right cells – something that wasn’t quite as difficult with vaccines. And it has to arrive before the large, unstable mRNA molecules degrade.

“Vaccines were quite literally the lowest hanging fruit,” Strand Therapeutics CEO Jake Becraft said in a video explaining the company’s mRNA technology.

The delivery problem

The delivery of macromolecules — including RNA and other nucleic acids — still preoccupies Langer. He and other MIT researchers in recent years developed microparticles that hold potential for delivering cancer and biologic drugs, using biodegradable polymers that are already approved for medical devices. These microparticles could also be used for self-boosting RNA vaccines that deliver their payloads at different times, as reported in a 2022 paper in Science Advances.

“When I first tried to put large molecules into nanoparticles and microparticles, everybody told us that was impossible,” Langer said. “The lesson that I learned is that probably nothing is impossible. No matter what problem you try to tackle, with enough work you might be able to solve it.”

After initially struggling with delivery, mRNA pioneers landed on lipid nanoparticles, bubbles of fat that protect mRNA and escort it across the cell membrane. Once inside the cell, lipid nanoparticles unpack mRNA’s essential protein-building instructions to create, for example, coronavirus spike proteins to prime the immune system or proteins that could activate the immune system against cancer.

Intramuscular delivery of mRNA vaccines is ideal, in part because the muscle contains important immune cells. However, it’s difficult to direct lipid nanoparticles to specifically target other types of tissue.

“The fundamental limitation now is being able to get to the right tissues,” said University of British Columbia molecular biologist Pieter Cullis, whose pioneering lipid nanoparticle technology was incorporated in Pfizer and BioNTech’s Covid-19 vaccine.

New tactics

To overcome delivery challenges, Vertex and Moderna partnered to put their twist on lipid nanoparticles, for inhaled delivery to the lung. Their program drawn from this technology, in Phase I, is aimed at cystic fibrosis. ReCode Therapeutics is similarly working on inhalable formulations of mRNA for delivery to the lungs.

The liver also represents a promising target for lipid nanoparticles, because anything injected intravenously passes through the organ, Cullis explained. Verve Therapeutics, for instance, uses a lipid nanoparticle package and gene editing to target liver cells. However, the FDA in November placed a clinical hold on the company’s program for a type of cardiovascular disease over fears of off-target effects. Verve said it “intends to submit a response as expeditiously as possible.”

“I think the editing field is probably going to be one of the more exciting places within mRNA,” CSO and CMO Andrew Bellinger said. “That’ll be initially delivering to the liver, but I think there’s a lot of progress with delivery outside of the liver and I think over the next five years, you’ll see that.”

Pfizer’s most advanced mRNA programs span infectious diseases, including a BioNTech-partnered flu vaccine in last-stage testing. However, that doesn’t mean the company is shying away from more difficult targets. Last January, the pharma giant put down $300 million upfront and more than $1 billion in milestones for a four-year research deal with Beam Therapeutics to use mRNA and LNPs to deliver base editors for therapeutic targets in the liver, central nervous system and muscle.

“I think we will see an expansion of RNA medicines first in the vaccine space, infectious disease being the predominant one, probably oncology vaccines as well,” said Uwe Schoenbeck, Pfizer’s chief scientific officer for emerging science and innovation.

Targeting cancer

Moderna is attempting to train the immune system to recognize and attack cancer cells with its Merck-partnered cancer vaccine, which was shown to reduce melanoma patients’ risk of recurrence or death by 44% in combination with Merck’s Keytruda, the companies said in December. Full results from the closely watched trial are coming this spring, president Stephen Hoge said on the company’s latest earnings call, followed by confirmatory trials in both melanoma and non-small cell lung cancer.

“Ultimately, we’ll go first into other adjuvant indications where we think there’s the most immediate biologic benefit — or biologic rationale for potential benefit that we’ll be looking to demonstrate,” Hoge said. “But obviously, as others start to move into the space, if they show benefits in other lines of therapy, we will absolutely want to proceed very quickly in those directions as well.”

Becraft’s team at Strand believes they can clear the delivery hurdle by what they call targeted expression, meaning its mRNA is designed to express only once they reach a specific tissue. They’re focusing on solid tumors first, and hope to be in the clinic this year. While they currently deploy LNPs and modified mRNA, Becraft said he’s open to other potential avenues.

“If someone comes in with a new technology, or we see something that could be leveraged in a way to get to a certain tissue for us, I’d absolutely do that,” he said.

BioNTech struck a deal with Matinas BioPharma last April for use of its lipid nanocrystal technology, which makes use of a spiral crystal that encapsulates and protects drug molecules while potentially avoiding off-target toxicities. The deal included a potential formulation for oral vaccines.

The field has come a long way since mRNA pioneer Katalin Karikó stood hunched over a dot-matrix printer with a fellow UPenn researcher in the 1990s, watching as proof appeared that she could successfully insert mRNA into cells and create new proteins. Karikó, who went on to become a senior VP at BioNTech, said delivery remains a focal point.

“The difficulty was delivery and even today, I can say that the future is about what the delivery will solve,” she said.

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