Research advances into the design of lipids that deliver messenger RNA (mRNA) therapeutics could result in more effective vaccines and treatments for conditions that range from genetic disorders to infectious diseases.
A new method by researchers at the University of Pennsylvania focuses on the design of ionizable lipids that form a key part of lipid nanoparticles (LNPs), which package mRNA therapeutics so they can be delivered deep within the body.
The approach, outlined in the journal Nature Biomedical Engineering, involves a step-by-step procedure called “directed chemical evolution.”
This mimics the process of natural selection to create the ideal ionizable lipid that allows LNPs to reach target cells and efficiently release their contents.
Preclinical studies showed that the redesigned lipid packaging performed better than the current industry standard for a COVID-19 mRNA vaccine and a mRNA therapeutic for a rare hereditary disease.
The approach could also shave years off the development of these lipids, reducing it from years to months or even weeks.
“Our hope is that this method will accelerate the pipeline for mRNA therapeutics and vaccines, bringing new treatments to patients faster than ever before,” said Michael Mitchell, PhD, an associate professor in bioengineering who runs a lab at the University of Pennsylvania.
mRNA-based therapeutics have revolutionized the treatment and prevention of disease, the authors noted.
They add that recent approvals for three LNP-based RNA drugs and advances in LNP technology for mRNA therapeutics and vaccines and CRISPR gene editing have further sparked interest in these non-viral vectors.
Conventional LNPs are composed of four components: ionizable lipids, phospholipids, cholesterol and polyethylene glycol-conjugated lipids.
The ionizable lipid plays a pivotal role in protecting and transporting the delicate RNA cargo, helping to determine both the potency of the therapeutic and LNP biocompatibility.
The new system for optimizing these ionizable lipids combines two conventionally used methods: medicinal chemistry, an accurate technique that involves laboriously designing molecules one step at a time; and combinatorial chemistry, which is fast but has low accuracy for finding lipids of high potency and biodegradability.
“We thought it might be possible to achieve the best of both worlds,” says researcher Xuexiang Han, who until recently was a postdoctoral fellow in the Mitchell Lab.
“High speed and high accuracy, but we had to think outside the traditional confines of the field.”
The team screened for lipids best able to deliver RNA and used these as a starting point to generate another round of molecular variants, with the process repeated five times until only the highest-performing variants remained.
Particularly important within this process was A3 coupling, a reaction which has never previously been applied to synthesize ionizable lipids for LNPs and is so called because of its three components—an amine, an aldehyde and an alkyne.
This enabled the rapid production of large numbers of ionizable lipid variants and allowed precise control over their molecular structure, which could be adapted to optimize mRNA delivery.
A proof-of-principle study revealed that a lead A3-lipid improved hepatic delivery of an mRNA-based editor for a gene implicated in hereditary amyloidosis, which results in abnormal protein deposition in the body.
It also improved the intramuscular delivery of an mRNA vaccine against SARS-CoV-2.
The researchers concluded: “We foresee that our directed-chemical-evolution methodology and resulting structural criteria can accelerate the development of desirable ionizable lipids for a broad range of mRNA delivery applications.”
