Rewriting the health code
how mRNA technology is shaping the future of medicine
The Covid-19 pandemic has ushered in a new era in medicine – that of mRNA technology. But the potential of mRNA for preventing and treating a whole range of diseases reaches further to infectious diseases, cancer immunotherapy, therapeutics for protein replacement and gene therapy. In this article we examine how mRNA technologies open the doors to a whole range of new gene therapies, and the role of lipid nanoparticles (LNPs) in current and future developments.
Before the pandemic it was inconceivable that a vaccine could be developed and approved in such a short space of time. Most conventional vaccines against viral diseases are made from attenuated, weakened versions of the virus, for example grown in chicken eggs or mammalian cells. The process of collecting the virus, adapting it to grow in the lab, and ensuring it is not causing disease any more can take months. The concept of mRNA technology is that it turns the body into its own drug factory and enables effective therapeutics that are quick to produce.
mRNA vaccines can be constructed quickly using only the pathogen’s genetic code. It takes roughly a week to generate an experimental batch of mRNA vaccine. Producing and scaling up production is also relatively simple because the technology requires a standard production platform. Another advantage is that mRNA is particularly safe because it does not integrate into the human genome. We have also seen from the Covid-19 vaccines that the level of immunity offered by mRNA vaccines is very high.
There are currently numerous clinical trials taking place for mRNA therapeutics, and these show great potential for tackling diseases. One application is in cancer immunotherapy, where mRNA vaccines can be used to encode tumor-associated antigens that are expressed in cancer cells, thus educating the immune system to eliminate these tumor cells. Another application is to develop therapeutic approaches for autoimmune diseases like multiple sclerosis (MS), where the technology teaches the immune system to tolerate the natural proteins attacking the immune system. A third area of interest is using mRNA to treat genetic diseases like cystic fibrosis through protein supplementation therapy – life-long supplementation. There is also potential in gene therapy, where mRNA could be used in CRISPR/Cas9 application to fix errors in the genetic code. A final example is myocardial infarction (MI) and heart failure (HF), which are major causes of death in developed countries. Here, studies have shown that mRNA encoding for a growth factor (VEGF) inserted shortly after MI has the potential to regenerate tissue and cells.
To make full use of these technologies we need to ensure the mRNA can be effectively and safely delivered into the cell. Lipid nanoparticles (LNPs) are crucial to the successful delivery of mRNA vaccines and other RNA and nucleic acid therapeutics.
The Importance of LNPs for mRNA Therapies
Encapsulation of mRNA is an essential component of the Covid-19 mRNA vaccines. Without the protection afforded by LNPs, a significant percentage of these large mRNA molecules would degrade, and those that survived would have difficulty entering human cells. Through encapsulation in LNP drug delivery systems, it is possible to ensure mRNA uptake in cells that need to produce the encoded protein, such as those in the liver or the muscle.
LNPs are attractive delivery vehicles because their lipids are a natural component of cell membranes, unlike other vehicles, such as viral vectors, which can elicit their own immune responses. LNPs containing ionizable cationic lipids allow neutral, non-charged particles to be administered to patients, and, because of the high biocompatibility of these LNPs, it is possible to deliver repeated doses without eliciting an unwanted immune response.
Formulation and production of LNPs
All the LNP delivery vehicles, particularly for delivery of mRNA, are typically structured with four basic components, in addition to the genetic material: an ionizable cationic lipid critical for the formation of the LNP particle, a helper lipid that constitutes the rest of the bilayer, a stabilizing lipid like cholesterol, and a PEGylated lipid that shields the particle from opsonization (destruction).
The ionizable cationic lipid is charged at low pH when the particle is formed, which enables it to self-assemble with a negatively charged oligonucleotide or nucleic acid. Once the particles are formed and exchanged into a neutral pH buffer, they remain neutral in the bloodstream, shielding the payload and preventing the rapid opsonization of the particles. Once the particles come in contact with the cell membrane and are absorbed into the endosomal space, the cationic lipid becomes charged again, and the particle releases the payload. The nature of the cationic lipid impacts the rate of release and thus plays a significant role in determining the efficacy of the formulation.
Robust scaling of LNP processes is a challenge and moving from lab to large-scale production requires the necessary expertise. Evonik is one of the few integrated development and manufacturing partners for gene therapies able to make Lipid Nanoparticle (LNPs) technology available in GMP quality (Good Manufacturing Practice) for use in clinical-stage developments and ultimately on a commercial scale.
Future opportunities for mRNA therapeutics
In terms of vaccine manufacturing, the Covid-19 vaccines have allowed infrastructure for vaccine production to be built up and this will open doors to the manufacture of further mRNA therapies. Different mRNA therapies will require the production of different amounts. For example, cancer immunotherapy will require a personalized approach and therefore only small amounts of vaccine will need to be produced. There are implications for protein therapy replacements, which may need to be taken over a lifetime – a higher level of safety would be needed for such applications in comparison to a therapy that is given in only one or two doses.
Evonik recognized the potential of gene-based therapeutic approaches early on. While the technologies were just emerging, Evonik made a targeted investment with the acquisition of Transferra Nanosciences in 2016. The Vancouver-based laboratories work on parenteral drug formulation development using lipid nanoparticles (LNPs) and liposomes.
Covid-19 has been a catalyst for the rise of a technology that was much overdue, and this technology will lead us into a new era of gene therapies that previously seemed at least a decade of development away.
