Estelle Beguin, Ph.D, Strategic Marketing Manager for SAFC® Synthetic Lipids portfolio, MilliporeSigma
RNA-based vaccines have played a starring role in the ongoing COVID-19 pandemic. There is also great potential for RNA to be applied to more indications, such as vaccines geared towards other infectious diseases or cancer.
As nucleic acids are highly negatively charged and fragile, the right delivery systems are needed to protect RNA from degradation. One technology — lipid nanoparticles (LNPs) — has proven to enable the drug delivery of RNA-based therapeutics.
Pharma Manufacturing recently spoke with Dr. Estelle Beguin, Strategic Marketing Manager for the SAFC® Synthetic Lipids portfolio, MilliporeSigma, to get a better understanding of lipid nanoparticles and the role they will play in the success of emerging therapies and vaccines.
Q: While they proved extremely effective in the fight against COVID, RNA-based therapeutics are not without challenges, especially in terms of formulation and delivery. Can you walk us through the importance of drug delivery for RNA?
A: RNA-based therapeutics and vaccines have certainly been in the spotlight with the development of COVID-19 vaccines during this pandemic, but actually, the first lipid-based gene therapy encapsulating siRNA was approved in 2018. The field has been gearing up for years now to harness the powerful and versatile nature of nucleic acid to treat and prevent diseases.
In the case of DNA therapies for example, a gene of interest can be delivered which can be used to purposely cause the sustained expression of desired proteins.
RNA can be used in different scenarios:
- Large messenger RNAs: mRNA can be used to only cause the transient expression of certain proteins, applicable in the case of protein-replacement therapies or COVID-19 vaccines. Once the mRNA is degraded, the protein expression then stops; and the mRNA does not integrate into the genome, providing a tighter control over when the treatment starts and stops.
- Shorter RNA strands: Small interfering RNA (siRNA) or short activating RNA (saRNA) can be used to silence or activate the expression of certain genes. This is particularly relevant when diseases are caused by the overproduction or insufficient production of a specific protein.
Overall, nucleic acids are extremely versatile in the way they can be used to modulate gene expression or protein production, but these are fragile systems that would degrade if administered as-is and then be cleared out prior to reaching the cells where they need to take action. This is when lipid-based formulations are crucial to promote their stability but also enable their efficient delivery into cells.
Q: What makes lipid-based delivery an attractive system for RNA therapeutics?
A: RNA, being highly negatively charged and very fragile systems, need to be protected to ensure they can reach the target cells and be released into the cytoplasm of cells in their active form. While other delivery systems are also studied for this purpose like viral vectors and polymeric systems, lipid nanoparticles stood out as a promising option. Indeed, LNPs demonstrated efficient stabilization of RNA and delivery into the cytoplasm of cells, but they also provide flexibility in the formulation and manufacturing of the final drug product. For instance, they can be customized to have specific encapsulation, release or targeting properties. Additionally, some lipids have immunostimulant properties and can act as adjuvants to also promote efficacy.
Q: The performance of lipid-based formulations is dependent on a few factors, one of which is the composition of the drug delivery vehicle. Why does this matter so much?
A: The composition of LNPs has a significant impact on the overall performance of the RNA-based drug product because the formulation affects the encapsulation efficiency of the RNA, its biodistribution, and how well it will be released into cells. For instance, the formulation would need to be optimized if a new RNA is to be encapsulated. Additionally, since the RNA is encapsulated within lipids, these lipids are then in direct interaction with the biological environment from the onset of administration, and therefore their composition also dictates to which specific tissues or cells the RNA is going to be delivered.
Q: Another important factor is the quality and consistency of the lipids used in your formulation. Why is this so vital and what can be done to ensure high lipid quality?
A: Lipid type, source and quality are essential factors to be considered when designing lipid-based formulations because these have a direct impact on the impurity profile and properties of the final drug product. For instance, they might impact particle characteristics such as structure, stability, and release properties. Additionally, to ensure the reproducibility of the formulation and associated results, it is essential for these lipids to be synthesized from high-purity raw materials with consistent quality because these characteristics are then carried over to the lipids and then to the final drug product manufactured with those.
Of course, when considering the need for consistent and high purity excipients, chemically synthesized lipids have a significant advantage over natural lipids because they are made from a single type of lipids of known quality, while natural lipids can be composed of a mixture of lipids and might present batch-to-batch variability.
To ensure the high purity of chemically synthesized lipids with consistent quality and good handling properties, the purity of the starting materials needs to be tightly controlled and optimization of the manufacturing process and purification methods is often required. It is particularly important to control any impurities in lipids, as these can alter the characteristics of the final formulation like the stability and the RNA release profile.
Q: During the pandemic, with so many RNA therapeutics and vaccines being developed, the industry urgently needed a large supply of lipids. How did MilliporeSigma rise to the challenge?
A: Within our SAFC® portfolio, we have over 24 years of experience in the GMP manufacturing of lipids and an established center of excellence that make us a trusted supplier for these materials.
We also have extensive experience with the successful execution of a large number of projects for different clients. Additionally, our SAFC® portfolio has a dedicated contract manufacturing organization and a global network of facilities and experts to efficiently enable scale-up processes as needed. All of these facilities are frequently inspected by the FDA, EMA, other health agencies, and customers. Therefore, we had the appropriate network and expertise within MilliporeSigma to support pharma companies developing vaccines against COVID-19 right as the pandemic started.
We were already working with mRNA companies before the pandemic actually, and the progress made in this field during this time just encourages us further to support the growth and development of RNA-based therapeutics and vaccines. The recent acquisition of AmpTec further expands our presence in the mRNA field, and this also reflects our faith in the technology.
Our lipid team is also highly experienced, with over 85 years combined working in this field. They have the deep know-how to develop solutions for even the most challenging customer projects. As an example, we were able to meet the challenge of producing very large quantities of lipids for BioNTech’s COVID-19 vaccine.
Our goal is to provide the best support possible to our customers — both our existing customers and other companies advancing the mRNA therapeutics and vaccines and the science behind them.
Q:. What role will lipid-based RNA therapeutics play in the future?
A: Before COVID-19, there were already many activities ongoing in the development of RNA therapeutics. It is however certain that the emergency approval of mRNA-based COVID-19 vaccines with their successful clinical results has fast-forwarded the development of other mRNA therapeutics in an incredible way.
There is a lot of potential for this technology to be applied to other indications outside of COVID-19, for instance against other infectious diseases or for cancer vaccines, and we have seen a rapid increase in the number of preclinical investigations and clinical trials using RNA or DNAs to support that. As more clinical successes are published using this technology and as we prove that medicine can be designed to act at the genetic level, there is going to be a paradigm shift in the way diseases are addressed — so lipid-based RNA therapeutics definitely have an exciting future ahead.