On average, it takes over 12 years [1] and often much longer, from discovery to commercialization of new medicine. However, COVID-19 vaccine development has proven that genomic medicines have the potential for faster drug development. Nucleic acid therapeutics that use ribonucleic acid-lipid nanoparticle (RNA-LNP) technology have emerged as a promising approach for creating safe, targeted treatments that act on specific cells in a much shorter time, offering endless possibilities for new therapies.  Along with therapies across screening, prevention, and treatment options, genomic medicines can target the disease-causing gene mutations, offering a more accurate diagnosis and tailored treatments.

The first step toward any new drug development is identifying a biological target (e.g., a receptor, protein, gene, etc.) that is dysfunctional in patients with the disease. The next step is discovering and developing new medicines with different modes of action or improving current medications’ potency, safety, tolerability, or convenience. The ability of mRNA-LNPs to induce the expression of nearly any protein makes them invaluable in personalized medicine, gene-editing, and immuno-oncology applications. However, the biggest hurdle in developing nanomedicine is the difficulty in delivering these therapeutics to target cells.

Nucleic acids require drug delivery systems to facilitate their intracellular delivery into target cells. LNP have been widely studied as a non-viral delivery vehicle for nucleic acids, especially after the approval of the Onpattro and COVID-19 vaccines. However, many potential drugs remain in research and clinical stages because of the delays in efficiently testing the clinical validity of drug candidates. 

LNP consist of ionizable lipids, helper lipids, cholesterol, and PEG lipids, each having a specific role. The ratio and chemical properties of each component affect the LNP efficiency and ionizable lipids are one of the key strategic components that can greatly influence the LNP properties and efficiency. It is significant to develop a reproducible and scalable LNP formulation. Microfluidic mixing is an established technology for producing RNA lipid nanoparticles. However, the mixing mechanism, temperature, pH, nanoparticle composition, and shear forces affect the self-assembly process during LNP production. Further processing steps are labor-intensive and can result in poor batch-to-batch reproducibility, making scaling difficult. This can result in low nanoparticle efficacy, impact particle biodistribution, and inconsistent results. Consequently, establishing trends or applying rational design principles becomes difficult, ultimately leading to delays in identifying the lead drug candidate for further clinical validation. To overcome these challenges, it is advantageous to use a technology that can be easily scaled up to develop a consistent potent formulation. NxGen™ technology, designed for genomic medicine development, can scale from lab scale to commercial batch sizes with the same mixer design with low hold-up volumes. It uses precisely controlled mixing to generate optimal particles through a single mixer enabling the reproducible scale-up of mRNA lipid nanoparticles and other complex nanomedicine formulations.

Also, optimizing lipids can help overcome drug-delivery challenges, unlocking potential new genomic medicines in a shorter time. Vaccines, gene therapy, and cell therapy demand different characteristics from lipid nanoparticles. Therefore, it is essential to test and optimize to make promising formulations. To save time and cost of raw material in developing these formulations, at Cytiva, we offer a lipid nanoparticle library and a GenVoy-ILM™ delivery platform comprising off-the-shelf research-use-only (RUO) reagents that quickly prepare RNA-LNP formulations for discovery and proof-of-concept studies with a clear path to the clinic for later development. These easy-to-use kits offer lipids for broad and targeted applications, saving time while validating target payloads and lowering the risk of developing a bespoke lipid nanoparticle formulation. This approach accelerates pre-clinical programs for genomic medicine development.

Access to advanced instruments for discovery at an early stage is another remarkable step forward. Pre-clinical program objectives are to deliver one or more clinical candidate formulations with sufficient biological activity evidence at a disease-relevant target while demonstrating safety and potency. To identify lead candidates for nucleic acid delivery to specific cell types, LNP formulations are typically screened using in vitro assays to identify top candidates for further investigation in animal models. The raw materials for running these assays are limited and costly, requiring exceptional proficiency to combine the nucleic acid and LNP components in the correct ratio and scalable manner to avoid complexities at the clinical scale. This is a critical stage in the drug development process, and choosing the right technology early on can save time and cost.

The NanoAssemblr Spark™ nanoparticle formulation system that works on NxGen™ technology considerably accelerates screening workflows for identifying novel LNPs for biological applications. It overcomes the challenges of traditional techniques for the controlled and reproducible manufacturing of LNPs at volumes from 50 to 250 µL, encapsulating several µg of nucleic acid. Formulation creation takes less than 10 seconds, and the resulting LNP can be diluted and applied immediately to cells in culture.     

Developing genomic medicines with LNP technology is faster and safer, but it is only possible with the right lipid formulations, innovative instruments, and collaboration with experienced service providers. At Cytiva, we offer end-to-end services for drug development, including instrumentation, and lipids, across all drug development stages. Our BioPharma Services offers support in payload design and lipid-based delivery systems across a wide range of disease applications, optimization and technology transfer of manufacturing processes for cGMP production, and assistance with chemistry, manufacturing, and control (CMC) regulatory submissions.

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References:

  1. Mohs RC, Greig NH. Drug discovery and development: Role of basic biological research. Alzheimers Dement (N Y). 2017 Nov 11;3(4):651-657. doi: 10.1016/j.trci.2017.10.005. PMID: 29255791; PMCID: PMC5725284.