In 2018, the FDA approved the first gene drug based on lipid nanoparticles (LNPs) - SiRNA Patiiran (ONPATTRO; Alnylam) - for the treatment of polyneuropathy caused by hereditary transthyroxine-mediated amyloidosis. LNPs have been extensively studied as delivery tools for decades, but they have recently gained significant attention as a technical platform capable of delivering mRNA.
LNPs typically consist of four components: cationic or ionized lipids, cholesterol, auxiliary lipids, and polyethylene glycol lipids. These components enable the encapsulation of various drugs, including small molecules, peptides, and nucleic acids, protecting them from degradation by enzymes and facilitating their transport across cell membranes. LNPs also support repeated and immediate administration, and their safety has been validated through the widespread use of COVID-19 vaccines. Moreover, pharmaceutical companies have established sufficient LNP manufacturing capacity during the pandemic.
LNPs play a pivotal role in advancing emerging gene drugs. Based on their potential mechanisms of action, gene drugs can be categorized into four types: 1) gene addition or substitution, involving the use of LNPs to deliver viral vectors containing specific genes or mRNA encoding genes; 2) gene expression control, which includes LNPs encapsulating siRNA or siRNA coupled with hepatocyte targeting ligand GalNac (N-acetylgalactosamine); 3) gene editing, which employs viral vectors or LNPs to deliver components of the CRISPR-Cas9 gene editing system; and 4) DNA or RNA vaccines, such as mRNA vaccines encapsulated in LNPs or polymer nanoparticles.
In order to comprehend the current and future significance of LNPs in the in vivo development of gene drugs, a comprehensive analysis was conducted on publicly available information regarding clinical and approved gene drug pipelines worldwide. This analysis encompassed 538 assets from 273 companies as of December 2021, evaluating the extent to which LNPs permeate the entire development pipeline and the global market of gene drugs based on LNPs from 2021 to 2036.
Among the four types of gene drugs, LNPs exhibit the highest average penetration rate (i.e., the percentage of assets employing this model) in nucleic acid-based vaccines and gene editing, accounting for 7%. This finding reflects the challenge of GalNAc coupling when delivering larger nucleic acids in these contexts. The permeability of LNPs in gene addition or substitution is relatively low, as adeno-associated virus (AAV)-based delivery offers greater utility. Additionally, due to competition from GalNAc coupling, gene expression control exhibits the lowest permeability. Generally, the gene drug pipeline initiated by LNPs predominantly focuses on DNA and RNA vaccines, primarily in phase I clinical trials.
The current market size of LNP-supported gene drugs is estimated to be around $51 billion, primarily driven by the revenue from two COVID-19 mRNA vaccines, with Onpattro being the sole product besides them. In the short term, the market size may shrink as the revenue from COVID-19 mRNA vaccines declines. However, it is anticipated that as the gene drug pipeline matures, companies will further invest in LNP innovation, resulting in market growth. By 2036, the LNP gene drug market is projected to rebound to $48 billion.
Over the next decade, it is expected that the sales of mRNA vaccines and co-stimulants in the context of COVID-19 will largely dominate the LNP market. With the approval of products from companies such as Intellia Therapeutics and Beam Therapeutics, in vivo gene editing is anticipated to gain some market share.
LNPs will continue to serve as a core tool for gene drugs, particularly mRNA vaccines. The broader application of LNPs beyond vaccines will depend on the ability of companies to tailor lipids for specific organs other than the liver. Other factors that could facilitate the wider adoption of LNPs in gene drug development include the capacity to encapsulate larger genes, particularly those exceeding 5kB in size, which is the packaging limit for many AAV vectors.
While the current generation of LNPs has undergone clinical verification and widespread use in mRNA vaccines, there are limitations in terms of delivery efficiency, immunogenicity, shelf life, and other application costs. The next generation of LNPs may utilize novel non-lipid components (such as fusion proteins and polymers) to address these limitations. In summary, LNPs hold the potential to evolve into a long-term fundamental drug delivery system, offering extensive application prospects in the field of gene medicine.
