Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety

Abstract

Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of interest, no genomic integration, and fast and efficient manufacturing process compared with other biologics have been verified, thus establishing a basis for a broad range of applications. The intrinsic immunogenicity of LNP formulated in vitro transcribed (IVT) mRNA is beneficial to the LNP-mRNA vaccines. However, avoiding immune activation is critical for therapeutic applications of LNP-mRNA for protein replacement where targeted mRNA expression and repetitive administration of high doses for a lifetime are required. This review summarizes our current understanding of immune activation induced by mRNA, IVT byproducts, and LNP. It gives a comprehensive overview of the present status of preclinical and clinical studies in which LNP-mRNA is used for protein replacement and treatment of rare diseases with an emphasis on safety. Moreover, the review outlines innovations and strategies to advance pharmacology and safety of LNP-mRNA for non-immunotherapy applications.

Reactogenicity Correlates Only Weakly with Humoral Immunogenicity after COVID-19 Vaccination with BNT162b2 mRNA (Comirnaty®)

“…These and other observations have supported the "no pain, no gain" concept [26]. mRNA vaccines formulated in lipid nanoparticles (LNP) exhibit a strong endogenous adjuvant activity, which is due to the LNPs, the mRNA and nucleic acid byproducts from mRNA synthesis [27,28]. On the other hand, the prophylactic intake of anti-inflammatory drugs such as paracetamol or cyclooxygenase inhibitors had only a limited inhibitory effect on the antibody response to various adjuvant-containing vaccines, including diphtheria, tetanus, pneumococcal or hepatitis B vaccines, which was much weaker or even gone after the second vaccine dose [29].…”

Lipid Nanoparticles for Organ-Specific mRNA Therapeutic Delivery

“…Additional modifications tuned the properties of LNPs. For example, in addition to ionizable lipids, LNPs contain phospholipids that serve as helper lipids, cholesterol to improve cell entry and polyethylene glycol (PEG) to improve stability and circulation time by preventing serum protein binding (Figure 1a,b) [27,[31][32][33].…”

Oligonucleotides-Based Therapeutics

“…Among the many reasons for this shift are the continued efforts by academic laboratories, now large biotechs (such as Ionis Pharmaceuticals or Alnylam Pharmaceuticals) and big pharmaceuticals (such as Novartis or Astra-Zeneca), to optimize ON-based drugs design, to study their pharmacokinetics and biodistribution in animal models or clinical trials, and, importantly, to understand in detail their mode of action and their cellular trafficking. This latter important issue has been the object of many studies using, as examples, association with cell-penetrating peptides or lipid nanoparticles (LNPs), as reviewed here by Boisguerin et al [8] or Vlatkovic [9]. Capitalizing on the key role of hydrophobic interactions on the delivery issue, Bazaz et al [10] have engineered a new family of orthogonally hydrocarbon-modified CPPs with good efficiency and tolerability, as demonstrated with in vitro and in vivo models.…”

“…Finally, mRNA has become a tool allowing the generation of proteins for protein replacement therapies or new vaccination strategies, as evidenced by the recent successes in SARS-COVID vaccination with approved mRNA drugs from BioNTech/Pfizer (see the contribution of Vlatkovic, [9]) and Moderna.…”

“…Lipid nanoparticles (LNPs) have been developed by Alnylam in partnership with Inex Pharmaceuticals, leading to Patisiran, the first FDA-approved siRNA drug. In addition, a slightly different lipid formulation has been engineered by BioNTech [9] for mRNA delivery that led to the highly successful SARS-CoV2 vaccine. A key to LNPs' efficiency is the inclusion in the formulations of lipids that become positively charged in the acidic environment of endocytic vesicles, thus leading to LNP conformational changes and the cytoplasmic release of their nucleic acids content.…”