N-acetylgalactosamine delivery systems for RNA therapeutics: a patent perspective

ABSTRACTIntroduction SiRNA molecules with a feature of good gene-silencing are critical for drug discovery and development based on RNA interference. GalNAc-RNA therapeutics is a rapid growing area in RNA therapeutics.Areas covered This article provides patent landscape and modification feature of GalNAc-RNA therapeutics. The US-granted patents from January 2004 to April 2023 were retrieved and analyzed.Expert opinion Globally, our study is first one to holistically depict a map of modifications and therapeutic applications for GalNAc-RNA therapeutics by patent data analysis. The results showed there were 8 major modifications and 5 new emerged modifications for GalNAc-RNA therapeutic agents. Especially, the study provides recent new emerged modifications in sugar, base and internucleotide linkage of GalNAc-RNA therapeutic agents, e.g. morpholino-type ring, 5-methylcytosine, and phosphorodithioates. In addition, our study systematically demonstrated major therapeutic applications for GalNAc-RNA therapeutics, including liver or gallbladder disorders, anticancer, antihyperlipidemics, and disorders of the nervous system etc.KEYWORDS: GalNAcRNAGalNAc-RNAN-acetylgalactosaminepatentDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsGlobally, our study is first one to holistically depict a map of modifications and therapeutic applications for GalNAc-RNA therapeutics.Eight major modifications and five new emerged modifications are identified for GalNAc-RNA therapeutic agents.The study provides recent new emerged modifications in sugar, base and internucleotide linkage of GalNAc-RNA therapeutic agents, e.g., morpholino-type ring, 5-methylcytosine, and phosphorodithioates.The study systematically demonstrates major therapeutic applications for GalNAc-RNA therapeutics, including liver or gallbladder disorders, anticancer, antihyperlipidemics, and disorders of the nervous system etc.Sugar modifications of 2’-O-R and 2’-R are most frequently modification for GalNAc-RNA therapeutic agents.There are considerable similarities in developing model between GalNAc-RNA therapeutics and mRNA-LNP therapeutics, e.g., just a few companies dominate all technologies.Declaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementDesign, data collection and analysis, and manuscript draft by Zhang, and data collection by Wang.Figure 1. US granted patent-filing profile of GalNAc-RNA therapeuticsDisplay full size Figure 2. Top countries of technology origin of GalNAc-RNA therapeuticsDisplay full size Figure 3. Top assignees of GalNAc-RNA therapeuticsDisplay full size Figure 4. The patent 3D Landscape of GalNAc-RNA therapeutics: Red Dot: Alnylam Pharm; Blue Dot: Dicerna Pharm; Purple Dot: SiRNA TherapeuticsDisplay full size Figure 5. A) Typical 2′-modified sugar modification. B) Internucleosidelinkage modification C) 5-methylcytosinemodification. D) Gapmerstructure. E) Atypical structural formula of the bi/tri-valent GalNAc ligand. F) Themain modifications involved in GalNAc-RNA therapeutic agents.Display full size Figure 6. The main therapeutic fields involved in GalNAc-RNA therapeutic agentsDisplay full sizeAdditional informationFundingThis paper was not funded.