Liver-Specific Biocompatible Lipid Nanoparticle-Enabled mRNA Therapy for Haemophilia B

Area of Science:

• Biotechnology
• Gene Therapy
• Nanomedicine

Background:

• Standard Haemophilia B treatment requires frequent factor IX infusions, posing financial and logistical challenges.
• Messenger RNA (mRNA) delivery via lipid nanoparticles (LNPs) offers a potential alternative but faces hurdles in achieving sustained protein expression.

Purpose of the Study:

• To develop an advanced nanocarrier system, GaLiNAx, for enhanced delivery of chemically modified factor IX mRNA.
• To evaluate the efficacy and safety of GaLiNAx for Haemophilia B therapy in a preclinical model.

Main Methods:

• Development of GaLiNAx incorporating an ionizable galactosylated lipid for receptor-mediated endocytosis and a cationic lipid for mRNA complexation.
• Incorporation of truncated albumin UTRs and base modifications into functional FIX mRNA to improve hepatic translation.
• Administration of GaLiNAx to a Haemophilia B mouse model to assess factor IX protein expression and safety.

Main Results:

• GaLiNAx demonstrated therapeutically relevant factor IX protein expression lasting approximately one month following a single administration in the HB mouse model.
• Safety evaluations confirmed no toxicity in major organs after multiple GaLiNAx doses.
• The developed system offers a potentially cost-effective therapeutic option.

Conclusions:

• Long-lasting mRNA therapy using GaLiNAx is a promising strategy for Haemophilia B protein replacement.
• This approach holds potential for treating other monogenic liver disorders.
• GaLiNAx represents a significant advancement in mRNA-based therapeutics.