Research area: Translational research

Jacqueline Ji1, Eva Lipkow1, Corine Crucifix1, Nicolas Anton², Jocelyn Laporte1

Rare muscle disorders, such as congenital myopathies, are life-threatening diseases for which no treatment is currently available. The most utilised gene therapy vectors for treating these genetic muscle disorders are adeno-associated viruses (AAVs). However, recombinant adeno-associated vectors (rAAV) face several limitations, including restricted transgene capacity (below 2.5 kb), immunogenic responses due to preexisting immunity, and particularly liver toxicity resulting from the accumulation of rAAV in the liver, which triggers a strong immune response. To date, gene therapy vectors that achieve high efficiency, muscle specificity, and safety have not yet been developed.

To overcome these challenges, we developed a novel lipid nanoparticle (LNP)-based delivery system specifically designed to target skeletal muscle. Since the success of the COVID-19 mRNA (messenger RNA) vaccine, LNPs hold substantial promise for expanding the landscape of mRNA-based therapy to gene therapy applications. LNPs have demonstrated a higher payload capacity, compatibility with repeated administration, and reduced immunogenicity compared to viral vectors. Moreover, we rationally designed LNPs to be muscle-specific by conjugating MyomP1, a peptide from the muscle-fusogenic protein Myomerger, onto the nanoparticle's surface. We encapsulated either pADN or mRNA encoding luciferase reporter genes. In vitro studies in murine C2C12 myoblasts, myotubes, and human myoblasts demonstrated that MyomP1-modified LNPs achieved a 10-fold increase in transduction efficiency compared to unmodified LNPs. In vivo, studies further demonstrated that MyomP1-functionalized LNPs significantly enhanced muscle transduction when delivering DNA cargo, whereas the same modification induced a liver-detargeting effect in mRNA delivery.