The 2024 Radboud iGEM Team, the first team of our university, is dedicated to addressing the daily challenges faced by patients with hemophilia A. This condition is caused by a genetic mutation in the FVIII gene on the X-chromosome, which prevents liver sinusoidal endothelial cells (LSECs) from producing coagulation factor VIII, a crucial protein in the blood clotting process. Our project aims to develop a more effective and comfortable treatment for this genetic disorder compared to current methods.
We propose the creation of ionizable lipid nanoparticles (LNPs) containing mRNAs that encode the coagulation factor VIII protein. LNPs administered into the bloodstream travel to the liver and target LSECs with the help of surface sugars. Once inside the cells, the LNPs will release the mRNAs, leading to the production of coagulation factor VIII. This approach enables patients to produce their own coagulation factor VIII, eliminating the need for frequent injections of plasma-derived or recombinant proteins.
Presently, patients experience large fluctuations in blood coagulation factor VIII levels after injections, leading to brief stable periods followed by rapid declines. This necessitates frequent injections and risks sudden drops in coagulation factor VIII protein levels, which can trigger hemophilia symptoms. Our mRNA delivery system is expected to provide more stable and prolonged protein levels, reducing the frequency of treatments.
Additionally, our system offers an alternative to intravenous administration. Recognizing the discomfort of this method, we propose a nasal spray delivery system using hydrogel and LNPs, which allows mRNA absorption through the nasal epithelium. We also try to eliminate the risk of viral infections, such as HIV and HCV, which can occur with human plasma-derived FVIII treatments. While rare, such infections are possible.
Hemophilia is a widespread condition affecting approximately 1,125,000 people worldwide and we, as a group of young scientists, are committed to enhancing the quality of life for these patients. In severe cases, hemophilia can lead to fatal blood loss, but even minor inconveniences, like restricted physical activities, significantly impact patients' lives. Our project aspires to contribute to a better quality of life for those affected by hemophilia, addressing both major and minor challenges of the current treatment landscape.
Reference Articles:
- Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909888/ - Systemic delivery of factor IX messenger RNA for protein replacement therapy:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347596/ - Advanced Strategies for Overcoming Endosomal/Lysosomal Barrier in Nanodrug Delivery:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10208951/