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Blood clotting cascade is like a relay race where the runners are clotting factors. In Haemophilia A, factor 9, after receiving a baton from factor 11, is racing to form a clot that will stop a bleed in a patient. However, the next member of the race, factor 8, is missing!
The Radboud iGEM team finds a solution to save the day, our improved Haemophilia treatment, InfinityF∞.
Factor 8 is a large glycoprotein which participates in the intrinsic pathway of the coagulation cascade.
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In the world, more than 400,000 male patients are living with HemA. HemA also accounts for 80% of hemophilia cases. A chance for a newborn male to acquire Haemophilia A is 1 in 5,000–10,000 males with a high risk of patient mortality when undergoing a surgery. Without treatment, even small bleeds can become dangerous and in serious cases, patients have a high risk of spontaneous bleeding [2, 3].
And, even though this approach has its benefits: it can be done by the patient themselves and there are possibilities for an implantable port for easy administration, there are still some limitations.
Injections are invasive and uncomfortable, which should always be important to consider when developing a treatment. On top of that, a Haemophilia patient has to make frequent injections - every 48 hours - to keep their FVIII levels on a normal level. The frequent injections are in part the result of the high clearance of factor VIII from the circulation with a half-life of 10-12 hours. This causes the factor VIII concentration in the blood to fluctuate a lot, spiking up after injection, then quickly going down until the next injection. Currently, there are multiple engineered recombinant factor VIII products available, but these are way more expensive than the cheapest variety of FVIII, which is purified from blood products and already has an annual cost of $300,000!
InfinityF∞ - an intranasal mRNA delivery system for Factor VIII using ionizable lipid nanoparticles.
We are hoping that this new system will give a more controlled release of factor VIII. The coolest thing about it is that the nanoparticles are small enough to be delivered via an intranasal route.
This means patients do not need to get injections anymore, and they can just use a nasal spray!
InfinityF delivers the mRNA sequence for factor VIII encapsulated by a lipid nanoparticle that serves as a carrier for the medicine. When the nanoparticle reaches its target in the body, the cells will take it up into a lysosome and break the LNP preserving the genetic sequence inside. After that, the cell produces the protein factor VIII from the mRNA and releases it into the blood.
The factor VIII mRNA is produced with in vitro transcription using factor VIII pcDNA as a template. Our ionizable lipid nanoparticles contain synthetic lipids as well as an ionizable lipid, which is essential for the release of the mRNA in the cells.
The factor VIII mRNA is produced with in vitro transcription using factor VIII pcDNA as a template. Our ionizable lipid nanoparticles contain synthetic lipids as well as an ionizable lipid, which is essential for the release of the mRNA in the cells.
Production of protein from mRNA occurs gradually and not in all cells at the same time, spreading out the high concentration spike that occurs after injection of FVIII. €
Costs are very important when speaking about medical treatment. Since the current Haemophilia medicine utilizes purified protein from human plasma, the price skyrockets to big numbers! Current price of Haemophilia medicine (in the USA): 8000 euro/week [4]. Estimated price of LNP dosage for InfinityF∞ medicine (for an average patient of 60 kg): 160 euro/week.
The Radboud iGEM team was started by a group of enthusiastic students that were looking to broaden their horizon and start something new. We hope to introduce the iGEM competition to Radboud university while also putting Radboud university on the map within the iGEM competition.
As a new team, we spent a lot of time navigating the organisational aspects within the university as well as familiarizing ourselves with the systems of the competition. With our efforts, we hope to pave the way for future Radboud iGEM teams.
We are beyond excited to showcase InfinityF as the first team to represent Radboud University within the iGEM competition, and it is with passion and determination that we say: