Public Funding for Scarlet Therapeutics Limited

Scarlet Therapeutics (Lead) is developing a pioneering platform that generates novel therapeutic red blood cells (tRBCs) to potentially treat a wide range of diseases. Red blood cells (RBC), which naturally circulate throughout the body, have a lifespan of up to 120 days. Therefore a therapy based on freshly produced tRBCs offers the potential for a long-lasting effect and infrequent dosing. Scarlet's technologies aim to address efficacy and manufacturing issues by ensuring a high level of therapeutic protein inside the tRBCs to enable more efficacious and therefore effective therapeutics, and production of tRBCs from cell lines rather than donated cells to reduce cost and increase reproducibility and quality of the tRBCs. This project will focus on proof-of-concept for product candidates for treatment of hyperammonemia and hyperoxaluria, for which there are currently no generally effective treatments. Hyperammonemia has severe effects on nerves and can cause death. Causes include liver disease, metabolic disorders including inherited defects in the urea cycle, and certain medications. Treatments: * Medication: to lower ammonia levels, but drugs are cleared from the body quickly, so need to be taken regularly. * Dietary changes: a low-protein diet can be beneficial, but has patient diet compliance issues. * Dialysis: a short-term emergency treatment requiring significant time and medical reosurce. * A liver transplant; costly, risky, and requires a compatible donor and reliance on immunosuppressive drugs. Hyperoxaluria's main clinical manifestations are recurrent kidney stones and build-up of calcium throughout the kidney inhibiting the kidney's function, resulting in eventual kidney failure. There are multiple causes separated into primary hyperoxaluria, caused by genetic defects, and secondary/enteric hyperoxaluria caused by a range of gastrointestinal disorders. Treatments include: * Specific medications depending on the subtype of hyperoxaluria, i.e., pyridoxine hydrochloride, recommended only for primary hyperoxaluria type 1 (PH1) patients * Also for PH1 there is Lumarisan, an siRNA designed to tackle the defect causing PH1\. * There are no specific treatments for enteric hyperoxaluria beyond the general oxalate lowering strategies (massive hydration, drugs to make the urine more alkaline to aid oxalate clearance) and dietary changes to reduce oxalate build up. * Following kidney failure, dialysis and kidney transplant (in the case of PH1 dual liver & kidney transplant) Project output has the potential to develop therapeutic medicines for treatment of hyperammonemia and hyperoxaluria, indications with high unmet medical need, impacting the UK patient population and making a significant impact to the UK economy.

Vast research and development spend is funnelled into next generation therapeutics - with gene therapy applications leading the field. Gene therapy is applicable to monogenic diseases but is more difficult to apply to more complex diseases that can arise due to alterations in more than one gene. Recombinant proteins are potentially an ideal modality for these complex cases - for example, metabolic diseases that result in hyperammonemia and hyperoxaluria- but they are incredibly challenging to deploy, having short life-times within the circulatory system. This project will develop an alternative to traditional delivery methods, using red blood cells (RBC). RBCs circulate in the body for about four months and have a much longer half-life as compared to conventional medications. RBCs do not have a nucleus/DNA and hence do not present the risk of uncontrolled cell division/cancer, thereby promising to be safe delivery vehicles for therapeutics. However, the generation of RBCs at commercial levels is not established so far due to the challenges of growing enough RBCs at commercially reasonable cost from donated stem cells. Scarlet Therapeutics aims to pioneer the commercially viable production of eRBC from cell lines and manipulating them to contain therapeutic proteins of interest. In this project, we will upgrade our RBC lines by sourcing cells from more universal blood donors to enable us to create a RBC platform that can be engineered to contain therapeutic proteins of interest and are suitable for use in humans. This would be designed to be applicable to patients of almost all blood types. We estimate that approximately 97% of people will be covered if we use O negative blood and 10 different blood type variations of the main important major and major blood groups. In the first instance (immediately post-project) we will deploy our engineered RBCs for the treatment of metabolic disorders. In the longer term (5 years post-project), our project output also provides the foundation for opportunities for meeting the high demand for blood transfusion, especially for rare blood types or those patients who require regular transfusions throughout life due to thalassemia or sickle cell disease (approx. 420 million people worldwide).