10101583Bioengineered reticulocytes containing metabolic enzymes to treat hyperammonemia and hyperoxaluriaClosedCollaborative R&DInnovate UKScarlet 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.