Supervisors
Giovanni Stracquadanio, giovanni.stracquadanio@ed.ac.uk
Eve Miller-Hodges, eve.miller-hodges@ed.ac.uk
Giovanni Stracquadanio, giovanni.stracquadanio@ed.ac.uk
Eve Miller-Hodges, eve.miller-hodges@ed.ac.uk
Project Description
Metabolic enzymatic deficiencies (MEDs) disrupt cell physiology, either by preventing the production of essential metabolic intermediates or by causing the accumulation of toxic levels of substrates. Lysosomal storage diseases (LSDs) are among the most devastating MEDs; they are caused by the deficiency of enzymes responsible for the catabolism of lipids and glycoproteins, which lead to irreversible damage of many organs. Enzyme inactivation is caused by inherited loss-of-function mutations; thus, they cannot be cured, but they can be treated using Enzyme Replacement Therapies (ERTs), which consist in the injection of a recombinant version of the affected enzymes into patients.ERTs are currently standard of care for many LSDs, including Gaucher’s and Fabry disease, but are not yet available for many others. In fact, developing ERTs is challenging, since enzymes are less catalytically active in blood, can cause immune response, have poor cellular uptake, and are extremely expensive to manufacture. For example, current treatment for Mucopolysaccharidosis Type IV A (MPS IVA), an LSD causing life threatening muscoskeletal alterations, can cost up to $6M per year per patient. Taken together, these factors are currently limiting the number of treatments available and have unsustainable costs for patients and many healthcare systems.
Metabolic enzymatic deficiencies (MEDs) disrupt cell physiology, either by preventing the production of essential metabolic intermediates or by causing the accumulation of toxic levels of substrates. Lysosomal storage diseases (LSDs) are among the most devastating MEDs; they are caused by the deficiency of enzymes responsible for the catabolism of lipids and glycoproteins, which lead to irreversible damage of many organs. Enzyme inactivation is caused by inherited loss-of-function mutations; thus, they cannot be cured, but they can be treated using Enzyme Replacement Therapies (ERTs), which consist in the injection of a recombinant version of the affected enzymes into patients.ERTs are currently standard of care for many LSDs, including Gaucher’s and Fabry disease, but are not yet available for many others. In fact, developing ERTs is challenging, since enzymes are less catalytically active in blood, can cause immune response, have poor cellular uptake, and are extremely expensive to manufacture. For example, current treatment for Mucopolysaccharidosis Type IV A (MPS IVA), an LSD causing life threatening muscoskeletal alterations, can cost up to $6M per year per patient. Taken together, these factors are currently limiting the number of treatments available and have unsustainable costs for patients and many healthcare systems.
Here we want to engineer new therapies for MPSIVA using generative artificial intelligence and engineering biology. Our goal is to design, build and test new, recombinant galactosamine (N-acetyl)-6-sulfatase (GALNS) enzymes in Chinese Hamster Ovary (CHO) cell lines, as a more effective and sustainable treatment for MPS IV. The project will be part of the broader program of the Stracquadanio lab on engineering ERTs for LSDs and will be part of the Engineered Genetic Control Systems for Advanced Therapeutics Hub at the University of Edinburgh, and in close collaboration with Dr Eve Miller-Hodges, a world-renown clinical expert in LSDs and leading the Inherited Metabolic Disease clinic in Scotland.
