The efficacy of enzyme replacement therapy in early-onset Tay-Sachs disease mouse model

Enzyme Replacement Therapy (ERT) is one of the alternative therapies for the treatment of lysosomal storage diseases. Usually, ERT enzymes are produced in mammalian cells, although alternative expression systems, such as microorganisms, have been proposed for their production. The Institute for the Study in Inborn Errors of Metabolism (Pontificia Universidad Javeriana, Colombia) has been worked for several years in the study, production, and purification of different recombinant human lysosomal enzymes in the yeast Pichia pastoris. It has been demonstrated that these enzymes are biologically active and, in the case of ß-hexosaminidases, with higher activity compared with native enzymes. In vitro assays have shown the capability of these recombinant enzymes to be internalized by different cellular lines and be delivered to lysosomes where they are able to degrade the stored substrates. Therefore, these enzymes represent a potential alternative for the development of cost-effective therapies for GM2 gangliosidoses, which is a group of lysosomal storage diseases produced by mutations in the lysosomal ß-hexosaminidases or in the GM2 activator. Tay-Sachs disease is a devastating disorder for the affected individual and his/her family, and success in treatment has been limited because of poor access to the brain, the most affected tissue. Currently, there is not approved therapy for this disorder and based on studies in mice, ERT is one of the promising approaches to treatment for this disease. Although in-vitro results have shown the potential of recombinant ß -hexosaminidases produced in P. pastoris, in vivo studies are necessary to confirm the therapeutic potential of these enzymes. In this sense, thanks to the collaboration with Dr. Seyrantepe¿s research group, at the Department of Molecular Biology and Genetics, Izmir Institute of Technology, we will assess a human recombinant ß-hexosaminidase A (rhHex-A)-based ERT in an early-onset Tay-Sachs disease mouse model, which exhibits high levels of GM2 ganglioside accumulation and rapid neurological deterioration, comparable to that seen in the Tay-Sachs patients. For this purpose, we will first characterize the biodistribution and pharmacodynamics of a rhHex-A. Different concentrations of purified rhHex-A will be administered into the mouse model. The efficacy of the rhHex-A treatment will be assessed by monitoring the health and survival of the animals, as well as by measuring ß-hexosaminidase activity in serum and tissues, and GM2 ganglioside levels in the brain. The enzyme replacement therapy using rhHex-A produced in yeast is expected to result in decreased storage of GM2 ganglioside and an increased life expectancy in Tay-Sachs disease mouse model. The development of improved approaches to ERT for Tay-Sachs disease would provide a step forward in the therapy of all GM2 gangliosidoses since each exhibit similar symptoms. In addition to the direct impact of this work on the Tay-Sachs, we believe that if successful, our proposed ERT method has the potential to be developed into an inexpensive approach to treatment and may open avenues to treatment for other lysosomal storage disorders affecting the central nervous system.