Industrializing enzyme replacement therapy development

Abstract

Today there are 10 FDA approved enzyme replacement therapy (ERTs), yet there are thousands of rare diseases where ERTs could extend patient lives. The pathway to develop ERTs is well understood. Besides the high costs of GMP manufacturing, we think the development of ERTs is being inhibited at the preclinical stage by the current research paradigm focusing on individual groups working on a ‘single protein-single lab’ approach until a point where they have proof of concept data. We could learn from other areas using higher throughput approaches, such as the Structural Genomics Consortium where over 1500 proteins have been produced in an efficient collaborative manner and shared. We now propose to integrate several commercially available technologies together to create a pipeline that will allow us to develop at tens to hundreds of proteins (including multiple Batten disease proteins) in 5 years. We will make enough protein to test the most promising candidates in commercially available patient derived cells to determine if they can return enzyme activity in vitro and enable in vivo testing in the appropriate knock out mouse models with a collaborator network. The ultimate goal is to create a sustainable pipeline that leverages the decades of insight and research into developing ERTs, and proteins in general. We anticipate that the development of new ERTs might open new avenues for a future lysosomal storage disease patient cell line bank that would be useful for testing ERTs that have been developed and for screening to identify small molecule chaperones. Besides these benefits, scaling ERT development for more diseases might also accelerate the development of diagnostics and earlier routine screening of these diseases once more treatment options are available. Our approach to creating a pipeline for protein development could accelerate treatment development and reinvigorate the pipelines of biotechs with ERTs.