Adaptive Translational Medicine: Towards New Therapeutic Approaches For Metabolic Diseases

Inborn errors of metabolism, also known as metabolic diseases, are caused by monogenetic variants and often follow autosomal recessive inheritance. These variants cause a change in enzyme function, including a partial or total loss of function or gained abnormal function, leading to changes in cellular metabolism, e.g., synthesis, breakdown or change of cellular metabolites. Thousands of enzymes, thus thousands of metabolic diseases exist. There is an urgent need for (curative) treatment options that are applicable to multiple diseases or that can be rapidly adapted for use in different diseases. In this thesis, three levels of possible therapeutic interventions are discussed, developed for patients from our own hospital. First, using the conventional approach for IARS1 deficiency, we utilize characterization of the disease and evaluation of the molecular mechanism to develop and test a substrate therapy. This approach is specific to a single disease. We continue to test similar treatments for patients with other ARS1 deficiencies, and further explore its use in patients with various ARS2 deficiencies. Second, we target the liver, as it has a central role in metabolism. Many metabolic diseases can be treated or cured by liver transplantation, but long-term survival of transplantation recipients has remained suboptimal. With the emergence of alternatives such as bankable liver stem cells, allogenous matched or autologous ex vivo genetically corrected stem cells could be transplanted. Improved donor-recipient compatibility could help improve outcomes. We therefore investigate the effect of HLA matching on liver transplantation outcomes. Third, we explore the use of in vivo genetic correction using prime editing, a precise search-and-replace genetic editing technique, which has the potential to cure almost any metabolic disease by directly targeting the underlying genetic defect. We pave the way towards the first in vivo genetic correction therapy of the brain and liver of patients with POLG-related disease.