Developing a Common Investigative Framework for the Intoxication-type Inborn Errors of Metabolism
Though individually rare, inborn errors of metabolism (IEM) collectively affect ~1:1500 newborns. A large group of IEM are sub-classified as intoxication-type IEM (IT-IEM), in which the loss of an intermediate enzyme of metabolism leads to the accumulation of toxic upstream metabolites. There are 10 main clinical syndromes classified as IT-IEM, which are caused by mutations in 22 different genes. Examples of IT-IEM include the urea cycle disorders, methylmalonic aciduria, propionic acidemia, glutaric acidemia type I, molybdenum cofactor deficiency and sulfite oxidase deficiency, among others.
Because the placenta and maternal circulation prevent fetal accumulation of toxic metabolites, IT-IEM rarely affect fetal development and typically present in the first weeks of life after toxic metabolites have accumulated. Though peripheral organ involvement varies, the central nervous system (CNS) is invariably affected. Fortunately, with the advent of new born screening programs and availability of tandem mass spectroscopy, patients can now be identified before irreversible brain damage has occurred, opening a critical window for treatment.
Advances in viral vector engineering have made the possibility of gene therapy for IT-IEM a reality; however, critical questions must first be answered: which organs systems need to be targeted? how much enzyme activity needs to be restored? and what is the optimal timing of treatment? To answer these questions, a deeper understanding of the pathophysiology underling IT-IEM is needed.
Our work explores the “inter-organ ecology of toxic metabolites”, a conceptual framework that integrates the production, distribution, metabolism and tissue specific impact of toxic metabolites to describe the pathophysiology of IT-IEM on an organ systems level. We employ a systems biology based approach, which is better suited than traditional reductionist methodologies, to model the dynamic inter-organ relationships and compensatory mechanisms (both preexisting and novel) that emerge during acute or subacute intoxication. Because intoxication is a central feature of all IT-IEM, our conceptual framework is easily adapted to model any of these disorders, thereby synergizing research efforts across multiple disease and accelerating the development of therapeutic modalities.
As an example of our approach’s utility, our early work suggests that 11 of the 22 IT-IEM genes and their associated metabolic pathways are utilized highly in peripheral organs and minimally in the developing CNS. Because their function in the CNS appears to be dispensable, gene therapy strategies could bypass the technical hurdle of CNS delivery and prevent the production of toxic metabolites with targeted therapy to peripheral organs alone. Based on this concept, we are developing novel metrics to guide gene replacement and empirically testing therapeutic strategies in IT-IEM mouse models that can be quickly developed for immediate application in patients.