Adapting protein homeostasis in inborn errors of metabolism: treatment of severe forms of phenylketonuria

Investigador: João Leandro
Instituição: Met&Gen, Faculdade de Farmácia de Lisboa

The aim of this study is to modulate the cytosolic proteostasis network to treat severe forms of phenylketonuria, caused by misfolding of phenylalanine hydroxylase.

When facing a loss of function misfolding disease, gene therapy and enzyme replacement therapy are in theory lhe front line options. However technical and safety issues have hampered their way into the clinic. The use of small molecules, pharmacological chaperones, able to stabiiize protein native-like states have been successively used in treatment or amelioration of both loss and gain of function misfolding disorders, with already approved drugs on the market and several others in late stage clinical trials, in particular for the treatment of lysosomal storage diseases. Unfortunately only mild forms of the diseases respond to these direct target protein binders. Adapting the cellular proteostasis, a network that control protein synthesis, folding, trafficking, aggregation, disaggregation and degradation has emerging as an alternative option per se or in combination with pharmacological chaperones to tackle the severe forms of misfoiding disorders. Here, a proof of principle is sought by modulating the cytosolic proteostasis network to treat severe forms of phenylketonuria, caused by misfolding of phenylalanine hydroxylase. lf the principle holds true, it has the potential to be applied to others inborn errors of metabolism involving misfolding of cytosolic proteins.