Bridging Nordic ATMPs – webinar series

Peppi Karppinen, Professor at University of Oulu, Finland, will speak on “HIF-P4H-2 Inhibiting Gene Therapy for Eye Diseases”

Prof. Peppi Karppinen (Koivunen) has over 30 years of internationally recognised research experience on 2oxoglutaratedependent dioxygenases (2OGDDs), spanning biochemical, cellular, animal and, more recently, human translational studies. She was the first to establish recombinant production of fully active human HIF-P4Hs and factor inhibiting HIF, enabling detailed kinetic and inhibitory characterisation, and providing the molecular foundation for validating these enzymes as bona fide oxygen sensors. These pioneering discoveries laid the basis for the development of the first-in-class HIF-P4H inhibitor, roxadustat, now in clinical use for renal anaemia, in collaboration with FibroGenInc. Her group has since generated extensive mechanistic insights into how cancer-associated 2-oxoglutarate analogues fumarate, succinate and 2-hydroxyglutarate modulate various 2OGDDs, publishing with her postdoctoral supervisor, Nobel Laureate W. Kaelin, several landmark findings that have contributed to the development of targeted therapies for IDH-mutant malignancies.

Karppinen’s research has also expanded the concept of oxygen-sensing beyond HIF-P4Hs. Together with Kaelin, she identified specific histone demethylases (KDMs) as direct nuclear oxygen sensors, demonstrating how their hypoxic inactivation alters chromatin and cell fate. Her group has further defined kinetic differences between KDM isoforms, providing a basis for selective pharmacological modulation.

In vivo, Karppinen’s team was first to show that partial HIF-P4H-2 deficiency protects against cardiac ischemia, metabolic disease, ageing-related cardiac hypertrophy and neurodegeneration, highlighting therapeutic opportunities for HIF-P4H inhibitors beyond anaemia. She also discovered and characterised a fourth prolyl 4-hydroxylase, P4HTM, demonstrating its essential roles in erythropoiesis, neuronal homeostasis and pathogenesis of the HIDEA syndrome.