Eradicating Hemorrhage by Inhibiting Prolyl Hydroxylase

Background & Unmet Need

• There are many potential sources of injury to the brain associated with free radical production and subsequent oxidative damage
• Following intracerebral hemorrhage (ICH), red blood cells break down over time to release heme and highly reactive ‘free’ iron, which can cause oxidative damage to the brain
• In brain ischemia, hypoxia also favors the production of reactive oxygen species (ROS) which in turn increases oxidative stress, causing cell death
• Hypoxia inducible factor (HIF) Prolyl Hydroxylases (PHDs) canonically effect the degradation of HIF, but have recently been implicated as neuroprotective factors in other, HIF-independent pathways
• Unmet Need: Treatments to abrogate oxidative damage in hypoxia and hemorrhage-related brain injury

Technology Overview

• The Technology: Novel inhibitors of HIF-PHDs for the treatment of TBI and brain ischemia
• The Discovery: The inventors have discovered a class of selective inhibitors of PHDs which protect against oxidative damage
• These branched oxyquinolines coordinate iron at the active site of HIF-PHDs, blocking their function
• These inhibitors suppress the ATF4 pro-death pathway and exhibit protective effects on mitochondrial function, indicating that they afford neuroprotection by an HIF-independent pathway
• PoC Data: In a mouse model of ICH, mice treated with PHD inhibitors had reduced numbers of degenerating neurons (p<0.001) and behavioral deficits (p<0.05)
• In a model of oxytosis, a cell death pathway involving oxidative stress, PHD inhibitors restored mitochondrial ATP production and increased cell viability (p<0.001)

Technology Applications

• Treatment of intracerebral hemorrhage or hemorrhage in other parts of the central nervous system
• Treatment of brain ischemia and cerebral hypoxia
• Treatment of neurodegenerative diseases associated with oxidative damage to mitochondria

Technology Advantages

• PHD Inhibitors readily cross the blood-brain barrier
• PHD inhibitors are highly selective and have few off-target effects on iron distribution or global histone acetylation and methylation
• Inhibitors of the same target have demonstrated safety in clinical trials