Many age-related diseases are characterized by mitochondrial dysfunction resulting from oxidative damage, aberrant calcium homeostasis and compromised energy production. The mitochondrial Permeability Transition Pore (mPTP) is a non-specific channel that opens in response to cellular and mitochondrial stresses. Prolonged opening of the mPTP leads to cell death via apoptosis or necrosis depending on the severity of the mitochondrial damage and extent of mPTP opening. Compromised mitochondrial function and cellular death ultimately lead to tissue / organ dysfunction and disease progression.
Stress-induced opening of the mPTP has been implicated in the aetiology and progression of several important diseases including:
- Acute Myocardial Infarction (Lethal Reperfusion Injury) and Stroke
- Alzheimer's disease and Amyotrophic Lateral Sclerosis
- Dystrophies (Duchenne, Ullrich and Bethlem)
- Diabetic complications (Nephropathy and Retinopathy)
and thus, mPTP inhibitors are expected to have broad therapeutic application
We are currently focusing our resources on developing inhibitors of the mPTP for the treatment of lethal reperfusion injury in the setting of Acute Myocardial Infarction (AMI)
Therapeutic focus - Acute Myocardial Infarction
Approximately 1.2 million Americans suffer a new or recurrent myocardial infarction per year and an estimated 600,000 patients will eventually die as a consequence. AMI remains a major cause of human mortality even though there is now widespread and large-scale use of reperfusion therapies. Paradoxically, it is the reperfusion of ischemic tissue that can cause cardiomyocyte cell death and can contribute up to 30% of the final infarct size. There are currently no registered therapies to treat this lethal reperfusion injury.
Opening of the mPTP has been shown to be involved in the fundamental mechanism of lethal reperfusion injury (Halestrap and Pasdois 2009, BBA 1781 (11), 1402-15) and inhibitors of the mPTP are expected to significantly reduce infarct size if given just prior to reperfusion therapy.
We are currently investigating the potential of our proprietary mPTP inhibitors to attenuate the progression of Alzheimer's disease by inhibiting the opening of the pore in response to b-amyloid-induced oxidative stress.
Alzheimer's disease is a devastating neurodegenerative disorder that affects approximately 25 million people worldwide and is characterized by progressive cognitive dysfunction and memory loss. The pathological hallmarks of the disease are neuronal degeneration and a progressive accumulation of neurofibrillary tangles (Tau protein) and senile plaques (b-amyloid protein). A growing body of evidence suggests that b-amyloid-induced oxidative stress plays an important role in neuronal degeneration (Chauhan and Chauhan 2006, Pathophysiology 13, 195-208).
Recent studies have shown that b-amyloid protein can accumulate in mitochondria and cause oxidative damage due to the production of reactive oxygen species (ROS) (Chen et al 2007, J. Alzheimer's disease, 12, 177-84). Further, b-amyloid-induced ROS leads to opening of the mPTP with a consequent loss of energy production and eventual neuronal cell death. Inhibitors of the mPTP may be able to prevent this aspect of b-amyloid toxicity and slow the progression of the disease.