Netrin-1 Compounds as Post-MI and Post-Angioplasty Therapeutics as well as for Treating Renal and CNS Reperfusion Injury

Summary

UCLA researchers have invented a method of decreasing myocardial injury and infarct size through the intravenous administration of the netrin-1 or netrin-1-derived peptides during a cardiac event. These agents have powerful cardioprotective effects and provide a novel and effective therapy for the treatment of myocardial infarction.

Background

Netrin-1 is a novel endothelial mitogen that stimulates production of nitric oxide (NO•) which has a well-established role in cardioprotection. In order to develop a viable netrin-1 therapeutic a team at UCLA has developed and optimized a series of novel short peptide derivatives of netrin-1 ranging in length from nine to eleven residues. The compounds have been validated in vivo in rodents, and porcine studies are underway.

These lead compounds function at three different mechanistic levels which may lead to three distinct cardiovascular therapeutic product concepts as well as therapeutics for renal reperfusion injury and stroke.

1. Prevention of reperfusion injury: The first level is acute protection to reduce post-MI infarct size more than 50% when given immediately at the onset of reperfusion or pre-reperfusion. The mechanisms involved include receptor DCC dependent ERK1/2/eNOS phosphorylation and NO• production to directly protect cardiomyocytes against injury. This mechanism may present therapeutic opportunities in renal reperfusion injury and stroke.

2. Prevention of post-MI remodeling and fibrosis: The second level is inhibition of oxidative stress and autophagy. This may lead to a chronic therapy to prevent post-MI remodeling and fibrosis of the heart and thereby sustain cardiac function and prevent development of post-MI heart failure.

3. Prevention of restenosis: The third level is inhibition of restenosis/re-occlusions of coronary arteries post angioplasty.In animal models this has been shown to be 100% effective.

Innovation

Applications

Based on the mechanisms of action for these lead compounds, there are at least three different therapeutic concepts for this: (1) acute therapy for treatment of reperfusion injury (post-MI, renal reperfusion injury and stroke), (2) chronic therapy for the prevention of post-MI remodeling and fibrosis to prevent heart failure and (3) post-angioplasty therapeutic to prevent restenosis.

Advantages

State Of Development

Patent Status

Related Materials

• Netrin-1 prevents ischemia/reperfusion-induced myocardial infarction via a DCC/ERK1/2/eNOS s1177/NO/DCC feed-forward mechanism.
• Pharmacological postconditioning treatment of myocardial infarction with netrin-1.
• Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy.
• Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS.
• Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO.