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We seek to define the cellular and molecular mechanisms that will lead to new immunological based therapies for cardiac arrest. 

1. Unmet medical need in cardiac arrest. Out-of-hospital cardiac arrest (OHCA) causes the same magnitude of deaths as all cancers combined (e.g., >330,000 OHCA versus >600,000 all cancer deaths per year in the US). However, there is much less translational and basic research in cardiac arrest than cancer. 

Brain injury is the most common cause of death for patients that are hospitalized after cardiac arrest. However, we have no medications to reduce this brain injury; the leading treatment is regulating the patient’s body temperature. 

2. Our candidate therapeutic targets 

Despite robust clinical evidence implicating the immune system in neurological injury, there are no immune- targeted drug therapies for cardiac arrest. 

 

Turning on the protective, anti-inflammatory pathways. 

- Immune checkpoint therapy revolutionized cancer therapy by unleashing the immune system against cancers. What if we did the opposite, and used immune checkpoints to “turn off” harmful immune responses after cardiac arrest? 

- Innate T cells can be fully activated in just minutes after a new stimulus (unlike adaptive T cells that need days). We found protective innate T cells that can be turned on by i.v. treatments just minutes after cardiac arrest.

 

Blocking harmful inflammation. We have found that cardiac arrest patients have very early increases in inflammation within hours after cardiac arrest, particularly in patients that go on to have brain injury. Blocking these inflammatory pathways in the mouse model of cardiac arrest improves neurological outcomes and survival. 

3. Our comparative advantages

 

I-CAN. In 2019, we and others formed the Immunology of Cardiac Arrest Network (ICAN), a multi-instiutional clinical database to study the immunology of OHCA patients. Using a combined approach of single cell RNAsequencing, ex-vivo cell culture, and bioinformatic analysis, we identified specific innate immune cell populations and unique molecular mechanisms that are expanded among patients with worse neurological injury. Our work with an experimental mouse model of cardiac arrest shows that specific subpopulations of innate T cells decrease neuroinflammation, neuron injury, and improve neurological outcomes. 
These clinical and experimental discoveries guide our ongoing academic, pharma, and biotech collaborations that we believe will lead to a new treatment class for cardiac arrest. 

 

Cardiac arrest is an unique opportunity to intervene clinically in the innate immune system. Cardiac arrest is unique in that we can administer drug treatments literally minutes after the start of the disease. In contrast, by the time a sepsis, influenza or COVID-19 patient presents to the hospital, the immune response has been operating for days, and the “innate immune horse” may be out of the barn.   
 

Immunology is (relatively) new to the cardiac arrest field. Unlike sepsis or respiratory illness, the cardiac arrest field has focused on non-immunological pathways (e.g., cell death pathways). To study the immune system, we have an unique cardiac arrest biorepository of viable peripheral blood mononuclear cells. 
 

Mouse model of cardiac arrest is like running a tiny intensive care unit. We intubate and mechanically ventilate the mice, place a femoral arterial catheter (to measure hemodynamics) and place a central venous catheter. After asystolic cardiac arrest (induced by KCl), we performed chest compressions (1 finger!) titrated by mean arterial pressures and infuse central epinephrine i.v.!  


 

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