New Potent Injectable Therapy Could Prevent Heart Failure After Heart Attack

S. Centers for Disease Control and Prevention, 6.7 million Americans aged 20 and older are living with heart failure, a condition in which the heart cannot pump enough blood to meet the body's needs. After being diagnosed with heart failure, 52.6% of patients die within five years. The leading cause of heart failure is a heart attack, which affects over 800,000 Americans annually. During a heart attack, the heart muscle often becomes damaged due to a lack of oxygen and increased oxidative stress. This damage can result in inflammation and scarring, which ultimately weaken the heart, leading to heart failure. While current treatments can restore blood flow, they do not entirely prevent the long-term damage that causes heart failure over time. Now, scientists have developed a new, potent injectable therapy that can protect the heart from damage following a heart attack.

The therapeutic approach developed by scientists at Northwestern University (Evanston, IL, USA) and University of California San Diego (San Diego, CA, USA) involves specially designed polymers that function like proteins. The research team focused on the interaction between two proteins: Keap1 and Nrf2. Nrf2 helps protect heart cells from stress and inflammation, while Keap1 binds to Nrf2, regulating its activity. This binding prevents Nrf2 from entering the cell’s nucleus, where it can activate protective genes. In previous studies, the team created the PLP platform, where nanoscale precision polymers mimic proteins to function as artificial antibodies. Once inside cells, these polymers “grab” biological targets. In this new study, the researchers engineered a PLP with multiple “arms” that bind to Keap1. These arms mimic a segment of the Nrf2 protein that usually binds to Keap1. Because the PLP has multiple arms, it binds tightly to Keap1, preventing it from binding to the actual Nrf2. With Keap1 out of the way, Nrf2 can enter the heart cell’s nucleus to activate its protective effects.

After developing the system, the researchers performed laboratory tests on heart muscle cells to assess its effectiveness. In these experiments, even at very low concentrations, the PLPs successfully protected cells from damage caused by oxidative stress. Next, the team administered a single intravenous dose of PLP in a small animal model of heart attack. The study, published in Advanced Materials, shows that the therapy not only improved heart function in the animal, but also remained effective for up to five weeks after the injection. Additional tests showed that the cells expressed more Nrf2-related genes, which are involved in healing. The researchers believe that this innovative PLP platform represents a major step forward in therapeutic development, providing a new tool to address challenging biological targets that traditional approaches have struggled to treat. The team is now working on developing PLPs to target protein-protein interactions in various diseases, with an initial focus on cancer and neurodegenerative disorders.

“Heart disease remains the leading cause of death worldwide, with heart attacks accounting for many of those deaths,” said Northwestern’s Nathan Gianneschi, a senior author of the. “Despite this startling regularity, there is relatively little that can be done to change the course of the subsequent progression to heart failure. Our work introduces an entirely new type of therapy capable of addressing previously ‘undruggable’ targets within the cells. It offers a promising strategy to change the course of this devastating disease.”