Scientists at Northwestern University and University of California San Diego have developed a new, potent injectable therapy that can protect the heart from damage after a heart attack.
The therapeutic approach comprises specially designed polymers that act like proteins. These protein-like polymers (PLPs) "grab" onto regulatory proteins, which blunt the body's natural healing process, in heart tissue. With those proteins out of the way, the healing proteins are free to do their job - preventing stress and inflammation.
After showing success in cell culture, the scientists tested their new therapy in a rat model of heart attack. Following a single, low-dose intravenous injection, the animals experienced decreased inflammation and cell death along with improved cardiac function and increased growth of new blood vessels.
The study was published today (April 25) in the journal Advanced Materials. The PLP platform is being commercialized by Northwestern spin-out company Grove Biopharma, which recently closed a $30 million series A financing round.
"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 study and scientific founder of Grove Biopharma. "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."
"Preventing heart failure after a heart attack is still a major unmet clinical need," said UC San Diego's Karen Christman, who co-led the study with Gianneschi. "The goal of this therapy is to intervene very soon after someone suffers a heart attack to keep them from ultimately going into heart failure."
Gianneschi is the Jacob and Rosaline Cohn Professor of Chemistry at Northwestern's Weinberg College of Arts and Sciences, a professor of materials science and engineering and of biomedical engineering at the McCormick School of Engineering and a professor of pharmacology at Feinberg School of Medicine. He also is a member of the International Institute for Nanotechnology, the Chemistry of Life Processes Institute, the Querrey Simpson Institute for Regenerative Engineering at Northwestern University (RENU) and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Christman is a Professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
From heart attack to heart failure
According to the U.S. Centers for Disease Control and Prevention, 6.7 million Americans over the age of 20 have heart failure, which occurs when the heart is unable to pump enough blood to the rest of the body. After developing heart failure, 52.6% of patients die within five years. The most significant cause of heart failure is a heart attack, which affects more than 800,000 Americans each year.
When a person suffers a heart attack, their heart muscle often becomes damaged due to a lack of oxygen and increased oxidative stress. This damage can lead to inflammation and scarring, which eventually weakens the heart and causes heart failure. Although current treatments exist to restore blood flow, these methods do not fully prevent the long-term damage that leads to heart failure over time.
To address this unmet need, the research team focused on the interaction between two proteins: Keap1 and Nrf2. While Nrf2 protects heart cells from stress and inflammation, Keap1 physically binds to Nrf2, regulating its function. This prevents Nrf2 from entering the cell's nucleus, where it can activate protective genes.
"Based on past biological studies, Nrf2 has been shown to have a positive effect on heart health following heart attack," Gianneschi said. "We wanted to see if boosting Nrf2 could act to help the body heal itself after a heart attack."
Freeing protective proteins
In previous studies, Gianneschi and his colleagues invented the PLP platform, in which nanoscale precision polymers mimic proteins to act like artificial antibodies. Once inside cells, they "grab" biological targets. In the new study, Gianneschi, Christman and their teams engineered a PLP with multiple "arms" that can grab onto Keap1. These "arms" mimic a part of the Nrf2 protein that typically binds to Keap1.
Because it has many "arms," the PLP binds strongly to Keap1, preventing it from grabbing onto the real Nrf2. With Keap1 out of the way, Nrf2 can move into the heart cell's nucleus to exert its protective effects.
After developing the system, the researchers conducted laboratory tests on heart muscle cells to evaluate its effectiveness. In experiments, the PLPs - even at very low concentrations - successfully protected cells from damage caused by oxidative stress. Next, the team administered a single dose of PLP intravenously in a small animal model of heart attack. Not only did the therapy improve how well the animal's heart functioned, it also remained effective up to five weeks after the injection. Further testing showed the cells expressed more Nrf2-related genes, which promote healing.
Tackling other 'undruggable' targets
The researchers say this novel PLP platform represents a significant advancement in therapeutic development, offering a new tool to tackle challenging biological targets where traditional approaches have fallen short. With Grove Biopharma, researchers are developing PLPs to target protein-protein interactions in various diseases, with an initial focus on cancer and neurodegenerative diseases.
"Proteins are the molecular machines that drive all essential cellular function, and dysregulated intracellular protein-protein interactions are the cause of many human diseases," Gianneschi said. "Existing drug modalities are either unable to penetrate cells or cannot effectively engage these large disease target domains. We are looking at these challenges through a new lens, and I am excited to continue collaborating with the Grove team to help advance this new modality to the clinic."
The study, "Protein-like polymers targeting Keap1/Nrf2 as a therapeutic for myocardial infarction," was supported by the National Institutes of Health National Heart, Lung, and Blood Institute (award numbers 2R01HL139001 and R00CA248715).
