Two, almost simultaneously published, very promising, but different studies about heart repair after heart attack by UCLA

Good news! 

About the first study:

"Key takeaways

• An experimental therapeutic monoclonal antibody therapy could become the first to directly enhance tissue repair in the heart following a heart attack. 
• Scientists ... blocked a protein called ENPP1, which increases inflammation and scar tissue formation that exacerbate heart damage. 
• One dose of the antibody was shown to reduce scar tissue formation in mice and improve cardiac function.

...

The new therapeutic approach aims to improve heart function after a heart attack by blocking a protein called ENPP1, which is responsible for increasing the inflammation and scar tissue formation that exacerbate heart damage. The findings ... could represent a major advance in post-heart attack treatment. ...

The researchers found that a single dose of the antibody significantly enhanced heart repair in mice, preventing extensive tissue damage, reducing scar tissue formation and improving cardiac function. Four weeks after a simulated heart attack, only 5% of animals that received the antibody developed severe heart failure, compared with 52% of animals in the control group. ...

Initial findings from preclinical studies also show that the antibody therapy safely decreased scar tissue formation without increasing the risk of heart rupture — a common concern after a heart attack. ..."

From the highlights and abstract of the first study:

"Highlights

• ENPP1 is known to initiate an aberrant metabolic cascade after myocardial infarction

• A humanized monoclonal antibody targeting human ENPP1 is engineered (hENPP1mAb)

• Systemic administration of hENPP1mAb rescues post-infarct metabolic defects

• In humanized mice, a single dose of hENPP1mAb rescues post-infarct heart function

Summary

Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction. Using metabolomics, single-nuclear transcriptomics, and cellular respiration studies, we show that the administration of the hENPP1mAb induces organ-wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies showed specific organ-wide distribution with the antibody being well tolerated. In humanized animals, with drug clearance kinetics similar to humans, we demonstrate that a single “shot” of the hENPP1mAb after MI is sufficient to rescue cardiac dysfunction."

About the second study:

"FINDINGS

UCLA scientists have identified the protein GPNMB as a critical regulator in the heart’s healing process after a heart attack. 

Using animal models, they demonstrate that bone marrow-derived immune cells called macrophages secrete GPNMB, which binds to the receptor GPR39, promoting heart repair. These findings offer a new understanding of how the heart heals itself and could lead to new treatments aimed at improving heart function and preventing the progression to heart failure. ...

Previous clinical studies have indicated that GPNMB, or glycoprotein non-metastatic melanoma protein B, has been strongly associated with cardiovascular outcomes of individuals with heart failure. What was not clear, however, was if lacking the protein was directly responsible for the development of heart failure after a heart attack. This important distinction — whether GPNMB is just an associated biomarker or one that plays a causal role — determines if the protein can be considered a therapeutic target for future studies. ...

Utilizing mouse models, the researchers first established that GPNMB is not natively expressed by the heart itself but is produced by inflammatory cells originating from the bone marrow. After a heart attack, these macrophages travel to the site of injury in the heart, where they express GPNMB. 

The team conducted gene knockouts — inactivating the GPNMB gene — and bone marrow transplants and observed that mice lacking the GPNMB gene exhibited dramatically worse outcomes after a heart attack, including a higher incidence of heart rupture, a fatal complication also seen in human heart failure patients. Conversely, mice with normal GPNMB expression that were given an additional dose of circulating GPNMB protein showed improved heart function and reduced scarring. Four weeks after a simulated heart attack, 67% of the animals lacking the GPNMB gene exhibited severe fibrosis, or scarring, compared with only 8% of animals in the control group. ..."

From the abstract:

"Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling."

New therapy could enhance heart repair after heart attack | UCLA "New single-dose therapy shows promise in enhancing repair after heart attacks in preclinical models"

A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction (first study; open access)

UCLA researchers uncover novel role of protein GPNMB in heart repair "New study highlights a target for therapies to prevent heart failure after heart attacks"

Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair (no public access)

ENPP1 is expressed in the region of scarring after injury to the heart. Cardiac muscle shown in red and ENPP1 in green demonstrates expression of ENPP1 in the region of scar formation.

Graphical abstract of first study