A fundamentally new therapeutic principle
The work describes a fundamentally new therapeutic approach: instead of replacing individual genes or correcting mutations, central cellular protection programs could in the future be specifically reactivated. This approach opens new perspectives, particularly for heart diseases, since they are usually not caused by a single genetic defect but by complex disturbances in gene regulation.
“Many forms of heart failure are not caused by a defective gene, but by the loss of entire cellular protection programs,” says senior author Laura Zelarayán from University Medical Center Göttingen. “Our approach targets exactly this point and switches these programs back on.”
KLF15 as a central switch in the heart muscle
The focus of the study is the transcription factor KLF15. This protein has been known in cardiovascular research for several years and regulates important metabolic programs in heart muscle. Previous work had shown that KLF15 can suppress pathological growth processes of the heart. However, in many forms of heart failure, its activity is significantly reduced.
The new study now shows that KLF15 plays a particularly central role in the genetic regulatory network of cardiac muscle cells. When its activity is lost, essential metabolic and stress-response programs become unbalanced—with far-reaching consequences for heart function.
CRISPR technology activates protective gene without altering DNA
While the importance of KLF15 was already known, there had previously been no way to specifically increase its activity in heart muscle. This is exactly where the new work comes in.
The researchers used a specialized form of CRISPR technology in which the genome is not cut or permanently altered. Instead, the system acts as a molecular tool that selectively enhances the activity of an existing endogenous gene program.
A harmless viral vector delivers the genetic blueprint for this CRISPR system into heart muscle cells. There, a modified Cas protein binds specifically to the KLF15 gene. Attached activation domains boost its transcription—reactivating the cell’s protective program.
The key advantage of this approach: no gene is replaced, no mutation corrected—instead, a natural protective mechanism that is lost during disease is restored.
Improved heart function and increased survival
In mouse models subjected to pressure overload of the heart, this intervention showed clear effects. The hearts of treated animals enlarged less, their pumping function remained more stable, and survival rates were higher.
The treatment was administered once via the bloodstream. Its effect persisted for many months. During this time, the genetic program of the heart muscle cells normalized: disease-promoting genes were suppressed, while metabolic programs of healthy cells remained active.
Protection against scarring of heart tissue
In addition, the team identified another previously unknown mechanism. Activation of KLF15 caused heart muscle cells to release increased amounts of the protein AZGP1. This protein acts on fibroblasts in heart tissue and slows processes that contribute to the formation of scar tissue.
The results therefore show that heart muscle cells actively influence their environment and that KLF15 has both cell-autonomous and non-autonomous beneficial effects. This allows them to limit the development of fibrosis in the heart.
Steps toward clinical application
Further steps are required before potential use in humans. These include safety studies, investigations into targeted distribution of the vector in the body, and studies in larger animal models.
The researchers have already confirmed their findings in human heart muscle cells derived from stem cells as well as in living human heart tissue. There too, activation of KLF15 significantly reduced pathological stress programs.
The study involved four DZHK sites: Göttingen, Heidelberg-Mannheim, Rhine-Main, and North.
Original publication:
Schoger E, Kim R, Bleckwedel F, et al. Enhancing KLF15 activity in cardiomyocytes: a novel approach to prevent pathological reprogramming and fibrosis via nuclease-deficient dCas9VPR. Signal Transduct Target Ther. 2026;11(1):76. Published 2026 Mar 3. doi:10.1038/s41392-026-02593-9
