CAR-T cells targeting cardiac fibroblasts to reduce pathological fibrosis and improve cardiac function
Most forms of heart failure are accompanied by cardiac fibrosis causing a “stiff heart” and contractile dysfunction, which most commonly refers to the excessive deposition of extracellular matrix in the cardiac muscle. Fibroblasts become activated, resulting in excess matrix deposition and stiffening of the myocardium. No therapies exist to effectively treat or reverse cardiac fibrosis.
Drs. Epstein and Aghajanian tested whether targeting activated cardiac fibroblasts could reduce fibrosis and improve heart function.
In a mouse model, engineered T cells targeting Fibroblast Activation Protein (FAP) expressed by activated fibroblasts in the heart are effective at reducing cardiac fibrosis and improving heart function in hypertensive-associated heart failure.
FAP CAR T cells can target cardiac fibrosis:
a. Schematic of experiments for FAP CAR T cell targeting of cardiac fibroblasts. C57BL/6 mice were continuously administered AngII/PE through an osmotic minipump to induce cardiac injury and fibrosis. FAP CAR T cells were adoptively transferred 1 and 2 weeks after pump implantation when fibrosis had already been established. Mice were evaluated and euthanized at 4 weeks to assess fibrosis.
b. Top, Picro-Sirius red staining of heart coronal sections in mice treated with saline (left), AngII/PE (centre) or AngII/PE and FAP CAR T cells (right) to evaluate fibrosis (red). Bottom, magnification of left ventricular fibrosis. Scale bar, 100 μm.
c. Quantification of cardiac fibrosis.
d. Comparison of cardiac functional parameters and body weight between experimental and control groups.
e. M mode echocardiography of mice treated with saline (top), AngII/PE (middle) or AngII/PE and FAP CAR T cells (bottom). Arrows indicate systole and diastole and highlight the difference. Representative images of two independent experiments, showing similar results
Treatment of cardiac fibrosis</rss.application
- Broadly applicable in range of heart diseases related to cardiac fibrosis
- Minimal off-target effects observed
Stage of Development:
- Target identified
- Preclinical discovery
- Nature, 2019, 573 (430-433)
- Penn Medicine News
Docket # 18-8420