In pulmonary fibrosis, the tissue between the small air sacs in the lungs becomes scarred. As the disease progresses, this leads to increasing shortness of breath due to stiffening of the lungs, and a lung transplant may even become necessary. There is currently no cure for pulmonary fibrosis. The causes are often unknown, and the clinical presentations vary greatly. To date, treatments have been limited to slowing the progression of the disease. Ideally, the scarring and stiffening can be halted. However, it is usually not possible to reverse the tissue damage that has already occurred.
A team of researchers at Hannover Medical School (MHH) is now working intensively on new, effective treatment options as part of the new BREATH-EC project – in collaboration with other university hospitals and companies from Germany, Sweden, England, South Korea, Portugal, Ireland, Italy and Belgium. From Germany, the Helmholtz Centre for Infection Research (HZI), the Fraunhofer Institute for Toxicology and Experimental Medicine and the University Medical Centre Freiburg are involved. The European Union (EU) is funding this project with around ten million euros. Of this, the MHH will receive 2.73 million euros, and Prof. Dagmar Wirth, who heads the research group “Model Systems for Infection and Immunity” at the HZI, will receive approximately 724,000 euros. The project is scheduled to run for four years.
“Our aim is to use certain immune cells to halt the progression of pulmonary fibrosis and possibly even reverse it. To do this, we are using genetically modified macrophages,” says Prof. Nico Lachmann from the Department of Pediatric Pneumology, Allergology and Neonatology at the MHH. He is coordinating the four-year EU collaborative project.
Immune cells recognize and inhibit fibrosis
Macrophages – also known as scavenger cells – play a central role in the human immune system. They are essential for defending against pathogens and for repairing damaged tissue. The research team generates these macrophages from so-called induced pluripotent stem cells (iPS cells) or isolates them from donor blood. “We then genetically modify the macrophages. This enables them both to recognize early signs of fibrosis in the lungs and to act directly against it,” explains Lachmann. “The macrophages intercept signaling molecules that promote fibrosis and produce antibodies locally that inhibit fibrosis.”
Dagmar Wirth's research group will contribute to this project by developing synthetic genetic circuits that enable macrophages to sense disease-associated signals and respond by producing therapeutic factors (e.g. antibodies) that target disease drivers and halt fibrosis progression. "In contrast to classical delivery of therapeutics, our cell-based ‘sense-and-act’ approach allows to mount a localized, dynamic and context-specific therapeutic response precisely tailored to the needs of the affected tissue," Dagmar Wirth explains. Such an approach can be expected to enhance treatment efficacy and precision and reduce unwanted side effects.
The long-term aim of the project is to administer the genetically modified macrophages to patients via bronchoscopy. The goal is to halt – and possibly even reverse – fibrosis in the lungs, at least in the early stages of the disease. Furthermore, the research findings are expected to benefit the development of further innovative treatments for fibrotic diseases, including those affecting the liver and the heart.
Cell and gene therapies for lung diseases
Macrophages are versatile immune cells which, in the lungs, are found – amongst other forms – as alveolar macrophages in the alveoli. There, they orchestrate inflammatory processes and regulate various cell types. The research team is utilizing the unique function of macrophages and aims to use these optimized cells to restore balance to the dysregulated inflammation. This type of cell therapy holds promise for a range of lung diseases. This is because the potential to equip immune cells with novel, therapeutically relevant genes – and thereby enhance their function – offers a wide range of applications. The BREATH-EC project thus fulfils a key objective of the German government’s High-Tech Agenda in the field of cell and gene therapies.
