Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which as yet no causal therapy exists. It is, however, known that the lung interstitium - the connective tissue between the air sacs in the lower part of the lung - is affected. There scar tissue consisting mainly of collagen accumulates, thus reducing lung elasticity and gradually impairing lung function. Patients with IPF have an extremely poor prognosis; on average they survive only two or three years after the diagnosis has been made.
Analysis of patient data
Prof. Dr. Oliver Eickelberg and Dr. Claudia Staab-Weijnitz of the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München and their colleagues at LMU University Hospital in Munich and Yale University School of Medicine have now discovered a new therapeutic target for IPF. The main focus of their research was to identify causative mechanisms involved in the disease. The researchers analyzed microarray data of samples from German patients and from an IPF cohort of the Lung Tissue Research Consortium in the U.S.
The analysis revealed elevated levels of the protein FKBP10 in the lungs of IPF patients. The researchers hypothesized that if the production or activity of the protein could be inhibited, this might lead to a new therapeutic approach. Further experiments confirmed that knockdown of this protein in IPF fibroblasts* diminished the collagen synthesis. “Thus, FKBP10 represents a potential new target molecule for the individualized therapy of IPF,” said Claudia Staab-Weijnitz. “In the future, these results could also lead to new therapeutic options for the treatment of other fibrotic** diseases.”
New ways to understand the disease cause
Eickelberg has made the study of IPF one of his key priority research areas. Together with his team of researchers, he is studying the pathogenic mechanisms with the aim to develop causal therapies - and thus one day to actually cure IPF. In the short term, however, the main focus is on delaying the progression of the disease and alleviating the symptoms. “My foremost objective is to help develop an effective treatment that will completely halt the progression of IPF in the patient,” said Eickelberg. “These approaches are best developed in international networks. This cooperative project is a direct result of the research stay of Professor Kaminski (Yale) at the CPC through the support of a Helmholtz International Fellow Award (HIFA).”
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).
Essential update: FDA approves two new drugs for idiopathic pulmonary fibrosis
The FDA has approved nintedanib (Ofev) and pirfenidone (Esbriet) for the treatment of IPF. Both drugs block multiple pathways that may be involved in pulmonary scarring, and both were granted approval through a triple-path process of fast track, orphan product, and breakthrough designations. In clinical trials, patients taking either drug experienced significantly reduced declines in forced vital capacity compared with patients who received placebo.
Nintedanib is not recommended for patients with moderate to severe liver disease and may cause birth defects or stillbirth. Pirfenidone is not recommended for patients with liver disease or end-stage kidney disease, and may cause photosensitivity. Adverse effects seen with both drugs include diarrhea, nausea, abdominal pain, vomiting, decrease or loss of appetite, and headache.
Signs and symptoms
The clinical symptoms of idiopathic pulmonary fibrosis are nonspecific and can be shared with many pulmonary and cardiac diseases. Most patients present with a gradual onset (often >6 mo) of exertional dyspnea and/or a nonproductive cough. Approximately 5% of patients have no presenting symptoms when idiopathic pulmonary fibrosis is serendipitously diagnosed.
Associated systemic symptoms that can occur but are not common in idiopathic pulmonary fibrosis include the following:
“With our translational approach,” said Eickelberg, “we want to help alleviate the suffering of patients with lung disease.” In the case of IPF, the researchers now want to establish a drug screening assay and begin clinical trials with an FKBP10 inhibitor, an agent to inhibit the production or activity of the FKBP10 protein.
*Fibroblasts: Fibroblasts are motile cells that are present in connective tissue. They play an important role in the synthesis of the extracellular matrix, the connective tissue between the cells. The products of fibroblasts primarily include collagen as well as proteoglycans, which strengthen the extracellular matrix.
**Fibrotic diseases are accompanied by an excessive proliferation of connective tissue.
Staab-Weijnitz C. A. et al. (2015). FK506-Binding Protein 10 is a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis, American Journal of Respiratory and Critical Care Medicine [Epub ahead of print]
As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de
The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC’s objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL).
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