Coordinator: Dr. Ernest Sala Llinas
Sporadic idiopathic pulmonary fibrosis (IPF) and familial pulmonary fibrosis (FPF) are respiratory rare diseases with a poor prognosis (mean survival 3-5 years).
Moreover the number of patients suffering from PF in a given EU member state is limited, which challenges the translational research among other clinical advances. Therefore, there is an evident requirement for transnational cooperation and multifaceted approaches. The PF line at CIBERES has gathered an international cross-disciplinary translational research network that is focused on lung fibrogenic pathways, which includes expert clinicians and excellent basic researchers with complementary skills in models of lung fibrosis and telomere mutations, cell regulation and therapy, vector and nanoparticles development, and rising biotechnologies required to generate a real translational approach for the treatment of lung fibrosis.
Nowadays, only two anti-fibrotic treatments have demonstrated to slow down the progression of the disease but with no curative effect. Furthermore, not all patients can benefit from these treatments, probably due to the heterogeneity of the lung fibrotic pathogenesis (biochemical, genetic, and epigenetic pathways) and the absence of a customized therapy based on specific deregulated pathways. Fibrotic lung presents a model of great complexity that can not perform a normal tissue repair because of different extracellular matrix and cellular mechanisms modifications which causes the typical scars of these lungs. Results of the previous pulmonary fibrosis line at CIBERES demonstrate the role of specific extracellular matrix glycoproteins in fibroblast activity, new fibrogenic pathways involved that could be regulated and, in some cases, genetic aspects that could allow earlier diagnosis, predisposition and can even identify some patients that could benefit from targeted therapies.
Recently, genetic alterations such as telomerase gene mutations with loss of function and telomere shortening have been described as the main factors of disease development in some cases. Shortness of telomeres has been observed in 25-50% of patients with IPF/FPF and it has been associated with worse prognosis. Mutations in telomerase complex genes TERT, TERC and DKC1 produce shortness of telomeres and accelerated aging.
During last 3 years, the line of Lung Fibrosis at CIBERES has contributed in the knowledge about telomere biology and the identification of its implication in a big proportion of IPF/FPF patients, what has lead forward to look for a cell treatment that would reverse this functional disorder. The line group has demonstrated a different fibrotic cell behaviour depending on telomere length and telomerase activity. A specific peptide recovers telomerase activity of certain mutated cells avoiding the progressive shortness of telomeres.
The aim of our current studies is to evaluate the benefit of this new peptide, already accepted by AEM and FDA for human use, and its modifications and delivery to specific cells in lung fibrosis. The project will use a mouse telomerase knockdown model and evaluate the anti-aging outcome in fibrotic cells from IPF/FPF patients. The new therapeutic approach pretends to be a first in class for personalized and curative treatment in IPF/FPF with shortness of telomeres.