A roadmap to precision treatments for familial pulmonary fibrosis

Abstract

Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.

Keywords: Familial pulmonary fibrosis; Induced pluripotent stem cells; Interstitial lung disease of genetic cause, precision medicine; Preclinical models; Pulmonary fibrosis; Surfactant related gene; Telomere related gene; Telomeropathy.

Fig. 1

Gene mutations and disease pathways found in familial pulmonary fibrosis (FPF): (A) Surfactant is a mixture of phospholipids and proteins produced by type 2 alveolar epithelial (AT2) cells, which prevents alveolar collapse at the end of expiration. The lipidic transporter ATP-binding cassette family A member 3 (ABCA3) is involved in the transport and storage of surfactant proteins (SP) into lamellar bodies. Secreted SP and phospholipids form the surfactant film at the air-liquid interface of the alveolar space. To date, in chILD, mutations have been described in genes encoding SP-C (SFTPC), ABCA3 (ABCA3), TTF1 (NKX2-1), SP-B (SFTPB), and in adult FPF, in genes encoding SP-A (SFTPA1 and SFTPA2), SP-C, ABCA3 and TTF1. (B) Telomeres are nucleoprotein structures at the ends of linear chromosomes which protect genomic DNA. The activation of telomerase, composed of TERT and its RNA component TERC, prevents the attrition of chromosome ends during cell replication. Besides the telomerase complex, telomere homeostasis also requires the shelterin complex. In patients with FPF, mutations in the genes encoding telomere components, the most frequently identified being in TERT, TERC, PARN and RTEL1, result in alterations in telomere homeostasis and shortened telomeres in cells, such as AT2 cells.

Fig. 2

Overview of framework to develop precision treatments for familial pulmonary fibrosis: The figure outlines the proposed engagement of people, resources and processes required to identify and test new therapeutics for familial pulmonary fibrosis (FPF). Future clinical trials could employ an adaptive platform design such as the proposed Randomised Embedded Multifactorial Adaptive Platform in Interstitial Lung Diseases (REMAP-ILD) to test multiple novel or repurposed pharmaceutical therapies in tandem. The European Respiratory Society promotes global chILD networking by funding and supporting the Clinical Research Collaboration for chILD-EU for over 10 years. Potential future funding sources for FPF registries and biobanking include the NIH's Rare Diseases Research Programs, the Horizon programme funding from the European Commission and the European Joint Programme in Rare Diseases. Collaborative efforts with pharmaceutical industries who may explore the repurposing of already approved medications for IPF, PFF and other lung diseases in addition to drug development companies who specialise in orphan drug development are crucial sources for support.