Pulmonary fibrosis is when the lungs become scarred over time due to chronic fibroblast and myofibroblast activation. It is estimated to affect at least 5 per 100,000 people annually in Europe and the US and can cause chronic respiratory insufficiency.
Pulmonary fibrosis affects the older population and rarely occurs before age 50, but it is frequently diagnosed at an advanced stage. There are limited treatment options currently available, and it is a critical medical need to find novel drugs to slow down, stop or even reverse the progression of the disease.
This article explores current pulmonary fibrosis knowledge and the available preclinical options for developing new therapeutic solutions.
Table of Contents
A complex and multifactorial disease associated with a short life expectancy
Several associated risk factors have been discovered, including exposure or irritation (e.g., dust, tobacco) and respiratory system infection. These types of aggressions can cause the triggering of a dysregulated scarring process.
However, fibrosis arises without an identified cause for between 20% to 25% of affected patients and, in these cases, is called idiopathic pulmonary fibrosis.
A progressive and fatal disease, idiopathic pulmonary fibrosis has a diversity of evolution across patients. For some, the disease is stable for some years (three to six years), while in others, the disease degrades, resulting in the patient’s death within a year of diagnosis. The estimated survival rate at five years does not go beyond 20%.
Limited treatment options offering only partial relief
The only currently available treatment that offers survival improvement is lung transplantation, which may be offered to patients at an advanced stage of the disease that are under 65 years of age. Symptom-reducing methods may also be utilized, including respiratory rehabilitation and oxygen therapy.
However, these methods only result in a partial easing of the patient’s suffering, instead of disease reversion, with no improvement in survival. Past a certain point, severe lung function loss can no longer be compensated.
Radiation therapy for lung cancer and bleomycin (an anti-cancer agent) are understood to cause pulmonary fibrosis to develop in most patients. Fibrosis is secondary to an inflammatory phase in both cases.
Regarding idiopathic pulmonary fibrosis, the fibrosis that develops in both cases forms a chronic progressive disease, debilitating patients due to the deterioration of ventilatory functions.
Triple therapy for idiopathic pulmonary fibrosis is based on the following being administered:
- Immunosuppressants
- Low-dose cortisone
- An antioxidant, N-acetylcysteine
These are administered to reduce the inflammatory response, inhibit the spread of scar tissue in the lungs, and slow disease progression.
Nintedanib*, a new small molecule and an inhibitor of non-receptor tyrosine kinases has recently been launched on the European and American markets.
However, these treatments only slow the disease progression and do not stop or reverse it. Their side effects can also occasionally lead to the patient spontaneously discontinuing treatment or justifying the medical decision to cease the medication.
Image Credit: Oncodesign Services
Preclinical tools for drug development: rodent models
Due to the limited treatment options available to tackle lung fibrosis, preclinical research is necessary to provide robust animal models recapitulating, or at least partly, the characteristics of the human disease.
The deleterious profibrotic consequence of radiation or bleomycin can be utilized in rats and mice. In practice, bleomycin is delivered locally and causes pulmonary fibrosis in three weeks in rodents, while radiation therapy causes pulmonary fibrosis within 14 weeks.
This is followed by administering test drugs in the fibrotic rodents via any relevant route in a therapeutic or prophylactic pattern. Nintedanib is typically utilized as the positive control to allow comparison of the new drug candidates’ efficacy to this partially effective small molecule.
Preclinical tools for drug development: disease readouts to evaluate the efficacy
To provide a reliable evaluation of the positive impact of any lung fibrosis treatment and to allow prediction of the potential efficacy in humans, lung functional evaluation must be conducted.
The development of automated forced ventilation systems enables such measures in deeply anesthetized rodents to be performed passively. These specialized devices can blow air into the lungs to mimic forced inspiration, or suck the air out of the lungs to mimic forced expiration, while the pressure being generated is measured.
Plethysmography measures lung function by evaluating the mechanical parameters of the lung tissue. This method evaluates the disease’s severity and provides a prognosis.
The more relevant parameters include lung capacity (the volume that the lungs can contain), airflow (the amount of air inhaled and exhaled), and lung compliance (the lung tissue’s flexibility, i.e. the ability to deform corresponding to the volume of air).
Oncodesign Services has vast experience with numerous lung fibrosis models, having implemented and validated the flexiVent® system (Scireq™). This system delivers clinically relevant readouts of lung function. Combining a range of readouts enables the supply of robust preclinical lung fibrosis models.
Such readouts involve the clinical scoring of animal health, histology, lung imaging (CT scan), gene expression, and lung functionality. This technique allows the evaluation of the efficacy of a client’s candidate drugs considering all relevant dimensions of the disease.
To learn more about inflammation studies, particularly fibrosis studies, and how Oncodesign Services can help your projects, contact the team using the contact form below.
Acknowledgments
Produced from materials originally authored by Pauline Bornert, PhD, DVM, at Oncodesign Services.
*FDA approves first treatment for group of Progressive Interstitial Lung Diseases, 09 March 2020, www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-group-progressive-interstitial-lung-diseases
About Oncodesign Services
Oncodesign Services is a Contract research organization (CRO) specializing in drug discovery and preclinical services. From target identification to IND filing, the company contributes to the development of innovative therapies in oncology, inflammation and infectious diseases, with high medical needs.
Through integrated capabilities in medicinal chemistry, DMPK, pharmaco-imaging, bioanalysis, in vivo/In vitro pharmacology, Oncodesign Services support the R&D programs of customers with a global footprint.
Based in Dijon, France, in the heart of the university and hospital cluster and within the Paris-Saclay cluster, Oncodesign Services has 230 employees in France, Canada and the United States.
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