Genomics: Insight

Research Question: What role do genetic factors play in the development and treatment of pulmonary fibrosis?

Introduction

What role do genetic factors play in the development and treatment of pulmonary fibrosis? Pulmonary fibrosis (PF) is the most common form of interstitial lung disease (ILD), impacting approximately 35,000 to 55,000 Americans each year4. PF is characterized by the progressive scarring and thickening of the interstitial tissue between the alveoli, the tiny air sacs responsible for gas exchange. This scarring interferes with the lungs’ ability to take in oxygen and expel carbon dioxide waste, leading to shortness of breath and chronic coughing. Understanding the genetic influences of PF is key to uncovering its underlying causes.

PF typically affects middle-aged to older men and leads to an average life expectancy of up to five years following diagnosis¹⁸. Diagnosis is often confirmed through tests like the predicted Forced Vital Capacity (FVC) and predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO), which assess overall lung function²⁴.

While genetic mutations are significant contributors to PF susceptibility, they do not act in isolation. Environmental exposures, such as smoking, occupational hazards, and particulate matter, can exacerbate disease progression, especially in individuals with underlying genetic vulnerabilities²². These environmental factors may interact with genetic mutations to accelerate epithelial damage, compounding the disease process²². This interplay between genetic and environmental factors is central to understanding PF’s multifaceted etiology and emphasizes the need for integrated research to advance targeted treatments.

PF can develop either sporadically or hereditarily, with a 30% increased risk if two or more family members within three degrees of relationship have PF7. Initially, PF may resemble other forms of ILD, characterized by milder symptoms, which can delay diagnosis until lung function has significantly deteriorated¹⁹. About half of PF cases are classified as idiopathic pulmonary fibrosis (IPF), where the cause of the disease remains largely unknown.

Genetic causes of pulmonary fibrosis

The possibility of a gene controlling PF and its transmission across generations was first suggested in the 1950s when it was detected in identical twins¹⁶. It is now known that familial PF exhibits autosomal dominant inheritance and involves multiple genetic components working together. 

To date, there are over 20 known mutations that can be categorized under two main genetic causes of PF—single nucleotide polymorphisms and shortened telomeres.

Single nucleotide polymorphisms (SNPs) of PF

Single nucleotide polymorphisms (SNPs) are genetic mutations in which one base in a gene sequence is substituted with another base. Many SNPs that target surfactant proteins have been linked to PF. Surfactant proteins are responsible for maintaining lung surface homeostasis by clearing various bacteria and fungi and reducing inflammation in the tissue⁷. These mutations cause an increase in tissue scarring and fibroblast formation. One of the common examples of an SNP causing PF is that of MUC5B. The MUC5B gene encodes for the MUC5B protein, which is responsible for mucus formation and maintenance of a healthy respiratory tract. This SNP is responsible for 30-40% of PF cases and is one of many genes factored into the familial and sporadic model of PF⁵.

Telomeres and telomerases

Telomeres are stabilizing regions at the end of DNA that prevent the chromosomes from degradation or losing genes while dividing. During DNA replication and cell division, telomeres continuously shorten until they are too short for the cell to continue dividing. Then, the divided cell undergoes apoptosis and dies⁷. Cells which regularly divide, such as epidermal cells, have an enzyme called telomerase, which helps maintain telomere length and prolongs cell life. However, when the gene that codes for telomerase is mutated, cells often die rapidly and prematurely, greatly impacting various tissues²¹. 

There are several telomere mutations associated with PF, including mutations in the telomerase RNA component, (TERC), and mutations in the telomerase reverse transcriptase gene (the TERT gene)³. TERC and TERT work together to maintain telomere length, where TERC acts as a template for telomere DNA, and TERT adds new DNA sequences to the ends of chromosomes¹³. Mutated telomere length is associated with a shorter lifespan and 20-30% of familial pulmonary fibrosis cases⁹.

Telomere shortening, also known as telomeropathy, along with genetic mutations, causes DNA damage over time. This leads to apoptosis (cell death) and poor tissue repair in the pulmonary epithelium, causing permanent scarring and the development of pulmonary fibrosis. Loss of telomerase function has further affects in other high-turnover tissues in the body, such as the GI tract and bone marrow²³.

Considering gene therapies to treat pulmonary fibrosis

Although many gene therapy options have been proposed for treating pulmonary fibrosis, none have yet been tested in clinical trials. A variety of factors have contributed to this, including the lack of animal models that accurately replicate human PF. 

Gene-based therapies introduce exogenous, or external, nucleic acids into cells to undo the effects of both loss and gain-of-function mutations1. Gene therapy can be executed using either viral or non-viral vectors. Generally, viral vectors utilize modified viruses to introduce and replicate new nucleic acids in cells. Non-viral vectors use physical and chemical techniques such as polymers and injection to directly deliver genetic material into the cell. With regards to PF, both vectors would look to target the TERT gene, either through replacing it or editing it using gene technology such as CRISPR-Cas9¹². Restoring the TERT gene’s function could potentially restore the lung cells’ ability to repair and regenerate, mitigating the disease progression.

Non-viral vectors are generally favored over viral ones because they cause a smaller immune response and are easier to produce. However, the mucus in the airways contains negatively charged particles that can bind to these vectors, leading to their destabilization and destruction¹. Additionally, macrophages in the alveoli and intracellular structures like lysosomes can further inhibit their effectiveness⁵. Although there are various types of non-viral vectors, such as lipids, polymers, and proteins, that could be used for this purpose, no clinical trials or commercial products utilizing these therapies are currently available.

When weighing potential therapies for PF, the administration of drugs through the nose or mouth is preferred to system-wide methods¹. Many pathogenic molecules present in PF are also responsible for other crucial bodily functions, and a generalized delivery can have off-target effects.

Although many gene therapy options have been proposed for treating pulmonary fibrosis, none have yet been tested in clinical trials.

Summary

PF is a complex disease, strongly influenced by genetic factors. Specific genetic variations, such as SNPs in surfactant proteins and the MUC5B gene, along with mutations in the TERT and TERC genes that impact telomere maintenance, play a crucial role in the development of this disease. These mutations contribute to lung tissue scarring and the overgrowth of fibroblasts, ultimately leading to reduced lung function.

Gene therapies targeting these genetic factors, particularly using CRISPR-Cas9 to address TERT mutations, present a promising treatment approach. However, physiological barriers such as degradation by mucus and uptake by macrophages in the lung tissue need to be overcome before effective delivery mechanisms in clinical applications can be considered. Non-viral vectors are preferred because they elicit less immune response and are a more targeted approach for treating the lung as opposed to systemic administration¹.

Despite these challenges, ongoing research holds promise for developing more effective PF treatments and moves us closer to personalized medicine for PF patients.

References:

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