A Potential Treatment For Idiopathic Pulmonary Fibrosis (IPF)!
How altering a gene can treat ~15% of IPF cases.
Honestly, I think it’s safe to assume you know what lungs are — a major organ in the chest that helps us breathe. They take in oxygen from our atmosphere and serve as a place for this air to enter the blood, just as carbon dioxide leaves.
So you can imagine how terrible it’d be if our lungs were damaged or scarred, correct?
Unfortunately, for those with idiopathic pulmonary fibrosis (IPF), this is the case. This progressive lung disease causes scar tissue—or fibrosis—to accumulate in the lungs, therefore resulting in an inability to effectively transport oxygen into the bloodstream. After diagnosis, most people with this condition survive around three to five years before death. The word “idiopathic” denotes an unknown cause for this severe disease.
But there’s a sliver of light at the end of the broad tunnel. In around 15% of familial IPF cases, mutations were found in the TERC and TERT genes. Why’s this a good thing? Experiments have previously been performed on different diseases with mutations to these same genes and positive results have been found. If we can implement such experiments to IPF, there may potentially be a treatment for this 15% of pulmonary fibrosis.
And what’s better than to start small, right?
Let’s get into it.
Intro to IPF
Idiopathic pulmonary fibrosis is a progressive lung disease. It mainly affects those between ages 50 - 70. Common signs of this disease include difficulty breathing and a dry, hacking, persistent cough. Some with this disease even have widened tips on their fingers and toes (due to a lack of oxygen flowing to the areas). If severe, sometimes patients may develop blood clots in the lungs, lung cancer, or high blood pressure in lung blood vessels.
Tissue between and around the alveoli (air sacs in the lungs) thicken and scar, which causes many complications to arise. Pulmonary hypertension, or high blood pressure in the lungs, may occur as the capillaries and arteries are compressed due to scar tissue. This causes a resistance to blood flow, which increases pressure in the pulmonary arteries and right ventricle (located in the heart).
There may also be right-sided heart failure, where the lower right chamber in the heart must overwork itself to pump blood through a pulmonary artery that is partially blocked. Lung cancer and respiratory failure may also appear—which have high chances of leading to death.
IPF affects over 5 million people worldwide. It’s rare, but deadly.
Currently, there is no cure for IPF. No drugs/treatments exist that can remove the scarring in the lungs. Although medications such as Pirfenidone and Nintedanib are used to slow the disease’s progression, they do have negative side effects that prevent some patients from being able to use them. Nintedanib, for example, may cause liver problems, a tear in the stomach/intestinal wall, a stroke, a heart attack, and many other issues.
So, where do we take it from here?
Many studies have been conducted in familial forms of IPF (which is around 15% of IPF cases). In one, they found heterozygous mutations in the TERC gene (telomerase RNA component) and the TERT gene (telomerase reverse transcriptase).
Background: TERC/TERT and Telomerase
TERT and TERC work hand-in-hand to aid the function of telomerase — a reverse transcriptase enzyme that lengthens the 3' end of telomeres. Telomeres are DNA-protein structures (or protective caps) located at the end of chromosomes with a DNA sequence of TTAGGG. Chromosomes are thread-like structures inside the nucleus of a cell that contain DNA and genetic information. These telomeres essentially protect the genome from inter-chromosomal fusion, nucleolytic degradation, and unneeded recombination.
In short, they keep each end from sticking together or fraying abnormally.
As a cell divides, small portions of telomeric DNA are worn down. Eventually, the telomeres reach a point where they’ve become too short and the cell dies (apoptosis). Telomerase, fortunately, is there to lengthen these telomeres so they’ll live for a longer period of time (although telomerase is only active in rapidly-dividing and germ cells).
This is why we need both TERC and TERT. Without them, there will be malfunctions in the way telomerase works.
The Function of TERC/TERT
The TERC gene, which is found on chromosome 3, creates instructions to make the DNA sequence of TTAGGG — used for telomerase to add to the end of telomeres. TERC produces hTR, an RNA molecule that provides the template for reverse transcription (or the creation of a DNA molecule from an RNA template).
Studies have been conducted to explore how disrupting TERC in mice would affect them. Eventually, they saw shortened telomeres and abolished telomerase activity in the test subjects.
The TERT gene, found in chromosome 5, produces hTERT. hTERT physically adds the DNA sequence to the end of chromosomes.
Long story short, TERC “creates” the DNA sequence, and then TERT delivers it. TERC/TERT both determine the telomere-binding ability and catalytic activity of telomerase.
Other Issues Related to These Mutations
A study analyzed 115 patients with TERC/TERT mutations (among others). 46% of this data set had a diagnosis for IPF. Those with TERC mutations had a higher chance of developing leukopenia (reduced white blood cells), myelodysplastic syndrome (immature blood cells fail to mature), thrombocytopenia (low platelet levels), or aplastic anemia (lack of blood cell production). Additionally, evidence for genetic anticipation was found in families with TERT mutations. This means they displayed worsening symptoms at earlier ages as the disease passed on through generations.
My Idea — How We Can Fight This Disease
We’ve seen this before—a mutation in TERC/TERT that rooted a condition. In a rare bone marrow failure disease known as Dyskeratosis Congenita (DC), patients have abnormally shorter telomeres, which accompany the issue. Scientists discovered similar mutations in the TERC gene.
This was experimented on by delivering exogenous TERC to hematopoietic cells, which are immature cells cable of developing into any type of blood cell. Exogenous denotes being originated from outside the body, so this TERC was essentially administrated to patients’ bodies. 2 lentiviral constructs were used. This is a method of inserting/modifying genes in organisms using a lentivirus.
The results of this experiment were positive. They saw increased activity in TERC mutant samples of DC. Telomerase activity was increased in primary T lymphocytes, which are T cells (a major part of the immune system) and cell death was overall reduced in B-LCL cultures. This means the malfunction in telomerase was being made-up for. Exogenous TERC, basically, was suggested to be lengthening cellular lifespan. In DC, this discovered how the shortened-telomeres issue could be treated.
So, what does this mean for IPF?
I believe that we can apply this to idiopathic pulmonary fibrosis. We can use this exogenous method to deliver TERC/TERT to their bodies and make up for the mutation. While this would not cure the disease itself entirely, it would serve as a form of treatment and may alleviate symptoms patients may be experiencing. I do believe undergoing an experiment with exogenous TERC/TERT and IPF patients would provide beneficial insight into the disease.
Vision of the Future
By using this method of treating such a disease, we’re potentially unlocking procedures for thousands of others. This can be applied in various other fields and make a considerable change in the way we approach similar mutations. Sure, we’re only beginning with the 15% of IPF patients. However, if we can figure out how to treat this subset, it only makes it all-the-more possible to treat the rest.
Soon, no one will have to suffer from idiopathic pulmonary fibrosis. And that is my proposal.
- Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease that causes scarring (fibrosis) to the lungs and causes death 3–5 years after diagnosis.
- In 15% of cases (familial pulmonary fibrosis), scientists found a mutation in the TERC/TERT genes.
- TERC/TERT work hand-in-hand with telomerase, which is an enzyme that lengthens telomeres (protective caps at the ends of chromosomes). TERC “creates” the DNA sequence, and then TERT delivers it. TERC/TERT both determine the telomere-binding ability and catalytic activity of telomerase.
- For IPF patients with TERC mutations, they were found to have a higher risk of developing leukopenia, myelodysplastic syndrome, thrombocytopenia, or aplastic anemia.
- In Dyskeratosis Congenita (DC), there is a similar mutation to TERC. In an experiment, scientists applied exogenous TERC to patients and saw positive results, including increased cellular lifespan and telomerase activity.
- We can apply experiments done with dyskeratosis congenita to idiopathic pulmonary fibrosis, and potentially see similarly positive results! This is a road that has not yet been ventured, but definitely should!
A Quick Message
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Check out the resources I used throughout this article!
Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive
Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about…
Treatment for Idiopathic Pulmonary FibrosisThere is no cure for IPF and there are currently no procedures or…
Idiopathic pulmonary fibrosis: MedlinePlus Genetics
Telomerase and telomere length in pulmonary fibrosis - PubMed
In addition to its expression in stem cells and many cancers, telomerase activity is transiently induced in murine…
Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis
Telomerase reverse transcriptase ( TERT ) or telomerase RNA ( TERC ) gene mutation is a major monogenic cause of…
Telomerase Reverse Transcriptase
Human telomerase reverse transcriptase (h-TERT) is overexpressed in more than 85% of tumors with diverse histologies…
Telomerase RNA Component
The TER component provides the template sequence for reverse transcription and helps to assemble the RNP complex during…