An already FDA approved cystic fibrosis drug could help tackle the gradual, clogging buildup of fibrosis as we age
Your immune system is essential, but it causes a great deal of collateral damage doing its job. As we get older, exposure to infection and injury lead to an immune response that results in increased fibrosis. Fibrosis is the thickening of connective tissue through the deposition of extra collagen. This begins to surround cells in many tissue as we age, and prevents them from doing their job properly. It also inhibits proper heart function and contraction.
"As we age, we typically accumulate more fibrosis and our organs become dysfunctional. We've documented in mice how deletion of a single gene, PAD4, has a drastic effect on curbing the complex process of fibrosis"
How does fibrosis begin?
In response to injury or infection a type of immune cell called neutrophils has a strange capacity to self destruct and unleash a web of its own DNA like a net. These DNA traps care called neutrophil extracellular traps (NETs), and may have evolved to encompass invading bacteria and block up holes in defences. This process happens in cystic fibrosis as an attempt to mop up infection in the patient's lungs, but leaves a sticky mess of DNA which makes lung function deteriorate. This NET process is controlled by the gene PAD4, which produces an enzyme responsible for triggering this reaction. Like inflammation, NETs may initially have a benefit but overtime that benefit is far outweighed by damage to surrounding tissue.
"Suppressing PAD4 activity and therefore blocking NET formation over the course of someone's lifetime could potentially have dramatic effects on overall organ function, we hypothesized"
When a research team deleted PAD4 in a strain of mice, they found that older mice in this group had hearts strikingly similar to young ones. They were much less inhibited by collagen buildup and had youthful diastolic and systolic function. Deleting PAD4 also improved lung function too.
Repurposing a cystic fibrosis drug
We have already developed an enzyme drug for cystic fibrosis that tackles some of these problems, called DNAase. This digests DNA present in these NET traps; unclogging the gel mesh in patients' lungs. Knowing this, the same research team tested DNAase mice that had undergone cardiac injury, and displayed subsequent fibrosis build up. Following injection of this enzyme, mice were highly protected in a manner similar to those mice with a PAD4 deletion.
"NETs are easily targeted and destroyed by DNase in the lungs of CF patients. So by extending DNase use to a much wider range of patients experiencing infectious illness or injury, we could potentially clear up NETs elsewhere in the body and prevent subsequent organ fibrosis. The development of orally-administered PAD4 inhibitors intended to be taken like baby aspirin could radically improve our quality of life as we age"
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