Fixing stiff collagens – damage to the extracellular matrix is the missing hallmark of aging

Over the past couple of decades there have been a huge number of exciting breakthroughs that have increased our understanding of how our bodies change as we get older and (eventually) sicker. These are collectively referred to by people in the field as the “hallmarks of aging” – biochemical changes like telomere attrition, epigenetic alterations, loss of proteostasis and many more. In the past decade since Lopez-Otin and colleagues released a paper establishing this paradigm, we have learned an enormous amount about the various hallmarks, as well as new aspects of biology, resulting in the authors expanding their list of hallmarks from nine in the 2013 paper to twelve in an updated version published at the start of 2023.

Although the twelve Hallmarks of Aging for 2023 are more inclusive and specific than in 2013, one important biochemical change that happens with age is notoriously absent from this class – stiffening of the Extracellular Matrix (or ECM), which binds together and connects cells in every organ and tissue of our bodies. In fact, a group of scientists released a paper in 2020¹ making a case for the ECM changes being a hallmark of aging, but not many are taking notice.

At Cambrian: we are. In our work creating translational drug development categories for the various hallmarks of aging, one of our 13 Drivers of Aging encompasses the changes to the ECM with age. For over three years now, we have been working to find new ways to restore or prevent ECMs from breaking down.

The ECM is a large, complex network of proteins and other molecules that surround, support, and give structure to cells and tissues throughout the body². When you fall down and scrape your knee, you can watch over just a couple days as your cells produce tons of new ECM components and pour them into the gap in your skin created by that scrape – creating a scar.

Our ECM is constantly being damaged, in both big ways – like when we cut our finger with a knife, scrape our knee, or have a heart attack – and small ways – like through UV radiation, the inhalation of polluted air, or the death of cells throughout the body. On top of that, ECM proteins themselves ‘age’ – accumulating modifications that make them more and more brittle the longer they live in our body.

When we're young, we break down the ECM and build it back up over and over. This takes a lot of energy, but it replenishes our ECMs with new components that are flexible and springy. When we’re old, instead of breaking them down, we tend to just attach these ECM components to their surroundings using chemical modifications called crosslinks. Crosslinking ECM components is good for saving energy, but dramatically reduces the flexibility of the ECM.

At any age, our ECM tries to balance between creating new healthy components and wanting our old components to survive longer by forging these crosslinks, but as we age, the balance shifts and we end up creating fewer new components and crosslinking more old ones. For most of our tissues, it seems the ability to make new ECM isn't lost with age, but instead the signal for making that new ECM disappears as our old ECM is locked in place by crosslinking. This might result in fibrosis which we can stop by inhibiting the signal and the crosslinking.

Some crosslinks are randomly formed, like Advanced Glycation End products (or AGEs), but most crosslinks are intentionally created by our own tissues as a way to save energy. In some of our most fragile and important tissues, such as the lungs, heart, kidneys, and liver, most crosslinks are created by an enzyme called Transglutaminase 2, or TG2. The modifications made by TG2 makes ECM components like collagen stiff and highly resistant to degradation. TG2 expression goes up in these tissues as we age, which is a major reason older tissues accumulate crosslinked, brittle proteins over time and cause the components of the ECM to stiffen. With time, this results in scar tissue building up in our tissues, or even pathological scarring that can cause disease – fibrosis.

Since TG2 increases with age in several animal models³ and in people suffering from idiopathic pulmonary fibrosis, or IPF⁴, we decided to create a drug that could stop TG2 from creating pathological crosslinks – restoring a youthful balance to our ECM.

The world expert in TG2 biology is Dr. Martin Griffin of Aston University, who has shown that if you prevent TG2 from creating crosslinks, the whole body produces more young healthy collagens, which can reverse the age-related changes in the ECM balance – convincing the body to make more new ECM components. On top of that, restoring this balance can allow fibrosis from a number of serious diseases affecting the heart,⁵kidney,⁶ and lungs⁷ to heal – reversing otherwise permanent scarring.

Based on these discoveries, we teamed up with ECM entrepreneur Dr. Sriniwas Sriram, Dr. Griffin, and his collaborators Dr. Vivian Wang and Dr. Dan Rathbone at Aston University to create Isterian Biotech a Cambrian Bio PipeCo developing drugs that can prevent ECM crosslinking and reverse pathological fibrosis. Isterian is led by Cambrian EVP of Drug Discovery Dr. Georg C. Terstappen and worked on by a joint team from Cambrian and Aston in the US and UK.

Isterian has created a completely novel class of drugs – irreversible TG2 inhibitors that act like precision-targeted warheads. They find and permanently deactivate any TG2 they encounter, even when it’s buried deep in a tangled net of crosslinked ECM.

We’ve synthesized and tested hundreds of variants of these anti-TG2 drugs to hone in on a small number of Lead-stage molecules that can reverse fibrosis and restore youthful ECM in both human cell culture and animal models of disease. And the next step for these molecules will be validating that they meet all requirements for a human medicine, then clinical testing in people.

‍About Isterian Biotech

‍Isterian Biotech, Inc. is a biotechnology company focused on developing novel drugs to remove excess pathological protein crosslinks from fibrotic organs for the treatment of fibrosis, and to extend healthy lifespan. The company's therapeutic agents in development target the enzyme transglutaminase (TG2), which plays a key role in protein crosslinking and in activation of TGF-β signaling. The company is a Cambrian Bio PipeCo. Check out the Isterian Biotech Press Release and for more information, please visit www.Isterian.com.

Sources:

¹ https://www.sciencedirect.com/science/article/pii/S156816372030232

² https://www.cancer.gov/publications/dictionaries/cancer-terms/def/extracellular-matrix

³ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868664/

https://www.frontiersin.org/articles/10.3389/fphys.2020.560019/full

https://pubmed.ncbi.nlm.nih.gov/30517326/

⁴ https://pubmed.ncbi.nlm.nih.gov/21700912/

⁵ https://www.nature.com/articles/s41419-018-0573-2

⁶ https://pubmed.ncbi.nlm.nih.gov/18003782/

⁷ https://link.springer.com/article/10.1007/s00726-020-02938-w