An Update on Revel Pharmaceuticals, Working on Glucosepane Cross Link Breakers

Revel Pharmaceuticals is the result of work funded in large part by the SENS Research Foundation, with the support of its many philanthropic donors. That part of the history of the underlying research isn't covered in today's short article on the company, so it seems worth mentioning here. Cross-links are chemical bonds formed between molecules in the extracellular matrix. Some are necessary to structure and function, but other unwanted cross-links are added over the years, creating stiffness in flexible tissues such as blood vessel walls and skin. In the case of blood vessels, stiffness causes hypertension, and eventual mortality. Revel is aiming to remove cross-links based on glucosepane, which appear to be the dominant type of persistent pathological cross-linking in human tissues.

The field of glucosepane cross-link research is an excellent example of the way in which philanthropy is required to make progress. There was compelling evidence that such cross-links are likely important in the aging process, and yet next to no-one chose to work on the problem. This was a bootstrapping problem: because no-one had spent a good deal of time on glucosepane, the tools to work with it didn't exist. Worse, glucosepane isn't a factor in short-lived mammals, their important pathological cross-links are chemically different from those in humans, so animal models of such cross-linking were a distant prospect at best. Thus scientists, funding sources, and others all turned their attention to other projects in other fields, because those other projects promised a more rapid path to what the world at large considers useful outcomes. Next to no-one funded or worked in the field of glucosepane cross-linking precisely because next to no-one funded or worked in the field of glucosepane cross-linking research.

How was this problem resolved? The SENS Research Foundation, a non-profit, stepped in and used funds provided by donors to fund the work to produce the necessary tools for glucosepane cross-linking research, as well as projects that identified bacterial enzymes capable of breaking down glucosepane. That work was licensed out to Revel Pharmaceuticals, and one of the researchers involved is now heading the company in an effort to turn those enzymes into therapies. The point here is that philanthropy works. This is one of any number of similar efforts to unblock research and development undertaken by the SENS Research Foundation and Methuselah Foundation over the past twenty years. The outcome will hopefully lead to a proof of concept to demonstrate that glucosepane cross-linking is an important aspect of aging, and that in turn will shortly thereafter become an industry with as much promise as the present senolytics industry when it comes to human rejuvenation.

A new approach to reversing tissue aging

The formation of Revel Pharmaceuticals is a reimagination and expansion of targeting AGE crosslinks using enzymes rather than small molecules as the therapeutic. "Enzymes are biologics, so we can be very precise as we make modifications to repair damaged proteins and break up crosslinks."

"We're quite unique right now, in the aging space - not many companies are focused on the structural, protein side of aging. If you look at the literature and clinical data, it's very clear that damage and crosslinking of collagen and other proteins is a significant contributor to aging. As the structure of the extracellular matrix surrounding cells becomes crosslinked and degraded, proteins begin to aggregate and lose functionality, tissues become stiffer, and the immune system becomes activated leading to low level inflammation. We're looking at the same targets that have been of interest for a long time, but no one's had a good way to correct or repair them. We started out looking at glucosepane, the predominant crosslink in aging human tissue, but there are many other important aging crosslinks and damage products to which we've expanded our scope."

"Our work has led us to five or six interesting targets, which also serves to de-risk our pipeline, so all of our eggs aren't in one basket. What we have now is a suite of enzymes targeting a suite of different damage products." Revel is preparing to move therapeutic enzymes into pilot studies in animal models and human cadaver tissue from biobanks. "If we have 80 year old tissue that comes from a biobank, then the gold standard is really to show that, when we add our enzymes to that very old tissue, we can repair these modifications and correct the damage. Once that critical milestone is met for each enzyme, we will immediately push into animal studies and eventually clinical testing."

Comments

It is very interesting. Hope it works , for the sake of all of us

Posted by: Cuberat at October 19th, 2021 5:22 PM

It's been many years of hoping, and may be many more - but it's always good to get an update from Revel. With bigger money coming in perhaps theses enzymes will make it to market sooner than expected. If only more philanthropy were directed at this type of research which is actually tackling the root causes of aging.

Posted by: august33 at October 19th, 2021 9:06 PM

I've got a feeling that even if they do succeed in removing all the unwanted cross links, it won't help at all.
If breaking them was useful, then humans and other mammals already would've evolved some kind of symbiotic relationship with the bacteria that can break them.

Posted by: Sanchez at October 20th, 2021 1:50 AM

There's very little selective pressure for such a thing to happen. AGEs take a really long time to accumulate to harmful levels, and in the wild you'll expect to have been eaten by a lion long before they have a chance to cause problems. It's only comparatively recently in evolutionary terms, since humans have developed civilisation and as a result mostly been free from predation, that humans have tended to actually live long enough for AGEs to matter.

Posted by: Arcanyn at October 20th, 2021 7:49 AM

Reason, you cite 'compelling' evidence for the importance of AGEs in aging. But if they were so important, then wouldn't their removal already have been demonstrated to be of benefit in shorter lived organisms like mice, given their crosslinks can already be broken? Or are you suggesting AGES aren't important in, say, mice, but are in humans? In which case, what is the compelling evidence?

Posted by: Mark at October 21st, 2021 5:13 AM

I think that evolution has no interest in discovering endogenous cross-link breakers for humans. By the time AGES cause serious problems for us, DNA has already been passed on, and the the next generation.has likely grown and matured. It is up to us, as relatively long lived organisms, who would benefit form AGE breakers, to discover and benefit from them.

Posted by: Eric at October 24th, 2021 11:43 AM

I have the unnerving feeling that enzymes might be too big to do the trick in animal and human trials. Do they address this somewhere?

Posted by: Sardaukar at November 18th, 2021 3:17 AM

Wouldn't there be a massive market for an anti wrinkle cream that actually works ?

Posted by: George McDonald at November 19th, 2021 4:24 PM
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