Revel Pharmaceuticals Finally Seed Funded to Develop Glucosepane Cross-Link Breakers

I'm pleased to see that the Revel Pharmaceuticals founders have finally sorted out a seed round to fund their work; the establishment of this startup has been in progress for a few years now, and some of us were beginning to think it a lost cause. Revel Pharmaceuticals is the biotech startup established to develop glucosepane cross-link breaker drugs based on work carried out by the Spiegel Lab at Yale. That team, supported by the SENS Research Foundation, first developed a means to synthesize glucospane, and then found bacterial enzymes that can break down glucosepane cross-links.

Glucosepane is the most prevalent form of cross-link observed in aged human tissues, hardy compounds that build up slowly over time as a side-effect of the normal operation of cellular metabolism, and are somewhere between challenging and impossible for even a youthful biochemistry to break down. We humans are just not equipped with the biochemical tools for the job. Cross-linking occurs when structural molecules of the extracellular matrix are linked to one another via bonds with a glucosepane compound, or other only short-lived and thus less harmful molecules, restricting their movement. This is a form of molecular damage that causes loss of elasticity in skin and blood vessel walls, among many other negative effects. The latter is quite serious, the starting point for hypertension, cardiovascular disease, and many other ultimately fatal issues.

The enzymes discovered at the Spiegel Lab and now under development at Revel Pharmaceuticals are a starting point for the development of a therapy that can break down glucosepane cross-links. In my view, breaking persistent cross-links will be as important to achieving rejuvenation in humans as the development of senolytics to destroy senescent cells. A similarly sized industry should arise given one group to light the path, many companies working towards therapies. I hope that the example of one company setting forth on this road to commercial development will soon enough inspire others to follow with their own approaches to the challenge.

Kizoo Technology Capital leads seed round financing at REVEL Pharmaceuticals

For the past 10 years, Yale Professors David Spiegel and Jason Crawford have been working on tools to enable the development of glucosepane-cleaving drugs. Kizoo Technology Capital investors say now is the time to advance this groundbreaking research toward the clinic and are leading funding of a new company, Revel Pharmaceuticals Inc., founded by Drs. David Spiegel, Jason Crawford, and Aaron Cravens. Kizoo leads the seed financing round at Revel, with Oculus co-founder Michael Antonov participating. SENS Research Foundation provided funding to the Yale GlycoSENS group for several years.

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to collagen and form toxic crosslinks that alter the physical properties of tissues and cause inflammation. As a result, tissues slowly stiffen with aging, leading to rising systolic blood pressure, skin aging, kidney damage, and increased risk of stroke and other damage to the brain. Perhaps the most important of these Advanced Glycation End-product (AGE) crosslinks is a molecule called glucosepane. Revel is developing therapeutics that can cleave glucosepane crosslinks thus maintaining and restoring the elasticity of blood vessels, skin, and other tissues, and preventing the terrible effects of their age-related stiffening.

The Yale group's first major milestone - the first complete synthesis of glucosepane - was highly recognized when published. Since then progress has been rapid, with development of glucosepane binding antibodies and discovery of therapeutic enzyme candidates capable of breaking up glucosepane crosslinks. Revel will build upon this progress by advancing the first GlycoSENS therapeutics into the clinic.

"This is truly a first. Revel will open an entirely new category in repairing a significant damage of aging - crosslinking of collagen. Glucosepane crosslinks may cause not only wrinkles on your face but also lead to age-related rising blood pressure and possibly stroke. Collagen is the infrastructure of our bodies - in every tissue, supporting cellular function and health - but with aging, this critical molecular infrastructure accumulates damage. By clearing out this damage, we can restore tissue function and repair the body. Revel is one of only a few companies taking a repair-centric approach to treat diseases of aging and one day our AGE-cleaving therapeutics will undo this damage at the molecular level."

Comments

Nice that they got seed funded after 10 years, but this IMO does not portend very well

"Seed funders" like Kizoo and Laura Deming's Longevity Fund serve an important role, but have small wallets, and much more is needed to traverse the "valley of death"

And Jim Mellon can't finance them all

Too many companies trying to drink at too few wells

Posted by: David Permisov at January 7th, 2020 1:40 PM

at last. good luck

Posted by: scott at January 7th, 2020 4:29 PM

Interesting to see that Oculus co-founder Michael Antonov was one of the backers.

Posted by: jimofoz at January 7th, 2020 4:34 PM

Great way to start the new year and decade, I really want glucosepane breakers.

Posted by: Corbin at January 7th, 2020 5:30 PM

This is great news! A sincere good luck to Revel, and Godspeed. I ain't gettin' any younger!

Posted by: Paul at January 7th, 2020 7:24 PM

The announcement is notably absent any discussion of the $$ raised.

Posted by: JohnD at January 7th, 2020 8:06 PM

I noticed that too - they didn't say how much money. I would like to know that.

Posted by: Trisha M. at January 7th, 2020 8:39 PM

@David Permisov
"Too many companies trying to drink at too few wells"

That view may have been a lot more true 2-4 years ago, but a lot of the talk I hear now is the opposite. Money is flowing. Lots of big money is starting to jump in. Besides Juvenescence there is Life Bio, Longevity Vision Fund, lots of tech VCs jumping in, there is big institutional money starting to dip its toes in the water through these and other channels, etc. Aubrey's recent talks count this big challenge as largely accomplished. A lot of people are saying the bottleneck now is not enough companies. That's why Juvenescence, Life Bio, Apollo, James Peyer, etc. are focused on company creation: finding promising lines of work and helping to turn them into companies.

So if you've got a promising line of work that could translate commercially or accelerate the pace of commercial progress as a service, definitely consider forming a company or getting help to do so.

Of course, NIH funding being too much late-stage clinical manifestation of age-related chronic diseases and not enough mid-age underpinnings (ie aging) is a bottleneck on how many promising lines of scientific research get pursued. And regulatory pathways still being indirect slows progress from what it could be if they were more direct. So those 2 are still challenges too.

Posted by: Karl Pfleger at January 7th, 2020 8:46 PM

Very good way to start the year! Many thanks to Michael Greve and Michael Antonov!

Posted by: Antonio at January 8th, 2020 1:32 AM

Reason, how many of the 7 sens categories do you see having early simple and cheap therapy option like D+Q in senolytics developed instead of gene therapies? What about glycosens?

Posted by: Walker at January 8th, 2020 3:59 AM

Thanks for the news, Reason. I'm happy they finally have some funding to do this important research.

Posted by: Quinn at January 8th, 2020 4:02 AM

It will be interesting to see the effects of a combination of glucosepane removal, senescent cell removal, oxidised LDL/7 keto cholesterol removal, thymus rejuvenation, LIfT's neutrophil cancer therapy plus other cancer immunotherapies, and epigenetic reprogramming of cells.

In the medium term it will be interesting to see the combined effects of the above with perhaps allotropic expression of mitochondrial genes, the removal and replacement of blood stem cells in the bone marrow, and lymph node rejuvenation or replacement.

And I'm wondering how soon all of this could be carried out in mice and dogs?

Posted by: jimofoz at January 8th, 2020 5:18 AM

@Karl Pfleger

Unfortunately, Juvenescence and Life Bio are not true investment funds, but are taking the "bio-conglomerate" model - a model that works well initially to raise a basket of funds (look at this great portfolio!), but then repeatedly runs into trouble due to the internal cannibalization of the lesser developed candidates that eventually occurs in later development

And as far as I'm aware, Longevity Vision Fund is still a concept that hasn't raised a penny

Posted by: David Permisov at January 8th, 2020 8:00 AM

I wish someone would create a "fan page" for Revel. How is this endeavor any less important than a sports team, and how are the scientists working on this any less important than the most accomplished pro athletes.

Reminder: This is the tech that will bring forth "90 is the new 50" as shown in the picture on the front page of mfoundation.org.

Posted by: Tom Schaefer at January 8th, 2020 8:05 AM

@Tom Schaefer: Maybe we could engage the prepper community in this. There are an estimated 3 million preppers in the US, some of them espending a lot of money on survivalism, and certainly they have a much bigger probability of dying from aging than from civilization collapse or natural disaster.

Posted by: Antonio at January 8th, 2020 8:41 AM

I would like to be able to invest in them through equity crowdfunding like MicroVentures for example if they only offered it.

Posted by: Corbin at January 8th, 2020 9:49 AM

@Antonio. Strange you would mention that. I'm a prepper - food storage, armed up, etc. etc. I wonder if the same personality traits regarding survival risk assessment on the tails of "likelihood" vs. "severity" are shared by other preppers.

Posted by: Tom Schaefer at January 8th, 2020 11:41 AM

Oh, what a surprise! Maybe linking both communities is easier than we think. I wonder whether Aubrey has already given presentations to prepper audiences and how they went.

Posted by: Antonio at January 8th, 2020 2:23 PM

Hi there! This is a great news. Just a 2 cents.

jimofoz,
I wonder too of the weigth of the effect of these multiple combinations of therapies; I have a good and bad feeling; but more good than bad. There will be some of them that will do something for sure. The good: Many of these therapies are about damage repair or junk clearance thus there should be improvements in health, nealrly 100% sure. On intrinsic aging, that is a bit more complex. And may require more than these therapies, yep all of them may Still not be enough to stop aging in entirety. I think it will have to be like a 'package deal' you get the whole thing - 'the clean up' and its Many therapies 'done once' per let's say 10 years or so..and then it'S done...kind of like your flu vaccine...you don't do it often; but you did it..once/long ago.

The bad: It may be redundant (for some), one therapy might be doing what another does or even Undoing it (already 'indirectly', not necessarily directly; but same result down the line - redundancy pathways). It may be 'negative' where it hinders another therapy (instead of helping it, we always think this combination Only brings positive, but sometimes it'S not the case because there are far more shades of gray (with aging) than simple yes/no. It's why many studies failed in the past because the 'expected result' was not so (was very much unexpected). Hopefully, they will test it all Together to make sure it blends well and causes no real 'stopping' in another therapy. All of the therapies have positives (damage repair someway..), let's hope they combine well to keep being positive.

Glucosepane removal will surely have a sizeable impact; mostly, cosmetically but also internally, as Reason said, with vasculature function/elasticity/ECM preservation. Which means more youth/younger looking - that's very important, because ECM is often correlated to the lifespan. For example, mouse accumulate pentosidine/AGEs (crosslink glucosepane) in an exact correlation to their speed of aging; in humans we accumulate AGEs/ALEs ten time less quickly than mice. A young, scaffold-organized, glucosepane-free/not just that whole AGEs free, much more collagen content...that is a sign a rejuvenation happening but it's just half-the-story.

Senescent cell removal: a direct health impact, for the most ill (first, 52% gain in progeria mouse, 16% in healthy mouse), healthy people won't get much out of that; except if they are very old/senescence burden high by oncogenes appearance and SASP inflammation all over.
But, surely, the appearance and youthfullness will improve even in healthy people; they will ahve a glow/skin will imrpove a little bit thanks to no senscentcells around. But the cosmetic effect will be mild. But on your Overall health, that will maintain it (if healthy already) or Seriously Improve it (if very ill or with progeria/accelerated aging type right now).

LDL/7-ketocholesterol: This is good news for me (being atherosclerosis stricken). 7 is now my favorite number (to be removed). Dramatic impact for people like me and others suffering of CVDs. Not just that, overall health improvements; cholesterol is Everywher in your body (down to mitos membrane for fluidity of them), and is needed, brain is rich in it. It's just the ratio that gets wack with age HDL:LDL..and the different deleterious signals they cause on immune system/macrophages if one takes over the other. 7-ketochol is a pernicious one, like 4-HNE or Acrolein; they cause havoc. Removing them will greatly improve these CVD disease. For heallthy people it will be maintaining health and never having what I had/have.

Thymus rejuvenation: Sizeable impact, immune system is crucial to longevity; thymus involution
is in inverse correlation to longevity (because immunosenescence/no more immune system); 115 year old woman with short telomeres in immune cells - she lived this long because she had her immune system. Thymus too, she kept it, did not involute/prune. The strongest therapy right now for it is darkness. Rat thymus grow 300% in darkness.

Cancer immuntherapy : you said it, immunity. No immunity, no protection; equals cancer. This should have happen a Long time ago already, I lost too many people to cancer...it's too late.

Epigenetic reprogramming: The Holy Grail or The Holy Bane; who knows; I wager it could be more the former but hopefully not the latter; it has the most potential because it can erase aging (not necesarrily the former lingering damages/junk of it though. But, as Ira, had pointed; it is capable of remorphing/morphodynamics of the body so it might remove a large % these damages though not entirely; mouse study showed that epigenetic reprogramming in them made them 'youther' but on maximum longevity it was almost null; except in progeria mouse (already fast aging); it seemed to be more a 'health improver/avg life' than max longevity extender). I wager (again) that we need to start this whole stuff very Young to gain benefit; older people we have to Rebuild/Reverse/Undo/Erase the Whole thing; that's a feat to defeat aging in seniors.

Stem cells might be a solution or an improver; but once aging ,stem cell injection for whole life in mouse gave 20% avg lifepsan extension..and we have to remember most Resultys in mice are much stronger..in humans it's weaker (because we are alaready optimized for extreme lifespan as 'outliers' in whole animals). Allotopic expression of mitochondrial genes holds great promise and might be the next best thing to nucleus tinkering; mitos are causal to max longevity (due to their ROS destroying DNA/DSB frags/telomeres shrinking DDR/epiclock advancement).
Replacement of blood stem cells would improve health/immunity; would do akin to mesenchymal stem cells replacement. Stem cells are not infaillible/they age (Except primordial ones in testicules/with telomerase)/lose telomeres; replacing them with new ones would allow to rebuild our tissues - but it may be not enough (as was shown in mice getting stem cells). It's why therapy combinations package deal is crucial to work. Same for lymph node rejuvenation, akin to thymus rejuvenation - immunity/no immunosenescence = 115 year old woman with great immune system. Not necessarily though, immunity is needed but just not that/there is still the 'aging proglem'/hayflick/epigenomic demethylation/replicative senescent... etc.

Finally, we have bacterial enzyme degradaion of glucosepane (it took way too long to happen/crosslinks should have been crosslinked-long while ago), let's hope the same for every AGE; and ALE too. Progress is fast but is illusion like mirage, it's slower (in reality, because of red tape and no funds/fund waisting for research for researching (instead of you know, building that glucosepan breaker. That moment they said : ''we have glucosepane sythethized, was joy and sorrow/joy because 1step closer...sorrow because...only 1 babystep closer..still a 100thousand more to do and only a 100 years to live).

Just a 2 cents.

Posted by: CANanonymity at January 8th, 2020 3:35 PM

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