Mois : octobre 2024

Life Biosciences is a company co-founded by the celebrity geroscientist David Sinclair and is based on his Harvard team’s research into partial cellular reprogramming. In the heated race to translate this promising technology to the clinic, Life has emerged as one of the favorites, inching closer towards clinical trials in humans. Life is counting on its proprietary reprogramming technology that uses only three out of four classic reprogramming factors and on its strong team of scientists and managers. We talked to Dr. Sharon Rosenzweig-Lipson, Life’s Chief Scientific Officer, about the company’s journey, delving deep into the technology and its future.

I’ll start by saying that Life Biosciences is one of the most exciting companies in the longevity field. You might actually become the first company to have a partial reprogramming-based therapy approved.

At Life Biosciences, we’re focused on something that matters to everyone: helping people stay healthier as they age. We’re working on what we call cellular rejuvenation technologies, basically finding ways to turn back the clock in cells and make them more youthful. I came on board as Chief Scientific Officer about a year and a half ago, but I actually got to know the company pretty well before that. I consulted for them for a year, which gave me a chance to look under the hood, see the science they were doing, and I got really excited about what I saw.

Tell me more about your background and your journey to Life Biosciences.

I’ve had an interesting journey getting here. My background starts with a PhD in behavioral neuroscience from Harvard’s psychology department. Then I did my postdoc at what was then American Cyanamid, though if you try to follow the corporate history, it’s like watching a bouncing ball. American Cyanamid was bought by American Home Products, which renamed itself Wyeth, which then got acquired by Pfizer. Through all those transitions, I was working in the neuroscience group, doing everything from early research all the way up to leading a team through a successful Phase 2 proof-of-concept study in schizophrenia.

By the time we got to the Pfizer acquisition, I was heading up the translational neuroscience group. I ended up making a “geographic decision” not to go to Pfizer and instead became the site head at our Princeton location while it was being shut down.

That’s when something unexpected happened – I fell into consulting, though I didn’t even know what consulting was or how to do it. I definitely didn’t know anything about networking. But I went to this conference and started chatting with friends and colleagues about what I jokingly called my “Pfizer paid vacation” – turns out that was networking! Before I knew it, I had several consulting opportunities, including at AgeneBio, where I spent 12 years working on mild cognitive impairment due to Alzheimer’s before coming to Life Biosciences.

So, how did Life Biosciences get to where it is now?

It all started with our focus on epigenetic reprogramming. You know Yamanaka’s work: he found these four transcription factors (Oct4, SOX2, KLF4, and c-Myc) that could take a mature cell and turn it all the way back into what we call a pluripotent stem cell. It was amazing science, but there was a catch: if you express these factors in a living organism for too long, you end up with teratomas, and the animals don’t survive.

Here’s where David Sinclair came in with a brilliant insight. He showed that if you use just three of those factors – Oct4, SOX2, and KLF4, or OSK as we call it – you could keep giving them for long periods safely. And the really cool part is that the cells keep their identity. A lung cell stays a lung cell, a heart cell stays a heart cell, and in our case, a retinal ganglion cell stays a retinal ganglion cell. When we saw the therapeutic benefits this could have, we knew we were onto something big.

Let me clarify this: you achieve partial reprogramming by eliminating one factor, not by intermittent expression. Expression is continuous, but it’s just three factors, correct?

Correct. That’s one of the things that makes our approach unique. We can give OSK continuously because leaving out that one factor means the cells don’t go all the way back to pluripotency.

Also, since c-Myc is an oncogene, eliminating it is a win-win.

Exactly. If you’re going to take one factor out, that’s definitely the one to remove.

The early studies showed us what was possible. The research team started looking at eye diseases: they looked at aging in the retina, at what happens when you crush the optic nerve, and at glaucoma models. What they found was remarkable. With OSK, they could reverse signs of aging, improving vision in older mice. They could show that the age-related DNA hypermethylation was getting reversed.

Then, when they tried it in the optic crush model, they saw actual nerve regeneration. When they moved on to the mouse glaucoma model, they saw improvements in something called a pattern electroretinogram – that’s where you flash an image on the mouse’s eye – plus better vision as measured by optomotor response.

All these results painted this amazing picture of meaningful improvement in retinal ganglion cell function. That’s what led us to focus on optic neuropathies, specifically the most common form of glaucoma, primary open-angle glaucoma (POAG), which is a chronic condition, and non-arteritic anterior ischemic optic neuropathy (NAION), which is acute.

NAION is a lesser-known but fascinating disease. Can you tell me more about it?

NAION is indeed fascinating – it’s like having a stroke in your eye. People can literally go to bed with normal vision and wake up the next morning having lost sight in one eye. What makes it even scarier is that if you get it in one eye, there’s a much higher chance you’ll get it in your other eye in the next five to seven years. You can imagine how terrifying that is – already having lost vision in one eye and living with the fear of losing it in your other eye too.

Both these conditions are diseases of aging and typically show up in people over 50 or 60. And vision loss isn’t just about not being able to see – it affects people’s whole lives. They often become depressed, start pulling away from social activities. When people can’t do their hobbies or regular activities anymore, they become isolated earlier than they should, and that has its own cascade of negative effects on their health. That’s why we think improving vision could have such a big impact on people’s overall health and quality of life.

Interestingly, recent findings show that GLP-1 agonists like semaglutide (Wegovy, Ozempic) can increase the risk of NAION in people younger than 50. A paper published in JAMA Ophthalmology over the summer showed a seven-fold increased risk in obese patients of developing NAION, and a four-fold increase in people with type 2 diabetes during the first year of treatment. The difference in risk might be due to dosing – people with type 2 diabetes are more often treated with Ozempic at a lower dose of semaglutide than Wegovy’s dose for obesity.

Do you understand the mechanisms behind this increased risk?

We’re investigating some of those mechanisms now. There are ideas related to blood pressure changes and other risk factors for NAION, but it’s too early to clearly identify the specific mechanism at work here.

What causes this type of glaucoma?

It’s an increase in intraocular pressure that ends up damaging retinal ganglion cells. When you go to the eye doctor here in the US, they do that test where they puff air into your eye – that’s checking your intraocular pressure. This lets them spot signs of glaucoma way before you’d go blind from it.

There are quite a few ways to treat it, all aimed at lowering that pressure in your eye. You might start with eye drops, or they might do laser surgery, or there’s this thing called MIGS – minimally invasive glaucoma surgery. But here’s the frustrating part: even after you’ve successfully lowered the pressure, the disease often keeps progressing anyway. That’s why we’re taking a different approach – we want to directly treat those damaged retinal ganglion cells, reverse the damage, and stop the disease from getting worse.

And at the cellular level, what’s actually happening? How do these cells get damaged?

Unfortunately, I can’t give you the full picture of how that increased pressure damages the ganglion cells. We know it’s affecting the optic nerve through pressure, but the exact chain of events at the cellular level – how we get from high pressure to cells degenerating – that’s still not entirely clear.

Your therapy can rejuvenate these cells and get them working again, correct?

Yes, and it’s quite remarkable. We can reverse the DNA hypermethylation state – basically making the aging retinal ganglion cell younger again. Let me give you a concrete example: in our optic nerve crush model, you can literally see where we crushed the nerve and no signal gets through. But after OSK treatment, you can watch those signals start moving along the axons of the retinal ganglion cell again.

We measure this with something called a pattern electroretinogram – we project an image onto the retina and measure how it responds. The response shows up as a curve, and we can measure its amplitude. With OSK treatment, we see that signal getting stronger.

The results in rats were quite impressive. What about your non-human primate studies?

I think the primate results were just as exciting. We could show these improvements in pattern electroretinogram signals with OSK treatment. Interestingly, we found correlations between how much initial damage the laser caused and what we saw at the end of the study in animals that didn’t get treatment. In the OSK-treated animals, that correlation just wasn’t there anymore. Basically, it didn’t matter how much initial damage they had, the treatment was limiting the damage in axons and improving the pattern electroretinogram signals.

Here’s the really exciting part: we can actually show that our treatment is getting exactly where it needs to go. We can see Oct4, SOX2, and KLF4 right there in the cells that handle the pattern electroretinogram response and in those dying axons. When you’re developing a treatment, getting it to the right place is half the battle, so this is really encouraging.

Some cells probably die because of the injury. So, when you apply the treatment, do you see both the rejuvenation of existing cells and some replacement of the ones that died?

What we’re doing is stopping that ongoing cascade of cell death. Think of it like this: you’ve got cells in different stages of trouble – some are just starting to have problems, others are further along that path. We can rescue the ones that are struggling but still hanging in there. But you’re right, once a cell is dead, it’s dead. There’s no bringing it back.

This is why NAION gives us such a good opportunity. We know these retinal ganglion cells keep degenerating for several months after the initial event, so we have this window of time to step in–we know exactly when it happened, so we can intervene quickly before too many cells have died off.

What seems to be happening is that some cells get hit hard and die quickly, while others are on this slower path to degeneration. It’s those cells that we think we can save. We’re seeing improvements in visual function in our non-human primates, and that’s what we’re hoping to replicate when we get to human trials.

Where exactly are you in the clinical trial process?

Right now, we’re wrapping up our Good Laboratory Practice (GLP) toxicology studies; those should be done in the first half of 2025. Once those are complete, we’re looking at starting clinical trials in the second half of 2025. We’ve got biodistribution studies running in parallel, too. You know how it is in this field – you never want to make absolute predictions, but everything’s moving along smoothly right now, and we’re feeling optimistic about where we’re headed.

Are you looking at other potential uses for your OSK technology?

We’re exploring other possibilities, though I can’t get into the specifics just yet. I can tell you why we started with the eye: it’s a perfect testing ground for this technology. The delivery system is straightforward – we know how to get the treatment where it needs to go. Plus, the eye has this great feature of being immune-privileged, so we don’t have to worry as much about inflammation. We still use steroids as a precaution, but it’s manageable.

For other applications, we’re working on figuring out the delivery systems. Each tissue type presents its own challenges, so we need to solve those puzzles one at a time.

The field of partial reprogramming is getting crowded – you’ve got players like Altos Labs and other well-funded companies. What’s your take on all this?

It’s actually encouraging. When you see other players moving in the same direction, it validates what you’re doing. We’re particularly excited about the potential to be among the first to actually test partial reprogramming in humans. And we think our approach with OSK gives us an edge – we don’t have to worry about the whole start-stop timing that you need with transient reprogramming.

What do you think about David Sinclair’s information theory of aging?

It lines up well with what we see in our work. David’s idea is that of having a backup copy. Think that aging isn’t a one-way street but something you can actually reverse. Even when you’ve accumulated all this damage, whether it’s DNA methylation or other types, that backup copy is still there. If you can clear away the damage, the cell remembers how to be young and healthy again.

Here’s how I think about it sometimes: it’s like a scratched record. Clear away those scratches, and suddenly, it plays perfectly again. Now, I’m not ready to get into all the molecular details of how that works beyond the DNA methylation piece, but the evidence supporting this model keeps growing.

I’ve noticed that you call yourselves a healthspan company rather than an anti-aging company. Some other companies, like Altos Labs, are even more extreme about that, they really push back against the anti-aging label. What’s the rationale behind this?

Here’s how we see it: we take what we know about aging biology and use it to tackle specific diseases of aging. This isn’t just semantics – it gives us a clear pathway through the regulatory process.

Extending life is great, but what we’re seeing now is people living longer but not necessarily better. You’ve got this extended period where people are alive but not healthy, and that’s what we want to change. At the end of the day, it’s about reducing suffering and helping people live better lives.

Speaking of the regulatory pathway, today, companies in this space have to focus on specific indications to get regulatory approval. Is this the best approach, or would you like to see regulatory changes?

It’s true that the FDA is set up to evaluate treatments for specific diseases. Aging itself isn’t considered a disease, and honestly, trying to change that perspective right now would be a tough sell. I think we might see changes down the road, especially if some of these anti-aging therapeutics start showing real results, but we’re not there yet.

Sure, it would be great if we could move things along faster when we’re seeing promising results. But the regulatory pathway exists for a reason – we need to prove these treatments are both safe and effective. If we start showing amazing results early on, it would be nice to have some flexibility to move more quickly, but that’s not our main focus right now.

Where do you see the whole longevity biotech field heading? Are there other approaches you find particularly interesting?

It’s an incredibly exciting time in this field. If you go to a meeting like ARDD, you see all these different approaches coming together – people working on inflammation, others focused on senescent cells, teams doing epigenetic reprogramming like us, and researchers looking at proteostasis. It’s like putting together pieces of a puzzle, and each piece has so much potential.

We’re obviously focused on our piece of that puzzle, but it’s fantastic to see all these different approaches moving forward. You never know where the next breakthrough might come from, or what direction Life Biosciences might explore next. We’re keeping our focus on what we’re doing now, but we’re always excited to see what everyone else in the field is accomplishing.

The way we see it, success for anyone in this field is good for everyone. We’re all working toward the same goal – helping people live healthier lives as they age. Right now, we’re just really excited about getting our treatment into the clinic and seeing if we can make a real difference in people’s lives.

In a world first, a pig kidney preserved at subzero temperatures was successfully transported across the Atlantic Ocean multiple times, demonstrating the potential for a novel technology to greatly extend organ storage and preservation, and make long-distance organ transportation a clinical reality.

Extending organ preservation time could bridge the organ supply-and-demand gap, avoid high-risk, time-critical emergency surgeries, and potentially achieve advanced genetic matching, ultimately leading to more transplants and saving more lives.

Dr. Gerald Brandacher led a surgical and research team that removed a kidney from a pig at the Johns Hopkins University School of Medicine in Baltimore, Maryland, and transported the kidney on a commercial aircraft to the Medical University of Innsbruck in Austria. Preserved for roughly 48 hours at subzero temperatures, the kidney was assessed in Innsbruck on a clinical-grade machine perfusion device and demonstrated viability and functionality.

The team repeated the process five times in the past 12 months with preservation times ranging from 48-72 hours. As proof of concept of the technology, the team performed a life-supporting transplant in a pig, with the kidney maintaining normal renal function during the entire observation period for 200 days post-transplant after 72 hours ice-free subzero preservation.

Dr. Brandacher is Professor of Translational and Experimental Transplant Surgery, Co-Director and Executive Vice Chair for Research of the Department of Visceral, Transplant, and Thoracic Surgery, and Scientific Director of the Daniel Swarovski Transplantation Research Laboratory at Medical University of Innsbruck. He is also a professor in the Departments of Surgery and Plastic and Reconstructive Surgery at the Johns Hopkins University School of Medicine and Scientific Director of the reconstructive transplantation program.

The kidneys were preserved in X-Therma’s XT-ViVo® solution in X-Therma’s TimeSeal® device. X-Therma is a biotechnology company developing a biopreservation platform for regenerative medicines and organs for transplant. Inspired by naturally occurring anti-freeze proteins found in Arctic species, XT-ViVo® is a non-toxic, serum- and protein-free organ preservation solution that uses peptoids to prevent damaging ice crystal formation, enabling ice-free preservation of organs between 0°C and -20°C. Therefore, the temperature is reduced, and time extends. With the ability to be carried on a commercial aircraft, TimeSeal® allows for precise monitoring of temperature, storage duration, and location without requiring external power, blood, or oxygen. In 2022, the U.S. Food and Drug Administration (FDA) granted Breakthrough Device status to XT-ViVo® and TimeSeal® for human kidney preservation up to 120 hours for transplant.

“By dismantling the traditional barriers of distance and time, our technology heralds a transformative era in organ transplantation, potentially making organs more accessible and saving more lives,” said Xiaoxi Wei, Ph.D., CEO and co-founder of X-Therma. “With recent legislation permitting organ transport in commercial aircraft cabins, X-Therma is at the forefront of flexible global sharing of organs, tissues, and cells, with pioneering technology that seamlessly integrates into existing peri-transplant workflows and ensures time is on our side.”

Since 1954, the gold standard for organ preservation has been static cold storage at 2-8°C using ice coolers, often leading to tissue and cell damage. X-Therma technology demonstrates incredible potential to overcome storage limitations with no additional steps and no additional perfusion instrument, blood, or oxygen. By extending preservation times beyond current standards—24 hours for kidneys, 4 hours for hearts—we could significantly enhance transplantation outcomes and open access to more transplants.

“The U.S. Department of Health and Human Services (HHS), in collaboration with the White House, has set an ambitious goal of 60,000 transplants in the United States by 2026, while we currently perform 27,000 kidney transplants yearly today. Extending the time that we can preserve an organ for transplantation is a game changer for the entire transplant community, with the potential to reduce costs, improve quality of life for transplant staff by scheduling surgeries during the normal workday, improve patient outcomes, and, someday, end the waiting list,” said Dr. David Mulligan, past president of UNOS/OPTN and Professor of Surgery at Yale University.

The results were presented to peers at several events, including by Dr. Brandacher on July 25, 2024, at the Society of Cryobiology’s 61st annual meeting in Bethesda, Maryland, and by Amanda Loftin, DVM, Ph.D. Candidate at the Johns Hopkins University School of Medicine<, on September 25, 2024, at The Transplantation Society in Istanbul. Dr. Loftin’s presentation was selected as one of the TSS meeting’s top four abstracts in the United States. The results have been validated through extensive pre-clinical studies in various organ systems.

About X-Therma Inc.

X-Therma Inc. (www.x-therma.com) is pioneering breakthrough cold chain technology via a convergent biopreservation platform, to advance regenerative medicine and make available safe and on-demand organs, engineered tissues, cell and gene therapies, vaccines, and beyond to patients in need. X-Therma is headquartered in Hercules, part of the San Francisco Bay Area. The company has an expanding presence in Austria, with parts of the TimeSeal® being developed and manufactured in Tyrol.

Contacts:

Media: Media@x-therma.com

Investor Relations: IR@x-therma.com

In Aging, researchers have described a subpopulation of fibroblasts that nurture ovarian cancer tumors and shield them from harm.

Cancer’s natural defenders

Ovarian cancer is particularly dangerous, both in death rates and in recurrence [1]. Normally, chemicals that contain platinum are effective, but this sort of cancer develops resistance to such treatments; after that, prognoses are usually very poor, even with modern drugs [2].

This cancer’s tumors, however, are not just made up of cancer cells: cancer-associated fibroblasts (CAFs) support its progression [3] and that of other cancers. These cells are in constant intercellular communication with the cancer, sending a steady stream of signals back and forth [4] and remodeling the extracellular matrix (ECM) around the tumor, which makes drug delivery uniquely difficult [5]. Even though the tumor microenvironment is highly inflammatory, which can be used to trigger immunotherapies [6], one particuar compound in these tumors, biglycan, impedes the effectiveness of such therapies [4].

CAFs are heterogenous, coming from multiple sources. Most of them began as resting fibroblasts, but others started out as muscle cells or structural cells of the blood vessels or other organs [7]. These cells do not even share the same differentiation, as some of them have stem cell origins [8].

Prior work has made efforts to describe these subpopulations of cells in order to more precisely target them [9]. Such categorizations include their origins, their development, their inflammatory status and antigens, and how they can be targeted in therapies.

dCAF is not good for you

After finding appropriate biomarkers for identification, this study divided fibroblasts into three of these categories: myofibroblastic (myCAFs), inflammatory (iCAFs), and desmoplastic (dCAFs), the last of which has been associated with poor prognoses. These three different types have very distinct clusters, both in gene expression and in physical distribution.

As expected, myCAFs express genes related to muscle function and iCAFs express inflammatory factors, while dCAFs express collagen-forming genes. While the iCAFs, as expected, communicated quite a bit, predominantly through their inflammatory factors, it was the dCAFs that communicated the most, using the ECM to do so.

Low-dCAF cancers were found to be far less dangerous than high-dCAF cancers. Genes associated with platinum resistance were much more upregulated in the high-dCAF group, and they showed signs of being resistant to multiple other drugs. As dCAF is correlated with collagen production, it is no surprise that the high-dCAF group’s tumors were richer in collagen, and therefore stiffer and tougher, than the low-dCAF group’s.

The researchers were able to use gene expression analysis to construct a prognostic test through a machine learning algorithm. Patients who had more dCAF genes expressed were, indeed, more likely to die of cancer under modern treatment conditions.

While this paper’s authors did not get into how dCAFs could be specifically targeted and eliminated, they hold that this is a promising therapeutic strategy. If these very particular cells are found to be vulnerable to a novel therapy, the prognosis of people with ovarian cancer or many other cancers may significantly improve.

Literature

[1] Siegel, R. L., Miller, K. D., Wagle, N. S., & Jemal, A. (2023). Cancer statistics, 2023. CA: a cancer journal for clinicians, 73(1), 17-48.

[2] Gaillard, S., Oaknin, A., Ray-Coquard, I., Vergote, I., Scambia, G., Colombo, N., … & Lorusso, D. (2021). Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: a multicenter, randomized, controlled, open-label phase 3 study (CORAIL). Gynecologic oncology, 163(2), 237-245.

[3] Rimal, R., Desai, P., Daware, R., Hosseinnejad, A., Prakash, J., Lammers, T., & Singh, S. (2022). Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting. Advanced drug delivery reviews, 189, 114504.

[4] Zheng, S., Liang, J. Y., Tang, Y., Xie, J., Zou, Y., Yang, A., … & Lin, Y. (2023). Dissecting the role of cancer‐associated fibroblast‐derived biglycan as a potential therapeutic target in immunotherapy resistance: A tumor bulk and single‐cell transcriptomic study. Clinical and Translational Medicine, 13(2), e1189.

[5] Guo, J., Zeng, H., & Chen, Y. (2020). Emerging nano drug delivery systems targeting cancer-associated fibroblasts for improved antitumor effect and tumor drug penetration. Molecular pharmaceutics, 17(4), 1028-1048.

[6] Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S., … & Fearon, D. T. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences, 110(50), 20212-20217.

[7] Huang, J., Tsang, W. Y., Li, Z. H., & Guan, X. Y. (2023). The origin, differentiation, and functions of cancer-associated fibroblasts in gastrointestinal cancer. Cellular and Molecular Gastroenterology and Hepatology.

[8] Kanzaki, R., & Pietras, K. (2020). Heterogeneity of cancer‐associated fibroblasts: opportunities for precision medicine. Cancer science, 111(8), 2708-2717.

[9] Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., … & Tuveson, D. A. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Journal of Experimental Medicine, 214(3), 579-596.