So, I would like to thank Vanda and the panel for the invite, and again, some of the questions that came up at the end of the session here can be answered partially with what I'm going to present here. So, how do I advance this? Oh, with the center button. Okay. Okay. So, before I go there, so, first of all, I would like to say that a lot of the science I'm doing, you know, has been funded by the NIH and the Department of Defense, and also all those people in the bottom of the slide here are people that has been contributing to the work, you know, by giving gifts. I'm having a hard time with this. Hold on. It's there. Just click it, not roll it. Okay. Mm-hmm. So, again, I think our regenerative medicine program, you know, has four pillars of research. The first one is biologics, where we use a lot of adult stem cells. Second pillar is regenerative medicine, you know, approach, where we do gene therapy, CRISPR-Cas9 gene editing. The third pillar is therapeutics, and this is where, you know, we're trying to use drugs and supplements to try to deal with aging-related disease. And, finally, the animal modeling, everything that has to be tested in animal model before it goes to the patient, as you know. So, osteoarthritis, I don't have to tell you, you know, this is the biggest problem we have in orthopedic surgery, and clearly, you know, we don't have a lot of options to those patients. And, again, it's not only older people, but sometimes you have PTOA, which is young patients. So, what we know now is, you know, when you develop osteoarthritis, we have a reduction in the chondrocyte ability to repair your articular cartilage, and that contributes to the OA. But what has become very clear is that, you know, when your chondrocytes, you know, lose their ability to repair cartilage, at the same time, you have an increase of cellular senescence in your knee joint. And we believe that, you know, cellular senescence plays a role in osteoarthritis. So, what are cellular senescence? Again, this is cells that become senescent, and what they do, they release a lot of inflammatory mediators, and they drive, basically, disease, aging-related disease. So, now we know that, you know, those cells are directly implicated in cancer, cardiovascular disease, neurodegeneration, and, more recently, osteoarthritis. So, those cells play a role in those diseases. And why we're so excited about this? Because now we have drugs and supplements that can kill them or eliminate them specifically. And those drugs now are being used, you know, to try to deal with aging-related disease. So, this is all a disease that we think senescent cells play a role, where senolytic drugs may be able to alleviate some of the symptoms here. And, of course, you know, what I'm going to be talking about today is really osteoarthritis. So, the work from Jim Kirkland at Mayo Clinic has shown clearly that if you take senescent cells from a whole mice and you inject them into the knee joint of a young mice, you develop osteoarthritis, showing clearly that those cells play a key role in the development of osteoarthritis. So, us, in our team, we have used an animal model that develops osteoarthritis. And, as you can see in those slides, those mice of Progeria, they age very fast. But you can see those black arrows here showing that those mice develop osteoarthritis like you and me, without having to injure their ACL or their meniscus. They basically develop osteoarthritis. And what we have known now for many years, that those mice contain a lot of senescent cells in their peripheral blood, bone marrow, muscle, and so forth. So, we think that senescent cells play a role in the development of OA in this animal model. And what we ask is, well, can we use senolytic drugs to try to delay OA? Here, we're not trying to repair cartilage. We're trying to delay cartilage degeneration. And, here's the results. Some of those mice were treated with senolytic drugs. We put this in their drinking water. So, here is the mice that has not been treated. And you can see, you know, the red arrow here. They're losing cartilage during the aging process. And the P16 is a marker for senescent cells. So, you can see a lot of senescent cells at the surface of the articular cartilage. But when you treat those mice, you know, basically with senolytic drugs, you don't see this degeneration of articular cartilage. And on the bottom here, you see a significant reduction in senescent cells into their articular cartilage. And here, I didn't even use a drug. I used a natural supplement that you can buy on GNC or Amazon. I'm not holding any stock to those companies, as you know. But the bottom line is, this thing seems to be very, you know, successful. And because of that, so we have a Department of Defense-funded clinical trials where we're treating patients with mid-OA. Some of them got the Fisetin, and the other group got the placebo. And the goal is to try to see if we can delay osteoarthritis in this population, you know, over a period of 18 months. So now, we have a lot of projects in the lab where we're trying to reduce senescent cells in animal models, and we're trying to do this in patients as well. And here, this is, you know, four or five clinical trials that we're doing right now to try to use those senolytic drugs to try to delay osteoarthritis after ECL or, you know, after, you know, just, you know, osteoarthritis. And you can see that we have projects on the knee, but also on the hip. But one thing was clear to us is, you know, it's nice to have drugs that can eliminate those senescent cells, but how many senescent cells do you have? So this is what we did next. We developed a test in our lab where I take your peripheral blood, and I can tell you how many senescent cells you have in your blood, and I can tell you how you compare with your age group. And after you take Pfizer, then we can see a reduction. As you can see here, we have over 350 participants in this group at different age, and they are split between men and women here, as you can see. But the message to take home here is the older you get, the more senescent cells you have in your peripheral blood. And we found that those cells, you know, are mainly T cells that become senescent in your blood. But the exciting thing is, if you start to take Pfizer in 100 mg per day, we see a sharp decrease in the number of senescent cells in your peripheral blood. Not only the senescent cells decrease, but the SASP, which is the inflammatory mediator that those senescent cells release, all decrease also in the blood of those patients. So now, you know, we said, well, do we have more senescent cells in OA patients versus normal patients? So what we did here, we used, you know, 30 LT patients, 30 OA patients. And as you can see here, you know, in the peripheral blood of those OA patients, they have more senescent cells than in the control group age match, clearly showing that the cells, when they increase in your blood, they correlate with aging-related disease. And here we're talking about osteoarthritis. So again, I just would like to finish that, you know, in the team that we're doing, we have, like, you know, eight current studies funded by the NIH where we're developing the new biologics for orthopedic surgery. And I just would like to say that, you know, when the biologics are safe and can be used, so we do clinical trials, double-blind clinical trials with a placebo group. And if we prove through those clinical trials that the senolytic drugs or other, like, Losartan and Cozart play a role, then it goes to the clinic, and now we call this evidence-based treatment. So this is really what we have developed here in Vail, Colorado. So this is a team. Again, you know, I want to thank Mark Philippon, who has been, you know, the person who recruited me in Vail. All the people around the slide here are scientists that work with us to try to develop new treatment for OA. But again, I think we are basically surrounded by a group of orthopedic surgeons that are so excited about these technologies, and they're ready to help their patient by using those treatment. And, of course, you know, we have, you know, all the clinical fellows, international fellows coming from around the world coming to train with us, and we use them as a bridge between the scientists and the surgeon. And I just would like to say that even if I'm middle of—we are in Vail, Colorado. This is not a big institution, so we are very well connected with a lot of institutions around the country here, and the work that I present is mainly done with Jim Kirkland at Mayo Clinic. So thank you very much for your attention. Thank you.

regenerative medicine

osteoarthritis

chondrocyte

cellular senescence

senolytic drugs