Bob Underwood, M.D. (Host): Welcome to Pediatric Frontlines from Shriners Children's, where we explore the best in pediatric care. I'm your host, Dr. Bob Underwood. With me is Dr. Farshid Guilak from Shiners Children's St. Louis. Join us as we talk about obesity and arthritis in children, and the link between the two. Dr. Guilak welcome. Thank you for being with us today.

Farshid Guilak, Ph.D.: Thank you for having me.

Host: Sure. So this is some complex but really interesting material. So what's some of the latest research findings linking pediatric obesity to the development of arthritis in children? And are there new drugs like say the GLP1 receptor agonists that impact obesity for children?

Farshid Guilak, Ph.D.: Well, that's a great question. I think as we're all aware, there's just been an epidemic of obesity, not just among our adult population, but among our children, and probably 20% of children are obese right now. The problem is that obesity leads to so many other conditions in children and in adults and in particular, we're finding that it's a major risk for arthritis.

Now, we generally don't think that children get arthritis, but in fact, they do get a lot of arthritis. We have various forms of arthritis such as juvenile arthritis, which is a autoimmune disease, an inflammatory disease, sort of like rheumatoid arthritis. But children get it, and believe it or not, a lot of children get osteoarthritis.

The major risk factors are joint injuries from sports, or accidents and obesity. So, the factors that affect many of the diseases in the body really derive from the inflammation that occurs with obesity and a lot of the underlying conditions that lead to obesity. So we've been very interested in trying to figure out, well, what is that link?

Why does obesity cause such an increase in the susceptibility for children to get arthritis and these many other diseases? And we've linked it to many factors. The obvious one that people have looked at, which turns out to be probably one of the least important ones is body weight. That yes, they do load their joints a little bit more, but it's not the wear and tear that's causing these problems because athletes will load their joints even more than obese people.

It's really the inflammation, and inflammation is a process that your body uses to fight certain conditions like infection, it helps repair wounds. But when it's unchecked or out of control, then it can lead to all sorts of problems. And this is the problem with obesity. It's turned out that it's a slow, chronic condition where we have just low grade inflammation throughout our entire body.

And this inflammation and the chemicals that drive it in our body are the same ones that cause arthritis. So they work together, particularly if there's an injury or other condition, to make our joints worse. And for children, this is very difficult because we don't have drugs that will really help them.

As you mentioned, there's been a, a huge wave of new drugs to treat obesity, Ozempic, and these other GLP1 agonists, and these are really diabetes drugs that are now being used to treat obesity. Well, they're not approved for children and they're not safe for children because they can cause growth problems.

They have a lot of side effects that we, we don't talk about quite as much yet, such as muscle loss, hair loss, bone loss. These are not things that you want your children to have at the developmental stage. It might be fine if you're our age and you want to lose a few pounds, but you don't want to do this to kids who are five to 18 years old who are overweight.

And the problem is once they're overweight at that age, they are really prone to being overweight the rest of their lives and being susceptible to all of these conditions, arthritis, diabetes, and many, many other conditions.

Host: So you mentioned inflammation caused by obesity, contributing to arthritis. How does that tie in to the mechanism in the gene therapy that you've been working on between Omega-6 and Omega-3 fatty acids? And why is this enzymatic pathway causing this and then how does the FAT1 gene, affect this role?

I know that's kind of a complicated multi-part question, but that's kinda your research area. We're very curious about that.

Farshid Guilak, Ph.D.: Yes, absolutely. So there's multiple mechanisms by which obesity causes inflammation. The earliest recognized one for systemic inflammation was that your fat just becomes inflamed. The reason is you start to get enlarged fat cells and then they get so big they don't get enough oxygen and nutrients, so they die.

And other cells, your immune cells go in to clean up the fat, but they just set up shop and they just continually make inflammatory molecules. So that's one mechanism. So another mechanism is what you mentioned, which is our actual diet. And things that we eat in our diet can be pro or anti-inflammatory.

And this can be sugars, for example, which are generally thought to be more pro-inflammatory. They feed the bacteria in your gut and cause inflammatory molecules to be made. But the fatty acids that we eat are one of the major drivers of inflammation or health, anti-inflammation in our bodies. And the problem with our diets is that we've really shifted from the diets that we evolved on, which were very high in Omega-3 fatty acids. When you think about them, they're the ones like nut oils like walnuts or particularly in fish. So salmons, seafood all have very high Omega-3 fatty acids, which are anti-inflammatory. And we've shifted to a very Omega-6 rich diet in our Western diet in particular.

So meats, fried oils, fried foods, seed oils have Omega-6 fatty acids. So as we evolved, our ratio of Omega-3 to Omega-6 probably used to be one-to-one. The Mediterranean diet is probably, three to one, five to one. And then our current western diet is probably closer to 20 to one Omega-6 to Omega-3 fatty acids.

And we think this drives a lot of the inflammation in the body, particularly for children who are on, oftentimes on not so healthy diets. Probably not getting a lot of fish or nuts in their diet. But they are getting fried foods and processed foods and this extra level of systemic inflammation, cooperates in a bad way with other factors like small injuries or major injuries in your joints to drive arthritis even further.

So we've tried studies where we supplement with Omega-3 fatty acids and that actually helps. So if nothing else, the one thing I recommend to people, and not being a physician, but a research doctor, I would still recommend taking Omega-3 fatty acid supplements at any age because it'll help shift the ratio.

But that shift is really small. It turns out by taking supplements, you can shift your, your ratio by a few percent, at most. So we decided this is a critical factor, and we started to look at ways to convert those bad fatty acids to good fatty acids. And we came across this gene. It's a piece of DNA that actually we as mammals don't even make. It's found in lower organisms like plants and certain types of worms.

But the gene is based on the same genetic code that we have. So if you put it in a mammal, it actually works. And this gene is called FAT1, and it is a desaturace. So what it does is it desaturates fatty acids from where they're saturated, which is that the 6th position. So it takes an Omega-6 fatty acid and converts it to an Omega-3 fatty acid, and basically takes your hamburger and fries effectively, as a fatty acid and converts it to salmon or fish oil in your body. So this gene is really amazing because all we have to do is get it into any cells of the body and it will function.

So we tried, first of all, with a very controlled study where we created mice that actually have this gene in every cell of their body, and it turns out they become super healthy. We can give them the worst fast food diet, which would make any other mouse really sick and diabetic, and they're incredibly healthy. They just convert those bad fatty acids to good fatty acids. And even though they still gain a lot of weight, because they're getting so many calories, they have much less metabolic disorders, they have much better cardiac health and they don't get arthritis, which was amazing to us.

Of course, we can't put those genes into ourselves easily. But we can put those genes into ourselves using a concept of gene therapy. So to do that, we can take a innocuous virus, something that doesn't replicate, it doesn't grow, it won't make you sick, but it can put that gene into cells anywhere in your body that you want.

We put it somewhere safe where it can process all the blood that goes through your liver, for example, and then it converts those Omega-6 fatty acids directly to Omega-3 fatty acids. And we did this again in mice. Because we, we need to test all of these procedures for safety and efficacy, way before we go into humans.

And what we found was that it was incredibly effective. That we could just, with one injection, we could get these mice to be as healthy as a normal diet, but by when they're under a very high fat diet with very rich and Omega-6 fatty acids, we were able to keep them completely healthy. So this really gives us the opportunity to think, well, of course we want to control people's diets and we would much rather have people eating healthy. But we also know how complicated that is from a socioeconomic standpoint. That there are places in the world, where you can't get Omega-3 fatty acids, that your diets are almost all, if you have fatty acids they're the unhealthy kind.

They're either saturated fats or they're these very inflammatory fats. And even in our US society, it's very difficult for cost reasons and accessibility to get people the fatty acids that are healthy. So this is with one injection that could last two years, maybe longer, you can get this conversion and this significant increase in metabolic health, reduced arthritis, and reduced diabetes among other factors.

Host: So that would be alongside diet, or even as an alternative too, because you kind of talked about the socioeconomic impacts, having dietary availability, as being a factor where this might be used. Is there an age that's optimal or a developmental window that's optimal in pediatric patients where this might be important to use to prevent or impact long-term complications in kids?

Farshid Guilak, Ph.D.: Well, that's a great question. We don't have the complete answer to it, but the more we look, the earlier we see these changes to the point that we've actually seen effects passed down from parents to their children before they're born. So this is a really interesting and new concept is that the parental diet, particularly the maternal diet, can get imprinted onto the

fetus and to onto children through epigenetic means. This means not the sequence of the DNA, but sort of the way the DNA is folded and read, and that can be passed down from generation to generation, so even beyond one or two generations. So this concept is mind blowing. What your grandparents ate can affect your health.

It's passed down that far through generations. So we think that one of the reasons we have such an obesity epidemic, is that these effects are just passed down and they're accumulating over generations. We have not just one generation of bad diets, but two or three generations, and once they're imprinted on your DNA, we need to get rid of them somehow.

So we're trying to figure out if this procedure, if this desaturace will actually help do that, to help reverse some of those changes so we can break that cycle. So the question you posed is really important. How early do we need to intervene? And we're doing some studies now to see, do we need to intervene with the parents and particularly the mother during pregnancy to prevent these changes going to children when they're born?

Host: Yeah, that's fascinating. So the therapy also appears to improve other metabolic markers, insulin sensitivity, fat metabolism, and reduce inflammation. So can you delve into these systemic changes and why they interconnect with joint health?

Farshid Guilak, Ph.D.: Yes, absolutely. So it turns out a lot of our inflammatory pathways in the body, which are, again, they're a natural response. We need them to fight infections. We need them to fight cancer. We need them to heal wounds, so we can't block them completely. And this is the problem with some strong anti-inflammatory drugs.

They suppress your immune system and make you sicker, so we need to modulate them properly. Well, it turns out a lot of these pathways are common. So the same molecular chemicals that control inflammation, they're generally called cytokines as the name of the chemicals that in your body that control inflammation.

They're the same ones that have been implicated in arthritis. So if you have the right levels of them, everything's fine. If you have too much of them, that's when you start to get joint problems and different forms of arthritis will show up in different parts of your body. So, for example, juvenile arthritis could show up in your eyes, in multiple joints.

Osteoarthritis usually shows up in one joint or another at a time. When you're older, it can show up in your hands. So the manifestation or the site where the, inflammation shows up is very much dependent on the disease, but the underlying cytokines or biochemicals are very common, and because of that, they affect a lot of diseases.

So the same cytokines will attack your pancreas that makes insulin, and if you kill the pancreatic islet cells in your pancreas due to inflammation, then you can get Type 1 diabetes and the same cytokines can lead to cardiac conditions and thrombosis or blood clotting, and the same ones can accelerate cancer.

So it's a lot of common pathways that are derived from these inflammatory conditions of either obesity itself or an obesity inducing diet, which is of course very high in saturated fats, sugars, or Omega-6 fatty acids.

Host: So what do you think are the next steps in translating this gene therapy from animal models to human clinical trials? What obstacles do we need to overcome to get it into that next phase of research?

Farshid Guilak, Ph.D.: So we're in that process right now and really the main obstacles which we're tackling are showing that it's safe. And the kind of gene therapy that we're using has been shown to be fairly safe in a number of different conditions. It's a virus called AAV, Adeno Associated Virus, which is a virus that doesn't really infect humans.

It infects adenovirus, which is a common cold virus. So it's a virus of a virus. So it's generally been assumed to be safe for people, but of course we don't want to do anything particularly in children until we've gone through all of the proper safety tests, things such as toxicity and making sure the dosing is right and so on.

So we're running a number of studies now, testing it again in animals first, which is the only way to really assure that we have some level of safety. And then if all goes well, we hope to proceed to a clinical study or a clinical trial in the next two to three years to show that it actually functions the way it should and we're at the right dose that would help in a human study.

Host: Fascinating subject and just amazing the amount of research that you've been able to do and the findings that you've been able to come up with. Anything else that we'd like to bring up? Any other topics or kind of next steps in this exciting research?

Farshid Guilak, Ph.D.: No, this is really it. And as we discussed before, our ideal solution would not be to go to this level of gene therapy. We would love it if kids had healthy diets and they weren't sedentary and they exercise and they had access to all the things they need to, and they could even control their omega rich diets through their diet.

But in the absence of being able to do that again from a socioeconomic standpoint where those healthy foods are so much more expensive than fast foods, they're, fast foods are so much more accessible; we have to come up with other solutions. And the sooner we break that cycle really early on, the better the health span of our kids will be in, in our Shriner System.

Host: Awesome. And to our audience for more information including the full range of care disciplines, please visit shrinerschildrens.org. To hear more Pediatric Frontlines episodes, please subscribe wherever you listen to podcasts.