What are the possibilities for gene therapy for the treatment of dementia or even to slow or reverse aging? Let’s find out as we review the field and take a look at a new publication from one of the experts in the area.
Patrick Sewell MD currently has an international medical practice specializing in regenerative medicine, gene therapy, stem cell therapy, and innovative cancer therapies. His background includes over 20 years of cancer research, including development of minimally invasive treatment and stem cell procedures. Dr Sewell’s training includes internal medicine, Diagnostic Radiology, and Interventional Radiology. He received his MD and residency from Louisiana State University School of Medicine. He completed fellowships at University of Mississippi Medical Center where he later joined the faculty.
Robert Lufkin 0:01
Welcome back to the health longevity Secret show and I’m your host, Dr. Robert Lufkin. What are the possibilities for gene therapy for the treatment of dementia, or even to slow or reverse aging? Let’s find out as we review the field and take a look at a new publication from one of the experts in this area. Patrick Sewell, MD, currently has an international medical practice specializing in regenerative medicine, gene therapy, stem cell therapy and innovative cancer therapies. His background includes over 20 years of cancer research, including development of minimally invasive treatment and stem cell procedures. Dr. shuls training includes internal medicine, diagnostic radiology, and interventional radiology. He received his MD and residency from Louisiana State University School of Medicine, he completed fellowships at the University of Mississippi Medical Center where he later joined the faculty. Now, please enjoy this interview with Patrick Sewell and D. Hey, Patrick, welcome to the show. Thanks,
Patrick Sewell Jr 1:13
Rob. Hey, it’s
Robert Lufkin 1:14
so so great to have you here. I can’t wait to dive into the latest news on gene transfer therapy and you know, how you’re applying it to Alzheimer’s and even maybe longevity. But But before we before we talk about that, I’d love to hear from you how you got interested in such a fascinating area?
Patrick Sewell Jr 1:38
Well, it started you know, actually looked back in my in my career, and I can see a link between my work and how I ended up here. And I started in March, after I finished my training, I was concentrating on cancer. And I was really focused on cancer because I was dissatisfied with the treatments that were available. Um, and so I embarked down the path of connecting imaging and surgery. And it’s basically minimally invasive image guided surgery. And so I pursued these technologies, about how to reach parts of the body with imaging and how to destroy tissue. And I had to get into the immune system. When I was really started getting into certain cancers, topics, and the immune system led me to stem cells and regenerative biology. And that led me to gene therapy. Ah, so to me, there was a direct link, although it spanned about 20 years. And so, probably about seven years ago, I really started shying away from focusing on cancer, and focusing on modulating the immune system. And really looking at gene therapy as a way to treat the immune system. And that got me into current diseases that people were addressing the gene therapy, and there and that got me into dementia. And hence the the our program. So you know, I say dementia, not specifically Alzheimer’s, because I’m the Group of neurodegenerative diseases that Alzheimer’s is a part of. There’s Frontotemporal dementia. There’s vascular dementia, but I was looking at a commonality that dealt with the immune system in genes and gene therapy. So that’s, that’s how I ended up here.
Robert Lufkin 3:56
Oh, right. Yeah, that’s great. Great. And this is such a, such an exciting area. So much has happened with gene therapy in the last few years. And now we’re even seeing it applied to humans. So we’ll hear about later, I guess. But before we dive into that, maybe take a moment and just what what exactly is gene transfer therapy? What’s the idea there that you’re doing?
Patrick Sewell Jr 4:21
So to understand gene transfer therapy, you have to look at the topic of gene therapy. We all you know, everybody knows we have chromosomes with genes on it. And some of the genes can be faulty genes gene, some genes are active and some are inactive. So many, many for a long time, it’s been postulated that it was hoped that we could repair a gene. Well along the way, scientists discovered and realized and developed ways to add gene cells not replace. Now we do have the ability to remove and replace genes. And that’s the most sophisticated type of gene therapy. And most people know that as CRISPR. There’s another one, two or three other enzymatic ways to remove genes and add genes to the DNA. gene transfer therapy is a simpler method. And it has some caveats that are particularly appealing to where we are right now. And our limitations of replacing of adding genes. So the crisper is basically considered a permanent change. And I’m not ready to permanently change somebody’s DNA until I know, everything there is to know about it, which takes 1520 years of size to really get a good volume of knowledge about it about a medical development. So a lesser step is gene transfer technology. And that’s where we give a copy of the gene to the cell, we leave the defective gene alone, or we leave the gene that’s turned off alone. But we give an exact copy. It’s a human gene made in a lab, and we give it to the cell and it does just what the defective gene is. So let’s say you have a gene that you need to you need to make it needs to make calcium and you’re not making enough calcium. If I give you an extra gene, it’s like turbo charging your engine, it produces little more. So the extra gene can produce make up the the deficit of your the gene you inherited. Now, why is that a big deal? Why not just replace it? The permanent change has implications is passed on to your offspring. And let’s say you don’t say there’s some unforeseen things that gene does, and you’ve made the permanent change, you can’t undo it. The gene transfer has some built in safety, it’s not passed on to your offspring. So if you’re say it’s a 28 year old person, and they have muscular dystrophy, and we’re treating them muscular dystrophy, and we do the therapy, and 20 years later, we found out there’s an issue, and they’ve had children then that you can see the problem. So right now, if we did gene transfer, I mean, sorry, if we did a CRISPR that way, but if we did a gene transfer, it’s kind of temporary. When a main temporary, when the cell reproduces, it duplicates the gene that I replaced doesn’t get copied, because it’s not part of your nuclear DNA, it’s not true chromosome. So in certain tissues, well, in all tissues, he gets diluted over time. Um, and that can be a good thing or bad thing in the brain is not bad, because there’s very little turnover of neurons that you, you have most your neurons, you can make neurons, new neurons, but most of the neurons you have, are there for your life. Um, so but in other parts of the body, the turnover rate, like in the skin, or the mucous membrane in your mouth would be several days later, that’d be a disadvantage. Um, so gene transfer therapy is where we are right now, for the for those reasons I discussed. Um, to get into some specifics about it, we take a virus, and we take some of the DNA out of the virus, and we insert the genes that we want to give the patient
with a case of dementia we experiment we did, we gave H turret and Klotho. And we grow that virus in the lab. And then when we get a sufficient number of viral particles that represents the the dose, we administer that to the patient, and the virus delivers the genes for us, just like viruses normally do when we inject the virus, it behaves like a virus always does, it goes to the cell latches on and injects its cargo, normally is cargo is its own genes. But with recovery, we’ve removed that and replaced it with the genes we want. It delivers our genes. So it’s like a UPS truck that we filled a cargo space, we remove the cargo that the gene that the virus had, and we put in our cargo. Now, that’s the whole function of the virus, and then the virus goes away gets consumed by the body, but it’s delivered the product after that is normal cellular processes that take over and the gene that was delivered is is through a variety of cellular mechanisms incorporated into the cell and ultimately into the nucleus next to your chromosome and it starts producing the product that we want. So that’s gene transfer. We transfer For a copy of your gene to your nucleus, next to your chromosome not weaved into your chromosome.
Robert Lufkin 10:08
I see. So the the transfer is. So it’s not reproduced when the cell reproduces, right, because it’s not part of the chromosome been
Patrick Sewell Jr 10:18
updated. So critical distinction. At some point, we will want that. But, you know, to put in terms of the pharmaceutical industry, the work I’m doing right now is equivalent to a phase one trial. It’s about safety. And, you know, it’s, it’s what I, what I really have specialized in is translational medicine, laboratory work translated into humans, that stage right there, but the step from mice, to humans, dogs to humans, whatever. That’s phase one stuff. So if I was developing a drug, you do it in the lab, and you test it on sales and animals. And then that first phase one trial is the translation or translational medicine step from lab to to clinic. And so that’s where we are right now. Um, and safety is an issue. Phase two is the largest study and phase three is really about how well it works. But along the way, you get data on all that. So gene transfer therapy is an excellent translational medical tool to investigate genetic therapy.
Robert Lufkin 11:32
And the idea of incorporating extra copies of the gene in the in the in the body to accomplish some some task. It we really have models for it, I’m reminded of the, that elephant famously, is an animal that that gets little or no cancer in their in their lifetime, unlike other mammals. And we read people recently found out that the P 53. Gene that that protects to some extent against cancer, which humans have one copy of elephants have 20 copies of that gene sign. Yeah, so it’s almost like, that’s the idea, we just put extra copies of whatever gene we want to produce more proteins from or have the effect of is that right?
Patrick Sewell Jr 12:22
That’s true. And that brings up a good caveat about translational medicine. Animals and humans are mammals, non human, animals, and human animals are different. And so it’s some sharks and elephants don’t get cancer. There are some animals did get a lot of cancer, and we use those to study in the lab. And, and but it also illustrates that what was true for a nonhuman animal may or may not be true for human animal. So that explains why many successful we hear about all these wonderful experiments where they cured cancer in this mouse, or they did this experiment, and it treated this disease successfully. It didn’t pan out in humans. And that’s why this step is so critical, this translational step to humans, is that is where we really start finding out was that our laboratory work that was so successful in that project animals isn’t going to work in us. You know, our chromosomes are very similar between species between mammals, but the expression of them, the enzymatic levels are quite different. I can give you lots of examples of mice, we can do all sorts of great stuff with mice, they’ve done work in people, and it has to do not with their genes, but with their expression of their genes. So the epigenetic stuff, which genes are turned on, and then the enzymatic functions after that, so it gets kind of complicated, but yeah, you’re you’re rattling on about the the difference in in jeans and an expression
Robert Lufkin 14:03
and before we get into the the particular work you’re doing because I want to review your your exciting paper that just came out but before we do that, and maybe you could sort of cover the landscape about some of the the other work that’s been done up to this point in gene transfer therapy for for dementia, some of the other interesting studies.
Patrick Sewell Jr 14:30
You know, I’m I’ll see what I can remember there’s been several over the last decade. Um, you know, they, the some of the topics that people might be familiar with are Apo E. BDNF brain, that brain
Robert Lufkin 14:48
drain of neuro chocolate neurotrophic factor, yeah.
Patrick Sewell Jr 14:51
amyloid beta, tau protein, oxidative stress, inflammation. These are All mitochondria hypo metabolism. Um so basically, there are a number of proteins, enzymes, structural abnormalities in the brain that are have been implicated, and even genes that have been implicated in and Alzheimer’s disease. And what that told me was that Alzheimer’s is a very complex system failure. And I’ll get to that, that led to me to the gene therapy for dementia, not specifically Alzheimer’s, um, it would take me a while to go through all the various all the different studies and I don’t remember off the top of my head, but suffice it to say, for about 10 Or maybe 15 years, there has actually been work done. And with gene therapy as far back as 2011, if I remember the most recent one I looked at with gene therapy for dementia, and for Alzheimer’s, and other neurodegenerative diseases like Parkinson’s etc. And they haven’t panned out, they look great in the lab. They look great in animals, but they don’t they hadn’t worked in humans. So it’s been an excitement and and letdown, excitement and letdown, um, the the take home message is Alzheimer’s itself is complex, and it’s a multi system problem. But, but outside that dementia, which includes vascular dementia, Frontotemporal dementia, and either other dementias is just as complex, more complex. But there’s some commonalities. And so there’s uniqueness to each disease, but the commonalities is what got my interest. And so that’s what we ended up focusing on, um, the failures of those other gene therapies were critical, and teaching us that it’s not a simple process to treat this disease, you know, as you know, from your other guests, nutrition, lifestyle. Everything, how much sleep you get, there’s a number of factors that affect your, your, the how bad your your dementia is, whether you’ll get dementia, and they’re not all genetic, they’re not biological, they are environmental. They are experiential, how you live your life, even how you think people believe, ah, your mood if you have, you know, depression or not depression, or positive thinking you never thinking. So I don’t get into all that, because there’s so many good people studying that, but they are so concentrated on the system problem of dementia. Now, what I do want to say is, the other thing that I realized is longevity, aging, disease and Aging. Aging is a system failure, a progressive system failure and your body. And Alzheimer’s and dementia are are similar to brain aging. It’s just that the disease Alzheimer’s or other dementias happens faster memory, we all have memory loss, decreased ability to concentrate our sleep is disturbed as we get older. If you think about it, the the problems that we that dementia patients suffer from we all suffer from to a lesser degree as we age, but as we age it the problem those problems get greater. So I think of dementia is things gone aging gone crazy in the brain, and it’s accelerated the the brain aging. Now that’s a real simplification, but it’s a mindset. It’s a it’s kind of a thought process I have because I think they’re really they all related. I don’t think they’re related. System declines and aging of the brain and dementia system. The problems of dementia are parallel and similar. Not identical, but there’s a lot of crossover.
Robert Lufkin 19:27
Yeah, absolutely. I mean, the single the single greatest risk factor for for Alzheimer’s and other dementia is age, you know more than anything else and also for heart attack, stroke, cancer. So yeah, all these things are tied together with longevity. One thing I wanted to underscore too, and maybe just summarize what you said too, about the past work was that others other groups have taken taken genes and proteins you mentioned AP two I think and they put one group put that in and then BDNF brain derived neurotrophic factor and put that in and they picked a few other ones and, you know, they’ve tried different gene transfer experiments. And so far, you know, not not much results. So that’s why it’s it’s so exciting to talk about. Talk about your your study here. And maybe first, let’s talk about the genes that that and the proteins that that you selected that other people haven’t used necessarily for this yet. And why did you select those and what are they?
Patrick Sewell Jr 20:38
Well, so like the Apo E and the BDNF? Those are, those are like the people who suffer from aberrations of Apo E is a subset of the dementia group. The BDNF is a subset of the dementia group. And so they might respond. But that does it address the other 90%. You know, it’s those. So those are outliers in Alzheimer’s, um, and there’s a and the rest of the group and Alzheimer’s is is presumed to be due to the alphabet, an amyloid beta protein is toxic, and the tau protein is toxic. So everybody who has Alzheimer’s has problems with amyloid beta, and, or in dementia, and tau protein. So those appear to be bigger problems. And a lot of people have chased down those even though recent pharmaceutical company that drug approved this year for the amyloid beta. Supposedly it’s think it’s a monoclonal antibody, and it binds to them or beta protein, protein, and the body the immune system, then removed the monoclonal antibody and amyloid beta goes with it. The the trouble and the distaste for that drug in the medical community is that it hasn’t shown any improvement in the patient’s symptoms. So if I say I can give you a cheeseburger in or reduce your amyloid beta program, amyloid beta build up, but it doesn’t make any better. Is that is that is that progress? You know? So I looked at, I looked at two genes that seemed to be involved, that I’ve that through a variety of experiments done by people over the last 10 years, that seemed to be involved in not only all of the dimensions but also brain aging. And it particularly interested me, it’s like, everybody with diabetes has trouble with insulin, you know, but not, but there’s different types of diabetes. And sometimes it’s not enough insulin, sometimes insulin is not effective, sometimes the immune system is attacking the pancreas and reducing the insulin produced. So the but the commonality was insulin problem. So with with dementia, I looked at h tered, which is a gene that makes telomerase and Klotho, which is a gene that makes a protein called Klotho. It makes several proteins Klotho alpha beta, but the Alpha One is particular for the brain. Um, and the reason and interested me is because an H turret will be familiar to a lot of people because it makes an enzyme telomerase which lengthens your telomeres. So there’s a lot of discussion papers talk on telomerase and anti aging and all the tissues, certainly the brain Klotho their’s is particularly interesting, because it’s very important to the brain and very important to kidney and mentally important everywhere else. So what caught my attention was the two together. There was some few papers that suggested they were synergistic, and they needed to be associated with one another, to do the best job they could. But more importantly, all the patients with the problems they addressed, which was the buildup of the amyloid protein that the tau protein, the opposite increased oxidative stress on the cells mitochondrial dysfunction microglia function, which is like your garbage truck system of your brain, I mean, it’s in your spinal cord too, but it’s in your neurological system. These to proteins from these genes seemed to be important for maintaining those when Klotho dropped. And when he dropped in neurological tissues and brain tissue, the symptoms of brain aging and symptoms of dementia increased and it stemmed proportional. So are we pursued that ah, those two is a treatment for is as a treatment for the cysts Same problem in dementia, it doesn’t address I knew it wouldn’t address a specific dementia. And I knew it wouldn’t cure a specific dementia but postulated that it would improve some of the symptoms of dementia, maybe restore their memory, maybe restore the personality to a degree, etc. So that’s why we chose those because it had multiple, multiple enzymatic effects targeting multiple pathologies that were high targets, the highest suspected pathologies, um, and so that’s where we came up with Klotho in aged care. So it’s almost
Robert Lufkin 25:37
like like you say Klotho and H turret.
Robert Lufkin 25:42
H turret human telomerase reverse transcriptase is our systemic systemic approaches. Whereas to all of all of the diseases and even even rolling back aging almost a little bit for longevity, whereas doing a pulley to transfer copies is only going to benefit people, potentially with a bowI for alleles there and BDNF may target a subset of dementia patients maybe with hippocampal atrophy or something like that. But hcrt and close though,
Robert Lufkin 26:23
are wide systemic, and rolling back longevity, which would benefit which will benefit dementia and and all sorts of chronic disease. That’s very, very exciting. Yeah. So yeah,
Patrick Sewell Jr 26:37
potentially. Multiple Sclerosis, Parkinson’s disease, ALS, these two enzymes, these two genes and the products they produce are implicated in all of the neurodegenerative diseases. Now, we haven’t pursued those. But But I hope somebody does. And we may we have to finish up the dementia, where does this go with dementia? But But you’re right, these are, these are global systems, that decline in everybody. And they particularly decline with the dementias. So that’s why they were so attractive, and they’re not so selectively targeted at the subsets. They’re a global problem, global metabolic problem, you know, in the middle population. Yeah,
Robert Lufkin 27:30
I mean, it’s very exciting, and especially when we hear the results, but just to be clear, to de emphasize everybody, this is a safety study, and a little bit of accuracy, efficacy, also that we’re going to look at, but it’s very, very early, very preliminary. It’s done in humans, as we’ll see. So, yeah, what did you how did you set up the study?
Patrick Sewell Jr 27:51
So, safety studies, if you look at, if you look at the gene therapy studies that we do in United States around the world, really, the initial studies are two to eight patients. So we had five, typically, for a safety study, you need a low number, and you’re not looking for statistical significance of does it work or not? You’re looking for complications from the therapy, does it? Does it not do any? Does it do anything you don’t expect it to do? Does it have any bad effects, that’s why we call it a safety study. Now, it’s great if you could, if you can also gather efficacy data, we were very fortunate and we can and and that really depends on the type of the disease you’re looking at. So we set it up to look at five patients. We gave them a fixed dose of H turret and Klotho a V, the A and no associated virus, very common virus use and it has some particular things that are very attractive to it, that people watching the show may want to know. So let me let me divert right back into that real quick. So what are the things about H htert that everybody is afraid of historically is is will it cause turn on a cancer? Will it cause a cancer? That’s a big fear, because it turns out that H turret makes telomerase, which is main role is normal role when it function normally is to protect the ends of your chromosomes from fusing together being recognized as a broken strand being subjected to mutations which could cause cancer. So the telomerase, the telomere, maintained by the telomerase is like this mitten over the end of your chromosome, and it gets removed the copies of chromosome the DNA gets gets put back. But as you go through life and that cell gets copied, the DNA gets copied. On and off, the mitten starts to shrink, it gets nibbled at it a little bit gets chewed off Every time and so the normal process is the the mitten eventually gets so short that the DNA can’t be protected any longer. And the cell gun is there undergo senescence, it says to itself, my DNA is at risk of mutation. So I’m gonna kill myself. So commit suicide, apoptosis plan programmed cell death. Well, cancer, it turns out way a lot of cancers work is they make telomerase they have a mutation allows them to make telomerase, not all of them, but enough, and so they can immortalize themselves. That’s one of the one of the very troubling things about disturbing things about cancer cells is they moralize themselves, and they grow and grow and grow. They don’t die of senescence, they don’t undergo apoptosis, when they get a mutation, they don’t say I’m faulty, I need to kill myself. They ignore it and grow more. So they mutate more and more. Um, it turns out that giving there’s been a number of studies, that giving telomerase giving H turret genes to cells does not increase the chance of cancer through AV because of where the the gene goes, and where it doesn’t go. So I won’t go into all the details. But there’s a long history. The undeniable scientific data, that documents that Avi delivered, telomerase doesn’t induce the cancer in patients. So so let’s just put that to risk. Okay. Now, um, where was I going when you vote the question you asked me? Oh,
Robert Lufkin 31:50
yeah, no, just talking about the one question just comes up on the delivery system you’re talking about? Oh, yes, it go.
Patrick Sewell Jr 31:58
Okay. Yeah, that’s how I got on navy. Yeah, so So we chose a V. Because it has been around for about almost 50 years, we’ve, it’s been used in the laboratory, and in many, many human in almost probably almost all the human gene transfer therapies that have been done in the world. It’s very common, it’s very common virus that we use this for, um, and the way it went in the way it works, um, it with the, I’m losing my train of thought here. Oh, no problem.
Robert Lufkin 32:39
One thing, one thing we could expand on a little bit is the delivery system, you went to the nasal mucosa. And,
Patrick Sewell Jr 32:48
and oh, yeah, okay, I’m sorry, what’s coming out of study, particularly? Yeah, so, so we chose the AV, and we load it into Klotho. And we’re loading the telomerase, and how to get it into the central nervous system is an issue. Um, you have to some of the studies in the past, there was a study where they injected it directly into the brain with a needle, which of course, you have to drill a hole through the bone. And that’s someone undesirable, as you can imagine, not many people would go for that. And this was actually a double blind study where they did placebo and gene therapy. So you know, it’s hard to talk people into getting a hole drilled in their skull and needle stuck in their brain and tell them you may or may not get the therapy, and there’s some ethical issues with that, too. So, the other way is injected into the cerebral spinal fluid, which, which is not a, it’s a, it’s a common procedure to access the cerebral spinal fluid, we stick a needle in the back into the spine, we sample that fluid all the time for looking for infection, meningitis, etc. But it does carry a risk and it’s a and there’s some problems, there’s some simple complications that can mess your life up few days, like a bad headache, where you can’t get up out of the bed, all the way to introducing an infection. Um, we came up with a less invasive way we go through the nasal mucosa in the nose, so I injected under the skin inside the node which we call the mucosa. And it gets absorbed and goes up the olfactory nerve one of the cranial nerves and it goes into the brain. How do we know this? We did some studies with rats where we tagged it with a radio nucleotide or fluorescent dye and we inject it and and then you sacrifice the rat and you look at the and you can you image the brain or you microscope look at the brain and you can see the tracer which carried the delivery the target with it. Um, so in this in the in the patient, they received intranasal dose of, of an enzyme which allow which which are to allow the improve the absorption of the virus into the olfactory into the CNS, um, and the gene. So they got an enzyme, and then a little bit a few minutes later, they get the gene therapy, and then 50 minutes later, we’re done. So it’s two little injections inside your nose, which is more palatable. It’s not comfortable. But it’s, it’s well tolerated. And it’s easy to do. So it’s particularly attractive, for a number of reasons, very little discomfort, it’s not complex to administer, you don’t need imaging equipment. But it’s it says it carries a low risk.
Technically, of messing it up, I mean, the worst thing you can do basically is not get it under the skin, but squirt it down their nose and waste it. So there’s a number of features it was, it was a number of reasons we, we liked that method. And but but more importantly, the studies we did and animals documented that it went to the brain where we wanted to go. Um, so that was the best actual procedure. Now, we wanted to know, with the study, once we did it, what was going to happen. And with the safety study, we’re looking for problems like with the brain stroke, intracranial bleeding, infection, any kind of morphologic change in the brain anatomy, etc. So before the before we injected them, we did an MRI of the brain and 10 months later, we did an MRI of the brain, we collected lab blood on them, we did chemistries, and all the blood studies, you can imagine, we looked at a bunch of a bunch of every parameter we could think of, ah, related to the procedure, and the gene therapy, and the cascade of metabolic events that would happen if the gene therapy work, we were prepared to detect any changes. Um, and we are, and we also measure the telomeres in the DNA. And we can do that we can do that in anybody by drawing their blood. It’s a test lab tests we do. And what does that what and and what that all these studies told us, I’ll get into in just a second. So, um, all this all the patients were recruited for the safety study and administered it the therapy after they had all their pre therapy, imaging and bloodwork. And we also did cognitive testing. There’s a full study called the full Stein test that you administered to Alzheimer’s patients. And it’s a it’s a word association, character recognition, memory test, cognition test, can you have you know, can you problem solve? Can you remember this five minutes later of this? Can you say this backwards? Can you count backwards, etc. It’s a very, it’s one of the it’s probably one of the most common tests that that is used for the assessment of cognitive function, and the decline of cognitive function in patients with dementia. Alzheimer’s patients typically drop routinely, or predictably dropped their score three points a year, it’s a 30 point 30 point score. So every year 27, next year, I’ll be at 24, then I’ll be at 21 Nobody reverses the nature of dementia is you your your memory starts, your memory declines, your critical thinking declines. Association declines. So we studied the patients with all that before and then we repeated it afterwards. Um, the most intriguing results came from the telomere analysis and the full Stein test. Now, the safety being the safety study, I was interested in the MRI, the brain MRI, a lot of people that I tell the results to were disappointed I didn’t see any changes in the brain and MRI and improve in the brain, but it was only 10 months apart. We saw I didn’t expect any regrowth of shrinking hippocampus, which is what you know, the reversing of that might mean two years I might show up in three years, we might be able to make some changes or with some more sophisticated imaging, but what I was mainly interested in was they didn’t have any abnormalities of the brain the brain looked identical which is good news. That’s what I wanted to see. Um, there there hematological analysis was straight was unchanged, no infection, no sign of infection and no immunological suppression etc. Now with the with the cognitive testing, the scores went up, which was evidence that the treatment improved them I mean, that is improvement, its definition of improvement their memory got better. There, they remember, we had a patient that remembered names of relatives that they had forgotten for 10 years, um, personalities came back patients, I had one patient that was a retired scientist, and he routinely read scientific journals and watch news programs and you quit doing that. And he started reading scientific journals again, um, I had patient one of the patients, well, several patients regain the ability to do simple everyday tasks, like make a meal for themselves, go into kitchen, make a meal, put everything out, get everything out, put everything up, the skills that they had lost, they got back memory that had declined returned memories that had been lost.
And the test scores reflected that all of the test scores went up some more than others, now that the which is very exciting. Um, and it’s been sustained over the year, there’s a sharp increase in three and a half up to three months, and then it’s sustained across the board, a tiny little dip a point seven per month, so it’s starting to slowly decline, but I have to follow that overtime. Um, the telomere analysis, when I measure your telomeres, if if you’re 50, and I measure your telomeres, and it says you’re 50, that’s your chronological age and your biological age. What if I can lengthen your telomeres, it means your cell will live longer, so you have a younger biological age. And that’s that’s a function of administering more H turret to someone. So with these patients will be measured their telomeres before and after treatment, and all of the telomeres were lengthened. The short, the cells approaching senescence became younger, will live longer. The ones with median telomeres, they will live longer. So we actually have a human study where we showed we lengthen telomeres in cells. And the implication is that those cells will live longer. But I mean, I can’t when that once they do live longer, I can say they did. But in animals they live longer, and when we can give telomerase to animals and make them live three times as long as their twin. Um, so that’s the highlights of those are the two really take home effects. Ah, the hard data showed increased both Stein test and lengthening of telomeres.
Robert Lufkin 42:32
Wow, that’s, that’s really remarkable that the telomere lengthening, if you measured it from the blood samples for the telomeres, it but the injection was in the nasal mucosa of the H turret because the effect on the blood is that just because it’s the sum of the genes were distributed some of the adenovirus vectors were distributed in the bloodstream in addition to saline is that why you see by
Patrick Sewell Jr 43:02
right they are the the virus travels up the nerve and disperses throughout the brain. In the brain tissue in the CSF in the blood is passing through the brain. And the blood passing through the brain has white blood cells leukocytes, we measure telomeres on leukocytes, why do we measure telomeres and leukocytes no matter what organ we’re talking about. If I injected your your kidney, I would measure the telomeres in your leukocytes and your blood. Because the there’s been a number of studies that have documented that leukocyte telomere length corresponds to somatic telomere length. So that cell, the telomere and your white blood cell is representative of the telomere length and your kidney cell in your neuron cell in your muscle cell. And because it circulates it picked up some of the went through the brain and the AV virus latched on to some of the leukocytes. And so that’s where we have the sample. Now we could sample the brain by drilling in the brain and taking a piece and that’s what we do in the animals course. But in humans, we have to this is the best we can do the non invasive method.
Robert Lufkin 44:12
So so the full Stein test is really the test for cognition, which is the definition of dementia and you showed reversal on that. And then the telomere measurements is for the H turret. Reverse transcriptase, telomere telomerase reverse transcriptase, and it shows the effect of that. I’m wondering, are there any biomarkers for Klotho that that would indicate that the cloth is working other than you know, secondary dementia, things like that?
Patrick Sewell Jr 44:44
Um, there are some there are some handmade Klotho lab tests they’re not you can’t they’re not available. So you have to be a scientist in the in the cultural world that you can make your reagent measure you yourself. So we don’t have that available now, hopefully one day, um, the evidence that the the Klotho worked is prior prior work with animals shows that the Klotho reverses, improves cognition and animals. In fact, we had, there was a study that of some mice that were there a number of studies to Klotho in animals, and but Klotho in general, improves intelligence in mice 30% The mice were 30% smarter. Within hours of getting close, though, and this one study, and by smarter they had them do on May amaze that you had them do some testing that that they felt represented their ability to problem solve. So what exactly goes on with how much the Klotho is effective is a mystery right now. But I think it’s a key part. But the the the dementia I mean, the telomere the telomerase has applications to to anti aging, which was why it was very interesting. While if I can lengthen your telomeres, human telomeres, and we know lengthen human telomeres make a cell live longer. I mean, this is really, I’m not aware of any studies that humans have gotten H turret and had their telomeres measured. And they’ve lived longer. So we’ll have to see how these these patients do. But that’s one of the promises of H turret and telomerase is a longer life. Yeah,
Robert Lufkin 46:44
now, now you just completed the safety study and published it. We’ll have the links down below for the publication, the safety and some beginning efficacy data. So what’s next on this? Are you starting another study? What’s What’s the roadmap downstream?
Patrick Sewell Jr 47:02
Right? Right. So, um, this study was sponsored by a nonprofit, this is expensive to do this. So the nonprofit gave us the money to treat these patients. Um, I’m hoping that there will be interest and more somebody more funding to do a larger study, because Phase two would be 30 to 50 patients, which is gonna be a lot more expensive, more sophisticated imaging, more sophisticated cognitive analysis. So it’s not just 30 times, I mean, not five patients, not six times, if I do 30 patients, that I’m gonna have to expand the doses that imaging, the cognitive testing is the the, the whole process is going to be multiplied and cost. So I don’t have a active next step until hopefully somebody calls me up and says, Hey, I love I want to pursue this mission. This I have, I happen to own a billion dollar company, and I want to invest in something. So here, here’s the lab, and here’s hire some scientists and hire some, you know who you need. And let’s, let’s go. So we’re gonna, yeah, I mean, yeah,
Robert Lufkin 48:29
biomedical drug development is hugely expensive. And Gene therapy, development is even more expensive. And the nice thing about drug development, at least when you get the drug, the actual per cost of the drug is fairly low, other than the research and development costs, but gene transfer therapy, on the other hand, as still a high cost of just the customization for individual patients. How do you see future economies of scale driving down that price? And what would what would this what what do you envision this in the future to look like if this could be rolled out at scale?
Patrick Sewell Jr 49:10
So there’s actually some recent work done by a guy at Harvard, who did some groundbreaking groundbreaking research on a V capstans. And the capsid is the coding is outside of the HIV virus, and it’s what your immune system recognizes. And he had discovered and developed a way to select out capsules that are tissue Avid, for instance, if I want to give it to the brain, there’s a way to finagle things. So I’m making AV virus with the capsules that my immune system looks at those capsules and thinks they’re the same as my neurons so but it doesn’t address it. Now. Why does that impact Orton, if I give you a dose of a drug, and and half of it is consumed by your immune system, then there’s a administered dose and there’s an effective dose, the administered dose might be 100 milligrams. But if 50 milligrams gets consumed or lost, then the effective dose is, is the other half, only 50 milligrams, so I’d had to pay for twice the drug for you to get, you only got half of what I paid for, because the other half was lost, can be lost in your GI tract, if it’s a pill, it cannot be absorbed, etc. So one of the things that will drive down costs will be being able to lower the dose of viral particles lower the dose of the drugs, instead of instead of a million viral particles, what if I get away with 100,000, then that would be 1/10 of the cost, you say, because the cost is directly related to the volume of the drug and charge of gene therapy right now. Um, so anything we can reduce do to reduce the administered dose, so our effective dose stays the same, we’ll give you a lower cost. Now, the other thing is, since this study, since we started the study, and when we finished, the cost of gene therapy is doubled. Because of the COVID 19 vaccines, they use a lot of the same reagents and laboratories that we use. And so there’s it’s a supply and demand, there’s a the prices have gone up, because it takes longer to produce the gene therapies now, because all a lot of the same technology, the gene transfer technologies used in the COVID vaccine production. That’s what I found a little humorous is the a lot of the talk about the vaccines was oh, this is brand new braking, blah, blah, blah. Technology’s not really brand new breaking the way they did it with removing some administrative restraints, etc. and sped up the process was, and there were a few things they did that were groundbreaking. But the but essentially, the COVID-19 vaccines are similar technology that’s been around for a while, and they’ve consumed a lot of the resources. So that’s got that. So once that stabilizes, and we get we get some expansion in that market, in the production side, that’s one way we’ll go drive it down. Another way is reducing the dose the required dose by modulating the immune system better by evading the immune system. And then lastly, anything you scale up, up, supply goes up, you make more of it, the price drops in general, I mean, like an iPhone, you know, are up, that’s just that’s the economic side of, of large scale use, when you personalize something and make it unique, it’s very expensive to produce because it’s a small scale. But if we can mass produce it or producing greater quantities will draw the scale down. Um, interestingly, though, you know, the drug that was approved, I can’t remember the name of it to bind to the amyloid the this year the the amyloid protein, I think it cost 5000 A month or 10,000 a month or something like that. The, the gene therapy that we do is comparable to that. But it’s only a one time dose, I mean, a year’s worth. So if I could give you if that’s what frustrates me sometimes is the money is there to pay for that drug, but not for this gene therapy. And the cost is comparable, if you look at a one year supply, so it’s expensive, but then it’s really not expensive. If you look at the cost of medicine.
Robert Lufkin 53:44
Yeah, and the drug doesn’t even reverse the symptoms.
Patrick Sewell Jr 53:50
That’s even more frustrating. So but, you know, this is brand new data. It’s, it’s was published last week, so I couldn’t expect them to know this eight months ago, you know, but hopefully, somebody will take notice. And, and, and with a little time this things will change. Yeah. I also,
Robert Lufkin 54:12
I also love the work you’re doing with your with your personal practice, and maybe you could take a moment and talk about how you you’ve you’ve crafted your practice around patients with challenging problems that may not be able to find solutions elsewhere and how you go about doing that. Right. So,
Patrick Sewell Jr 54:33
um, you know, the greatest satisfaction a physician can have is being successful and helping somebody and helping them and I’ve expanded in my perception of helping them is not just me helping them, but by association helping them get where they need to be sometimes that means I’ll refer them to the right physician. It’s hard to find if you’re not in the medical field It’s hard to know where to go. So it’s not uncommon for me at all to speak to patients is I don’t, I don’t, I don’t have anything to offer you. But I know somebody who does, or I know somebody who is researching that. So I do a lot of that. So I like to hear about unusual problems, because it it piques my interest. And there’s a lot of overlap, if you look at my career between cancer, and I mean, who would think cancer and gene therapy are connected, but they’re actually more connected. And we can’t go into this show into this while we’re here. But gene therapy and cancer for cancer is a possibility in the very near future, something I’m working on, just to give example, but nobody would ever thought gene therapy and cancer, I mean, they just don’t sound like they go together. So you never know what’s going to connect. So I spend my time patients contact me for things they think I can help them with things that they hope I can help them with. Or maybe just because nobody else will listen to them, and I might be able to steer him in the right direction. So I have I have patients and doctors who say, call Patrick soil him, he might be able to help you. Or you might know somebody who does. And that’s kind of the nature of my practice. And out of that I get a lot. I mean, a lot of interesting people, I get to help people, some directly in some indirectly. Um, that’s, that’s the way I like to do it.
Robert Lufkin 56:32
Yeah. So how can people what’s the best way for someone to get in touch with you? And also, how can they follow you on social media and other contacts?
Patrick Sewell Jr 56:41
Um, well, I really, you know, what, I don’t really do any social media. I mean, I’m on LinkedIn. And that’s a professional thing, because that’s where I keep track with a lot of the doctors I’ve met over the years, but I guess they can email me, um, is there’s I don’t know if you can put that in the
Robert Lufkin 56:59
Sure. We’ll put it in the show notes. And also, some of our audience will be listening to this on on headphones. So maybe you could just tell us tell us your email address as well. Okay.
Patrick Sewell Jr 57:09
Yeah, it’s Dr. Zul at cancer immune bio.com is kind of screwed up. It’s not easy one. Cancer cin car immune I m m u n e bio big o.com?
Robert Lufkin 57:24
Oh, excellent. Excellent. Well, we’ll include it in the show notes as well. So people
Patrick Sewell Jr 57:30
oh, can can find it there. Yeah, it’s Dr. Seuss. Not not the word doctor, but d r s e w e ll at cancer noon. bio.com. Yeah. Ah. So, I mean, I’ve talked to so many patients, but interesting, complex problems that if, which then sparks me to read about stuff, which sparks other ideas. And that’s how I ended up putting stuff together. So
Robert Lufkin 57:58
yeah, this is this is such an exciting time in medicine with so many new ideas and and like the work that you’re doing with your project as well, it’s a great time to be in the space, not only for the providers like us, but also for the people and the patients out there because they’re things are possible now that weren’t possible, five or 10 years years. Exactly. Well, thanks so much, Pat, for taking an hour of your time to chat today and get to know you. And I just want to thank you for being on the show. But also, thank you for all the great work you’re doing.
Patrick Sewell Jr 58:37
Absolutely. Rob, I appreciate you having me.
Unknown Speaker 58:40
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