Chapters Transcript Video In Utero Enzyme Replacement Therapy Hi, everyone. Thank you so much to the organizers for inviting me to be a part of this exciting meeting. My name is Tippi Mackenzie and I'm a pediatric and fetal surgeon at UCSF. And I'm going to tell you about a prenatal enzyme replacement therapy clinical trial. It's a phase one international clinical trial. These are my disclosures. I have research funding currently from Novartis and biomarin. I've received research funding from all transgenics which funded the enzyme replacement therapy work that I will tell you about. And I'm on the scientific advisory board of a gene editing company called AC region. So the fetus used to be this mysterious elusive being that we met only after birth. But in the 19 eighties, with the advent of ultrasound, we started being able to peek in on the fetus before birth. And this actually ushered in a whole new field of medicine called fetal surgery. And it was invented right here at UCSF by a brilliant pediatric surgeon named Dr Mike Harrison. And today there are fetal treatment centers all over the world during a range of operations, usually for structural or an atomic problems. So this is kind of the range of things we're able to do for prenatal therapy right now. Uh And like anything in medicine we're really moving from the world of open fetal surgery, which is what we're doing for things like spina bifida to lessen listened of things like laparoscopic or endoscopic surgery, catheter based interventions. And what I'm really excited about is medical treatments for genetic conditions using things like stem cell transplantation or enzyme replacement therapy or gene therapy. Uh And these therapies can actually be delivered right into the umbilical vein of the fetus using just ultrasound guidance. Uh using a very common procedure that we do for blood transfusions routinely in pregnancy for patients who have r h incompatibility between the mother and the fetus. And there are lots of maternal fetal medicine or obstetrics doctors who know how to do this umbilical vein procedure. So, as I mentioned, we already do routine prenatal diagnosis for an atomic conditions using ultrasound. Uh But if you think about it, this is just the tip of the iceberg. There are a lot more genetic conditions in the fetus that could be diagnosed. Uh And right now, we only really recommend carrier screening for a handful of conditions. Uh And if there's a family history or other reason to test, we can test the fetus using chorionic villus sampling or sampling of the placenta for sampling the amniotic fluid. Uh and for certain conditions like Down Syndrome, that there are blood tests that can um look for the chromosomal issues in the mother's blood. Now, you may ask yourself why would you want to diagnose a disease before birth when it wouldn't necessarily change what you would think about the pregnancy? Uh And there are two main reasons for this. One is that um early prenatal diagnosis can actually help you coordinate the post natal therapy for the child. You can coordinate delivery, for example, at a specialized center that has um the various specialists that the child might need. You can actually meet with those doctors and specialists uh during pregnancy and learn more about the condition and uh and have a better idea of what to expect. Uh And you can even get started on insurance approvals for costly therapies. Hm And in some conditions, actually, prenatal therapy might improve the outcomes. Um The fetus is a really wonderful environment for prenatal therapy. Uh One is you can potentially prevent organ damage for conditions that start before birth like many MPS diseases. Um the fetus has a very unique and naive immune system. So you can potentially induce what we call tolerance to certain proteins. Uh so that the uh child after birth doesn't develop an allergic reaction to a new protein and there's also no blood brain barrier. So the medicines that we give can potentially better cross into the brain and treat the neurological problems. And this is actually a really exciting time to be thinking about prenatal therapy. For genetic diseases because of this convergence, a unique convergence of technologies and ideas. Uh So we can now do rapid genetic diagnosis for many diseases. We can even sequence your sequence your entire genome in a matter of days. Sometimes the fetal surgery field, as I said, has really expanded and disseminated all over the world. And there are new medications and even gene therapies being developed for a number of diseases. So the number of techniques that we can use to treat genetic diseases before birth include the ones I've listed here. Uh stem cell transplantation can be used. And we're actually running another phase one clinical trial for blood disorders. Uh enzyme replacement therapy, which is what I'm going to be talking to you about today. And then there's a lot of really exciting work in development for gene therapy or genome editing for genetic diseases. These are just an animal models and nothing is really ready for prime time yet for clinical applications. Uh So focus on enzyme replacement therapy for today. So you guys are all experts and MPS disorders. Uh And so I won't give a background on that, but just to, to talk a little bit about why we might want to treat an MPS disorder before birth. Um Number one is sometimes fetuses with MPS disorders, most notably MPS seven don't actually survive to birth, they get sick um as fetuses and we can follow them actually getting sicker and sicker on ultrasound. And sadly, there's nothing we can do. Um before this trial for that. Uh number two is a number of Children can develop antibodies against the enzyme. The recumbent enzyme replacement therapy, which their body sees as foreign because their body doesn't usually make it. Uh And so by giving the enzyme before birth, you could potentially induce tolerance. So, prevent the development of those anti drug antibodies. Number three, you can potentially deliver enzyme to the brain before the blood brain barrier has formed. Uh And number four, you can potentially prevent organ damage, most notably, the heart and the liver, which are some of the organs that are already damaged at the time of birth for some diseases. So, we wanted to test this uh test this idea in, in mice. And so in my lab, we did uh in utero enzyme replacement therapy experiments. Uh that was led by two really talented students Russell Wit and Keanu Yen. Uh And what we did was we took mice with MPS seven. Uh And we um we did the fetal enzyme injection, which we can do pretty easily in the lab. And then after the mice were born, we continued to give them uh recombinant enzyme every few weeks after birth. And uh at the end of the experiment, we analyzed for a number of different things like survival and organ damage, bone length. Um Did they develop antibodies? And what were the neurologic outcomes? So, this experiment worked incredibly well. It was sort of beyond our wildest expectations. Um and I'll show you some of the results here. One is that the mice with MPS seven also died before birth and we had much improved survival. We had improved histology, which is the level of organ damage that you can see on slides. And what you're looking at here is that in the untreated animal, uh there are these little white areas which are the vacuum als that build up. But with the enzyme replacement therapy given before and then also after, after, after birth, we didn't see that you can see also graphed here um where there were a lot more of these vacuums and the untreated animals compared to the treated animals, we measured their bones and we saw that they had improved bone length. We saw that the enzyme penetrated into the brain, uh and especially into the cells in the brain called micro glia, which are the really important storehouses of this enzyme. And we also induced tolerance to the enzyme. So based on these um interesting results, we wanted to develop a safe protocol for in utero enzyme replacement therapy. Uh And the heroes here were Dr Paul Harmetz who's an expert on mps and license almost storage disorders. Um She's one of my colleagues at Children's Hospital, um Benny at Children's Hospital Oakland, as well as Marissa who was a surgery resident, a student working with us. Uh We had conversations with national and international experts. We surveyed patients groups such as you the MPS Society, as well as other um patient groups around the world. Uh And um we were able to get an investigational new drug approval from the FDA last year and we're launching our clinical trial now. So the way that this trial will work is that we will um anticipate having a diagnosis of genetic diagnosis of the condition. Um either with the chorionic villus sampling or amniocentesis. Uh And the FDA did give us permission to treat a number of different disorders under the same clinical trial. So for the M P S S will be able to treat fetuses with MPS 1 to 4 a six or seven. Basically, all of these are the related diseases for which there is a post natal FDA approved enzyme replacement therapy that's given through the vein Will be giving the treatment through the umbilical vein every 2-4 weeks, between 18-35 weeks of gestation. And then after birth, the patients will get the standard of care. So standard enzyme replacement therapy um and for conditions, if they were to get a stem cell transplant, they would also get that if they, if the family chose to do that. Uh And then we'll do a yearly follow up for five years. So what are our end points? So it's important to keep in mind that this is a phase one clinical trial, which means it's really the earliest investigational study. Uh So we're really trying to just see whether this therapy is safe and whether it's feasible to do. You know, are we going to even diagnose these patients before birth? But of course, in order to do any clinical trial in the pediatric or fetal population, you have to have some hope also that you're going to improve the outcome. So, although it's not a guarantee, we do hope to improve the outcomes um that are listed here. One is decrease, the gags are the glucose amino glide cans which are the toxic metabolic byproducts that build up in tissues and, and you can diagnose them in the urine. So we'll be looking for that. We'll be looking at whether we induce tolerance to the recumbent enzyme. And so are we preventing the formation of those anti drug antibodies? Uh and we'll also be looking at long term outcomes especially during formal neurologic testing every year on the Children um to see if we've improved that. So for any trial, it's important to really understand who um could participate in the trial. So these are the inclusion criteria. So it's a fetus is between 18 to 35 weeks gestation. Um And this is really partly practical and partly um you know, based on the scientific rationale, um we're not really able to do a safe injection before 18 weeks gestation in the fetus. The umbilical vein is too challenging to find um and before 18 weeks, we don't anticipate most of the fetus would get diagnosed anyhow. And then after 35 weeks, gestation, it doesn't make sense to do any other procedures. You might as well deliver the child and, and, and give the enzyme replacement after birth. And we definitely want to make sure that we have confirmed the presence of the license almost storage disease by genetic testing, either by CVS or amniocentesis. Um And also that we've confirmed that that particular genotype is going to give us severe enough disease so that it makes sense to treat before birth. And then there are also what we call exclusion criteria where we don't think it would be safe to enroll at patients. Um And those are patients that have any other major other problem like a structural um problem that we can see an ultrasound or a chromosome problem like Down syndrome or any other major genetic mutation. Uh and also maternal conditions that we just wouldn't make it safe to do the fetal intervention. So, fetal surgery is a really unique field where we have two patients, right? We have the mother and the fetus and we want to make sure that maternal safety is really um you know, paramount. Uh and so we want to make sure that if there's anything that's going to make it too risky for the mother to undergo the therapy that, that they would not be included in the trial. So, uh the way that the trial will work is that if we have identified a fetus with an M P S disease, anywhere in the country or even the world, we would do a video consultation with the family. Um And the physicians, we've all gotten really good at doing that through COVID. Uh And then uh if we think that they meet the inclusion criteria based on all the pregnancy and genetic information that we have. Uh And if the parents are considering participating, uh then we would invite them to U C S F for the evaluation. We do have funding for all of the travel and the screening evaluation um and the medical care involved with the, with the trial. And then once we do the evaluation in person at UCSF, again, if we don't think that it's safe to enroll um that patient, then they would be excluded. But then we could still help with organizing the post natal care. But if they meet the inclusion criteria, uh and they would like to be included. Um And they would like to participate in the trial. Uh Then we would do the in utero enzyme replacement therapy at UCSF. We do need to do the treatments at UCSF. And we would repeat every 2 to 4 weeks because of the half life of the enzyme. And we've had patients participating in other trials to either stay in San Francisco for the duration of the pregnancy or who fly back home in between the therapies because, you know, you definitely have several weeks to go back and forth and the delivery would be at home unless the family chose to stay in San Francisco. And that would be the routine post natal care. Uh But then once a year, we would invite the family back to U C S F to have the follow ups. Some neurological testing and other testing that would be really monitored by Dr Paul Harmatz, who's our expert here. Uh And then in conversations with the F D A, we've decided that it's really important to do a long term follow up because this really is the first time that in utero enzyme replacement therapy would be given for MPS disease. So we would be looking to see whether that we've induced tolerance to the enzyme replacement therapy. We would be looking at the glucose, amino glycogen levels. Those are the toxic metabolic byproducts. We'll be looking at the mobility of the Children as they grow uh neurologic function uh as well as um growth. So for any therapy, of course, it's really important to look at the risk benefit analysis. Uh We've talked a lot about the potential benefits, but what are some of the risks of participating in this therapy? So, one potential risk is an allergic reaction. Um We are hoping to induce tolerance and that's what we've seen in, in any pre clinical animal study, both with the enzyme replacement or um introducing other proteins in utero. But, but there could be conversely an allergic reaction. Um Even a reaction in the mother, we think it's less likely because we are dozing directly into the fetus. And it's a tiny dose compared to the mother's weight. But it's, it's definitely something that will be monitoring very carefully for over time. Bleeding is a risk of any procedure that you do any time. Uh And then the other risk is preterm labor. Um We are injecting the medication directly into the umbilical vein, which as I mentioned, it's a common procedure that we do for blood transfusions. But it's definitely, um you know, can be, can be risky in inexperienced hands. Uh This is how we do the procedure, it's ultrasound guided. Um And we have uh Doctor Juan Gonzalez on our team does all of our umbilical vein injections for transfusions and, and other Medication administrations. We have reviewed our experience in more than 100 infusions. Uh and we've had no fetal loss and the risk of preterm delivery is less than 5%. But I think this is the most important risk to consider when you're considering participating in this trial. And it's important to really consider the feasibility um of really doing accurate and timely prenatal diagnosis for patients with MPS diseases. We think that we're most likely to identify fetuses in families who already have a known carrier status, perhaps known affected child because we don't do universal screening during pregnancy for MPS or any license almost storage disease. Um And we don't do the screening because we don't yet have a therapy. But of course, if you have a viable therapy that changes the equation for recommended screening and with any new therapy, it's really important to engage the patient community. And uh we have surveyed the U the MPS Society. Um And so thank you for participating in the survey. And if you would like to fill out our survey, please let me know we've really been overwhelmed by the positive reaction that we've seen for this um in utero enzyme replacement therapy trial. Uh and so just to give you some of the results, when we surveyed 169 parents, really mostly parents, 90% parents uh in some patients with license almost storage diseases um on the likelihood of ending a future affected pregnancy. The majority of said of our patients or parents said that that was unlikely um of choosing a fetal enzyme replacement therapy if it weren't established therapy, which is, which is not yet. Of course, um The majority of them said that they were likely. Uh and then when we phrased it, as would you enroll in a phase one clinical trial for fetal enzyme replacement therapy? So this is investigational, no guarantee of success. Um Again, the majority said that they would be likely to enroll. So in summary, our clinical trial is now open for enrollment for people really anywhere in the world. Um And as I mentioned, we have funding to support the travel to U C S F as well as the medical costs associated with the infusion. Uh And if you would like more information, please let me know you can email Billy our genetic counselor or myself. And I want to acknowledge the giant team of people who make this work possible, especially Dr Harmetz, whose uh really are expert in licensed storage disorders. Um as well as Marissa Schwab surgery resident who did a lot of incredible work on the FDA application on setting up the clinical trial, Billy, our genetic counselor. Um Juan Gonzalez is our maternal fetal medicine doctor who's done a lot of work on the clinical protocol to make sure that we're really acknowledging safety for, for mom and fetus. Uh Renata is our, is another genetics expert. Theresa Sparks is another uh genetics expert and Ramo Bia Anvil our program managers. Uh So thank you. And I'll be very excited to take any questions and interact with you. Published March 7, 2023 Created by
