Early fetal therapies have the power to change everything for babies and families affected by alpha thalassemia major or lysosomal storage diseases. Hear about the identification and treatment processes; windows of opportunity; and exciting potential benefits, risks and ethical considerations. Our presenters, fetal surgeon Tippi MacKenzie, MD, and genetic counselor Billie Lianoglou, also provide valuable info on patient registries and current clinical trials.
Refer to Fetal Treatment Center
Uh So we're gonna be talking to you today about fetal therapies for single gene disorders. Um Yeah. Next. Um I have a couple of disclosures receiving research funding from Novartis and biomarin for fetal gene therapies and past research funding from ultra gen X that supported the enzyme replacement therapy project. And I'm on the S. A. B. Of a gene editing company named Ac Regent. Thanks. So the past 30 or so years have seen incredible innovations and fetal surgery. Um And we're so lucky to be here at UCSF kind of the birthplace of fetal surgery uh where you know dr Harrison performed the first open fetal surgery. And now dr john Manley um continues to innovate the field. And so if you sort of think about the innovations and fetal surgery, going from open fetal surgery which is a mile a minute to seal that you see here to feed aske opic interventions to catheter based surgery. Uh And really what what my group works on is some of these interventions that can be delivered through a needle place into the umbilical vein that we do for a new york transfusions. Of course all the time with the idea that we can deliver stem cell transplantations or other medical therapies such as enzyme replacement or gene therapy to repeat fetuses with genetic diseases. Next, so if you think about obviously prenatal diagnosis right now we can do ultrasound and there are sometimes ultrasound findings of genetic diseases. And you see ultrasound finding of high drops here with the asides and skin edema but obviously some genetic screening such as carrier screening or see a CVS or amniocentesis and even non invasive prenatal testing for some conditions. Next. And of course the benefits of prenatal diagnosis can include coordinating this early postnatal therapy to coordinate delivery, identify specialists and even obtain insurance approvals for costly therapies. But the needle therapy actually offers a unique advantage because you can potentially prevent organ damage for some of these genetic diseases like Lexus, almost storage disorders. The fetus has a unique naive immune system where you can transplant stem cells without having them get rejected and potentially induce tolerance to new proteins. And of course there is lack of a blood brain barrier. So the therapies that we infuse can are more likely to penetrate into the brain. Thanks. So we sort of think about this evolution of fetal surgery. Were on the left here, you see that we are currently doing an atomic diagnosis. So radiological diagnosis of an atomic problems. And those are kind of the bread and butter issues that you see uh listed there. Congenital diaphragmatic hernia congenital heart disease et cetera. And then moving to the middle where we can do radiologic diagnosis of genetic problems. And Teresa sparks in our group has done a beautiful study of whole like some sequencing in fetuses with high drops where she's seen that these fetuses um overwhelmingly have genetic diseases such as rats sympathies um and other disorders such as alpha thalassemia license almost storage disorders also sort of manifest in the spinal common pathway of high drops as you know. But then sort of really thinking of into the future of being able to do genetic diagnosis of genetic problems which we of course don't currently do as a routine. But if we were to do that then you sort of imagine the dam breaks and then we can diagnose and treat a number of these severe disorders, many of which have post natal therapy is available and the fetuses before diagnosis at birth or after birth continue to have ongoing organ damage. So that's kind of the world that we're imagining next. And as I mentioned, you know, specific advantages of treating the fetus in terms of the biology. Next. So here's a pipeline of the molecular fetal therapies we are offering currently at U. C. S. F. So we have a stem cell transplantation clinical trial which will tell you more about for alpha thalassemia major. We're working on expanding the disease indications for that to beta fell or sickle cell or even fanconi anemia. And really thinking in the future, you know, we see these fetuses with lower urinary tract obstruction who end up getting a transplant often from their mother or father. Can we sometimes somehow tolerance them to the to the donors so that we don't have to do lifelong immuno suppression and the next we'll talk about in utero enzyme replacement therapy where we have just launched a new clinical trial of in utero enzyme replacement therapy for fetuses with one of eight different storage disorders. So we'll tell you more about that. And then we're doing pre clinical studies of prenatal gene therapy. This is all in somatic cells. Um for some of the diseases that I've listed there. So we'll talk a little bit about that at the end of the talk. Thanks. I'm going to talk about really. Thanks to be. Um so regarding alpha thalassemia major. Um just to set the background for you, it is a common condition with 5% of the world's population being a carrier globally. And in some areas where it's most endemic, including southeast asia Thailand, Vietnam, southern china. To name a few, The carrier rate can exceed 40%. Alpha thalassemia really is a range a spectrum of anemia and this can be um resulting from the number of alpha glove and genes that are impacted. So on chromosome 16 there are two alpha globe in jeans. Um In total with the two chromosomes 16th, we should have four copies of the alpha club. In gene. The most mild clinical picture is a silent carrier meaning someone who has one gene that's deleted and they don't even have evidence of anemia. There. M CVS are usually normal to the most severe end of the spectrum where all four copies of the alpha glove and jean are missing, which results in alpha thalassemia major. Um and in untreated cases. This can be a very significant outcome including high drops um In utero fetal demise, miscarriage or stillbirth. There are thousands of pregnancies that are affected globally with alpha thalassemia major. Many of these affected pregnancies go unrecognized because of a failure of arriving at a diagnosis in a failure of recognizing carrier parents. Alpha thalassemia major, specifically the gene that's responsible for causing this. The alpha globe in gene produces alpha chains and these chains contribute to the development of normal hemoglobin and adults. Which is a composite of two alpha chains into beta chains um unique to alpha thalassemia and different from beta thalassemia is the alpha globe in is active both in the prenatal and also in the post natal period. So prenatally we don't make this form of hemoglobin. We make fetal hemoglobin, which is a composite of two alpha chains into gamma chains. When the alpha teens are not produced, the gamma tines come together in a tech amir which is called the hemoglobin bart structure. This structure has a very high affinity for oxygen and so it is not able to release the oxygen to the developing tissue and fetus. And so in alpha thalassemia major you have this part structure. You're not producing any alpha chains. The gamma chains uh form this tetra mirror which then does not release the oxygen to the developing tissue. And you see the presentation of high drops which is a result of that severe in utero hypoxia. Yeah with this condition because these fetuses will already require an immediate transfusion to mitigate the complications from fetal hypoxia and replace the nonfunctioning red cells with functioning donor red cells. Um these fetuses already requiring a transfusion, recognizing this intervention, we determined that in utero stem cell transplantation should start with this disease because there's an ethical rationale that they're already undergoing physiotherapy. And so the in utero stem cell transplantation study started with alpha thalassemia due to this need to intervene with these fetuses um different from beta thalassemia where the presentation doesn't occur until after birth. So in in your intervention would not normally be offered in the setting of a diagnosis of alpha thalassemia major. Many patients are council determinate because of a failure to recognize the potential value of in utero transfusions. And also due to concern on providers parts regarding the potential neurologic outcomes related to alpha thalassemia major. Whether or not that those neurologic compromises are intrinsic to the diagnosis of alpha thalassemia or if they're secondary to the complications of high drops. So can at the same time of launching the in vitro stem cell transplantation study. We also opened an alfa 1000 near registry. This consisted of all patients that were referred to our center for evaluation for the in vitro stem cell transplantation study patients retrospectively cared for at UCSF And then also patients that were referred specifically for the purposes of our of our registry so that we could learn and better informed the medical community regarding the potential impact of in Utero transfusion for this diagnosis. As of late last year, we are working on our manuscript, we had 59 patients in this registry. We now have an excess of 90 patients. Um 48 were prenatally diagnosed. 11 were post natally diagnosed, meaning they were born. And later they learned that their um complications in the perinatal period were due to alpha thalassemia major. Um The prenatally diagnosed cohort 29 proceeded within you with termination of pregnancy. Five of these patients had either zero or one transfusion. And later on when we're talking about outcomes, we refer to this cohort as those sub optimally transfused in combination with those diagnosed post natally. That would be Who were referring to when we're talking about sub optimal transfusion and 14 received two or more transfusions. And later we'll be talking about those patients as optimally transfused patients. So what we found is the potential impact of fetal treatment improving the overall outcomes of Alpha Thalassemia major. Um when we look specifically a prenatal presentation and whether or not there was resolution of high drops, we found 100% of those patients that received two or more transfusions had resolution of high drops and 40% to it's suboptimal transfusion also had resolution of high drops. So it's interesting in the sense that even with the singular transfusion, you can reverse that complication of high drops. We also found gestational age and birth for those patients optimally transfused was dramatically improved with closer to term deliveries, on average, about 36 weeks gestation as opposed to those sub optimally transfused where their delivery was closer to 32 weeks gestation and consistent with that the length of hospitalization from birth to discharge Was significantly reduced in the optimally transfused group close to 20 days as opposed to those three times greater, closer to 70 plus days. I just want to acknowledge a lot of this data that I'm presenting and specifically the neurocognitive assessments were performed by a surgery fellow in Dr. McKenzie's lab, Marissa Schwab and she's done a great job with this as well. Mhm. In addition to the registry that we are putting together for publication, we also wanted to improve our understanding by performing a meta analysis of two other series published in the literature to improve the number of patients um to increase the number of patients that were evaluating with these outcomes. So We performed a meta analysis from including a series from Hong Kong and a series from Canada which increased the number of optimally transfused patients to um to add 14 more and the sub optimally transfused cohort. We added eight more In that data. The Meta analysis is consistent with our single registry data here. I'll show you that gestational ages delivery and if you pay attention to the later shade pie pieces, about 80% of those optimally transfused delivered. Either term or late preterm with an average gestational ages delivery of about 36 weeks. In comparison to those sub optimally transfused where you see this large dark Piece of the pie, about 70% who delivered early preterm. Those that received zero or one transfusion with an average gestational age of about 32 weeks of birth. So optimal iot enabled significantly longer in utero survival and that was statistically significant. The Meta analysis also vetted the length of hospitalization which is consistent with our singular registry data about 25 days on average to discharge for those optimally transfused as opposed to about 73. In those sub optimally transfused, we also looked at needs for mechanical ventilation and those optimally transfused about 50% required mechanical intervention as opposed to 90% in the sub optimally transfused group. Yeah. In our registry specifically for all patients enrolled that pursued in utero transfusion, we offered the opportunity to participate in a neurocognitive assessment which was a telephone survey between marissa and the parent or marissa and the patient themselves. In one case this is called the violence three study. It was overseen by one of our neurologists that you've heard from in this series before, Dr Don Gano And the violent looks at three different domains. The communication, daily living skills and socialization here, I'm representing the data in the composite score with a normal um neurocognitive outcome being two standard deviations from the mean or a value greater than 2.5%ile. And in this group we found 75% of patients performed average or above all patients performed within the normal range. And one thing we appreciated from this data is that earlier in utero transfusion um demonstrated an improved neurodevelopmental outcome and so on the Y axis you see here violent overall composite percentile and on the excess. The X axis is the gestational age at the first in utero transfusion and the earlier the transfusion you can appreciate. The higher um the higher violent composite score. And it was um in a linear fashion that we appreciated that the meta analysis, we also looked at the neurological outcomes. 100% of patients from the meta analysis demonstrated average or above neurological outcomes and about 60% of those sub optimally transfused for below average level. And so this forest plot is a little complicated, I always find. But in summary, when we look at the meta analysis, um the odds ratio of having an average or above average neurological outcome was 2020 times greater and those that were optimally transfused. And this was statistically significant. So optimal transfusion really allows for a significantly better and neurological outcome in this disease for those patients in our cohort that were appropriate for age over two years old. We also offered to evaluate their quality of life. Using a standardized tool called the Pedes QL and we found that these families reported a higher quality of life score as compared to other published literature of patients with a child with another chronic disease namely diabetes and also compared to healthy Children. And so this really is encouraging data to us to show that not only neurologically are they doing well but the concern regarding the burden of the chronic disease. Um maybe less of a concern for these families because they are truly reporting a very high quality of life scores and measures. So in conclusion, the registry from our site, in addition to our meta analysis demonstrated that patients treated in Utero deliver near term and have a shorter hospitalization after birth. That these in utero transfusions allow patients without the Palestinian major to have good neurological outcomes that that earlier intervention for in utero therapy allows for a better neurological outcome. And so for us that really resonated in the sense that oftentimes we're getting referrals from patients that they are suspicious of a diagnosis of alpha thalassemia major but awaiting the results of the annual synthesis and in our center our practices if we have a suspicion for alpha thalassemia major and we're seeing evidence on ultrasound of this diagnosis including either high drops or elevated M. C. A. Dobler's not waiting for that amniocentesis results to come back but rather offering the patient of diagnostic pubs to confirm the anemia and an intervention in utero transfusion. In those patients that choose to pursue fetal therapy. And then finally, Children with alpha thalassemia major do appear to have an excellent quality of life as reported by their parents. Another interesting outcome from our registry is looking at the genetics and the genotype phenotype correlation of alpha thalassemia. Here. At the top of the screen, you can see um the alpha globe in locus where you see the two copies of alpha, alpha globe in alpha one and alpha two. And upstream from that is the side of the globe. In gene, this gene is responsible for creating embryonic hemoglobin. Below this, you see the different sizes of the deletion that's responsible for alpha thalassemia major. There are many different deletions reported in the literature all cause the deletion of both alpha one and alpha tube but not all overlap with the zeta gloving gene. In our cohort, the prenatally diagnosed patient population, about a third of them had a deletion that overlapped with zeta globe in as compared to the post natally diagnosed group where there were no patients that had a deletion that overlapped with the zeta globe in gene that um supports the notion that data globe and maybe protective in this disease to allow for survival to birth. And uh and in some cases were also appreciating a later presentation of high drops and Phil anemia. In those patients that don't have a deletion overlapping with the zeta group in this is an important aspect to consider as far as other targets for treatment of this disease, a potential opportunity here in considering up regulation of this data globe in similar to how therapies have been targeted for beta Palestinian and sickle cell. Looking at gamma globe in an up regulation of that gene. Um So Dr Mackenzie is now going to speak about the clinical trial and um take it from here. Thank you so much billy. Um Yeah so based on some of the so I I run a basic science mouse lab where we do in utero stem cell transplants. And one of the things that we've been really fascinated with is um is this notion that you know you can potentially tolerance a fetus to accept stem cells from a different donor and basically do a bone marrow transplant before birth without doing any immune conditioning. Uh And we and others have shown that the fetus is actually tolerant to the mom uh during pregnancy. Uh And therefore if you want to do a fetal stem cell transplant you should be transplanting cells from the mother. Uh And so um based on some mouse work that we did and then some um pre clinical studies in the dog model that were done in the lab of Alan flake at chop. We apply to the FDA for an I. N. D. To do a phase one clinical trial in alpha thalassemia. Um And really our initial goal wasn't necessarily to focus on alpha thalassemia itself as the best popular target for a bone marrow transplant. But but to see to say that's probably the best first disease to do this in because those fetuses already are getting an in utero transfusion. And so there's there's definitely, you know, an ethical reason because you know, you're you minimize any additional procedural risk. So we launched this trial in 2017. And what we're doing is transplanting cells derived from the mother with the idea that the fetus should be tolerant to the mom. So we're not doing any immuno suppression or any conditioning in the bone marrow to create space. But we're just putting in a very very high dose of these maternal cells. Uh and we're doing this between 18 to 26 weeks gestation through the umbilical vein. That time window is basically based on the fact that before 18 weeks, it's really not too safe to do an umbilical vein uh Infusion. And the majority of the patients don't really get diagnosed before 18 weeks anyway. And then beyond 26 weeks, that immune privilege of the fetus probably fade. So for this phase one trial, that's the gestational age window. And we've been continuing transfusions every three weeks. So, um so we're in discussions with the FDA, as I mentioned for expansion into beta thalassemia. We have transplanted five patients. So we're actually pausing now, the recruitment so that we can evaluate the data from those five patients next cloud. So here's kind of a uh excuse me, a photo montage of how this all works. So we do the maternal bone Mayor harvest. It's it's an old fashioned bone marrow harvest because we're not mobilizing peripheral blood stem cells during pregnancy. We do this with Krista Barack and his team. Uh And then the pediatric cell transplant laboratory process the process of the cells just like they would for any post natal stem cell transplant. And they they purify the C. D. 34 positive stem cells. Um They do antitoxin testing, gram stain testing etcetera. Uh And then juan Gonzalez whose them a famine. Our team does an ultrasound guided infusion of these cells into the umbilical vein which you see here. And we sort of give the give the little dose of cells which is a very concentrated two mL that we put the cells in and then we chase it with a blood transfusion. Thanks. Um and so as I mentioned we've transplanted five patients so far and we're working on analyzing the data in terms of you know the safety, the efficacy and graft meant etcetera. Um but I think that the main benefit that that we've gained from this clinical trial is really this laser focus on alpha thalassemia major as a disease. Um And I really appreciate the incredible work that billy lee and lulu and Mercy Schwab have done in in the registry and and you know the information that we learned from that on optimal outcomes. If you simply bother to do an enduro transfusion on these patients. Uh And so we um we have been working on disseminating some educational materials and actually organized an international meeting last january. And I put the slide up here because it's sort of two hours, two days worth of talks. But we had a lot of talks with the families of patient panel etcetera. So if any of you are interested in learning more, all of the all of it was taped and it's freely available on the internet. So just just email us. Uh And uh we've also actually worked with the documentary filmmaking uh company uh to feature five of our families who sort of, you know, went through this pregnancy journey trying to find providers who would be willing to give them in, you know, transfusion. So it's a longish mini documentary. But we're going to play you like a two minute clip of it here and you can just Youtube. Mhm. What flavor is it? Chocolate? He plays hard. Just like the other kids do when I found out that I was pregnant. The first thing I thought of how can I surprise Mark with this? I was really excited. I was like, we're having one more. Yes, we got the diagnosis of alpha thalassemia major and that was the first time I have heard of the condition. I was just shocked and confused. The doctor said, let nature take its course and try again. You know, nine months from now are thought of course was babies don't survive with this diagnosis with this disorder. That's the information that we got from the doctors. Because that's pretty much the information they have. My doctor was saying. You know, she had heard some things about blood transfusions were like, what is that? We had no idea what that was. We knew that this is the right course to take the fight for her. Uh huh. Fluid was slowly disappearing. He was growing when we delivered her and she took that first cry. I think both of us kind of looked at each other like oh my God, she's she's here and she's breathing on her own. Just hearing you have cried. It was like everything is here everything. This is a miracle baby. His name is Caleb person in Hawaii We have the inaugural transfusion. Hi this is Oliver like I say hi, I would put her inside my shirt. That's how little she she was. And we just hug her. You feel your heart girl. Um She was this little tiny thing they put right on my belly to finally hold my son in my arms. It's such a great joy just waiting for the transition to end. But she won hospital bingos. And when for my flagship. All right, we are in the hospital, twice a month for blood draws and transfusions. He says bye to the nurses, blow them a kiss and says see you later. He can have this normal life and that these transfusions are working. It is by far not a death sentence. So you never know what's around the corner. Who knows what they're gonna come up with in in Milos lifetime. Mhm Mhm. Mhm Yeah. Whoa. We've learned so much from our patients and um we're so grateful for their participation. Mhm. Mhm. Okay, ongoing research at UCSF to improve patient care for alpha thalassemia includes this in utero stem cell transplantation. Were hoping to decrease the disease burden of the disease. Um We continue to enroll for alpha thalassemia major registry and this can include patients that were in your care that chose to pursue transfusion that you never referred to us or chose to um interrupt their pregnancy or even those that had, you know, chosen to proceed with expected management where every patient we learned from um and every patient is valuable to us and so meaningful for the work that we're doing. Um and also um specifically we're currently enrolling for patients um to be um to share any samples at delivery of a baby that's born in transfused within euro transfusion or patients that choose to interrupt their pregnancy to move forward initiatives including gene therapy and gene editing for this disease. And if you have a patient that you'd like to refer, you'd like to talk to us more specifically about these initiatives. Please feel free to email Dr Mackenzie or myself tip is going to speak more about the license almost storage diseases and the program we have related to that now. Thank you. So, shifting gears license normal storage disorders. Can we do prenatal therapy? So as you all know, these are genetic diseases, they're all sort of cousins of each other in that they are each a deficiency in one critical license normal enzyme. Um and many of them cause multi organ failure as you know. So patients uh sometimes get prenatal findings like asides um or even high drops, they have liver accumulations, um they get um growth restriction, skeletal dysplasia is uh and neurologic uh disorders because of those accumulations and some of them can be treated with infusions of a recombinant enzyme or even a stem cell transplantation where the transplanted cells then secrete the enzyme. Um but there are shortcomings with these post natal therapies um which we hope to address with a prenatal therapy. So the rationale for the prenatal therapy is one you can potentially prevent in utero demise, especially for the segment of these fetuses who present with high drops, such as those with mps seven. You can potentially induce tolerance to the missing enzyme. Uh you often that that recombinant enzyme is actually seen as foreign by the patient's immune system. And some patients such as those with infantile onset pompe disease actually need some pretty big gun immunosuppressants to actually tolerate the enzyme. You can potentially deliver enzyme to the brain before the blood brain barrier has formed. Uh and as I mentioned, there's progressive ongoing organ damage such as cardiomyopathy. Again, in pompeii disease or liver damage, that hopefully you could ameliorate if you start the enzyme replacement early in life or early prenatally next fight. So, as I mentioned that I run a mouse lab and so we did the experiment experiment in mice. Um this was spearheaded by two amazing surgery residents in the lab, russell wit and Kenyan. And so what we did was we bred hetero zegas, mps seven mice to each other Such that 25% of the litter would be affected by MPS seven. And we have this really cute procedure where we can, you know, poke the little mouse fetuses and deliver the enzyme before birth, usually around 13 days gestation. So kind of corresponding to second trimester and a human next. And then we gave them post natal enzyme boost next. So I just kind of go through these animations and then we analyze the survival organ damaged bone length, whether they made antibodies and different neurological outcomes. And this is published and I can give you guys a copy of the paper if anybody's interested and then just click through these animations if you don't mind billy. So we found that the in utero enzyme replacement therapy significantly improve the outcomes in these mice. The mice were basically cured. It was everything works really well in mice. Um if you're a fetal mouse with any kind of genetic disease, you know, we say fear not, you've already been cured with, you know, gene therapy, enzyme replacement therapy. Lots of things work well. But these mps seven mice did really well. We definitely improve their survival. We improve the histology as you can see those white license normal accumulations and the untreated liver up top and then they're all gone in the treated mice. Now, the bones were longer. Um the enzymes definitely penetrated into the brain and actually into the important cells in the brain, the micro glia, which are the usual storehouse of this enzyme. And we were able to induce tolerance to this human recombinant enzyme in the mice length. So based on this experience, we worked really closely with paul harm. It's who's one of our post natal genetics colleagues and runs a post natal license almost storage disease clinic again with marissa Schwab and also with Billy to really work on a safe protocol, clinical protocol for an in utero enzyme replacement therapy. We've also reached out to some national experts um as well as serving the patient groups with uh such of the Mps society. Because we think that probably if there's a patient who's prenatally diagnosed, it's most likely to be in a family who already has an affected child. Um, and I'll show you later. We did some surveys of those families. Uh and I'm happy to say we got investigational new drug approval from the FDA last year and we have now launched our clinical trials. So do let us know we are recruiting for patients with one of these eight license almost stored to disorders. So here's sort of the timeline of how we think things are going to shake out. So we think that the prenatal diagnosis again, probably in a family who already has an affected child would be done by CVS or amniocentesis. I think some of these patients are going to come through as a result of the high drops prenatal sequencing program. Uh, and then we would do the in utero enzyme replacement every 2 to 4 weeks because that's the half life of the enzyme between 18 to 35 weeks. Obviously not going past 35 weeks because you might as well just deliver. Then the post natal care is going to be just standard enzyme replacement therapy and whatever other standard immune monitoring etcetera is done. But then the patients are going to come back here um yearly for five years and being a phase one trial. The primary objectives are of course safety and feasibility. But we will be looking at some efficacy parameters such as decreasing the storage material which is called gags, the glucose amino glide cans. We'll be looking at whether we induce tolerance to the enzyme and then long term outcomes such as neurological outcomes. So these are the inclusion and exclusion criteria. So as I mentioned, it's between 18 to 35 weeks, gestation and we will have the genetic testing by CVS or amniocentesis. And we'll be looking very carefully at the genotype phenotype correlations to make sure that we're only enrolling patients who have a confirmed severe infantile onset genotype if there's any ambiguity. And then the exclusion criteria are really standard exclusions for any sort of fetal intervention. If there's an other structural or chromosome anomaly or of course if there's a maternal condition that would preclude fetal intervention. Thanks. And so basically we think that the way we would do this is similar to what we're doing for the alpha tall clinical trial is if a fetus is identified with Mps disease, we would do a video consultation with the family uh do the non directive counselling. Obviously in this situation we would talk to them about you know how this is. This is literally kind of a first and human. Um and if they're excluded, we can still use that time to organize the post natal care. The insurance approval for these enzymes is pretty costly. Uh But then if they do meet the inclusion criteria, then we would enroll them uh and then do the enzyme replacement at UCSF every 2 to 4 weeks. And then routine postnatal care at home next and then yearly follow up at UCSF. So um so the five year follow up after birth is going to involve looking at tolerance, glucose, amino glycogen levels, mobility, neurological function and growth. So, you know in terms of the potential benefits we discuss those. But next the potential risks are really important because these fetuses unlike those with Alcatel major do not need an umbilical vein stick. So it's important to think about the procedural risks such as bleeding or preterm labor as well as the potential risk of having an allergic reaction to the recombinant enzyme. Obviously we think that's a remote possibility. We think that we're actually going to induce tolerance but we'll be checking for anti dark antibodies throughout this study. Uh and this is the you know the same set up as the uh as any in utero transfusion. Uh and and we did review dr Gonzalez is um you know track record at UCSF with over 100 and 39 in utero transfusions And the risk of preterm delivery with umbilical vein injections with less than 5%. But obviously a really important part of the consent conversation. So we think a lot about feasibility. Right? So um you know can we actually do accurate and timely prenatal diagnosis of these genetic diseases as I mentioned at the start and as you all all know better than I we're not currently doing any you know routine genetic screening for these disorders. So we think will identify families as I said with a known carriers uh status. But then thinking really into the future, you know we don't do universal screening because we have no therapy to offer. But if we do have a therapy to offer, then it might change the equation for recommended screening down the line. So we did engage the patient community. As I mentioned, this was the MPS Society as well as the Duke Pompeii Clinical Research Network. So we interviewed over 145 or we surveyed over 145 patients. And you can just kind of see from the Facebook post. People thought there was maybe a cool idea. Next line. Um 100 and 69 were up too. So we surveyed them on the likelihood of ending a future pregnancy. And you can see that the majority of them actually said no, they would be unlikely to terminate a future pregnancy, 71% were likely to choose fetal enzyme replacement therapy if it weren't established therapy. So not as part of a clinical trial, but you know, if it were established, would you choose it? But then over half of them. So 60% said they would enroll in a phase one clinical trial for fetal enzyme replacement therapy. So this is encouraging for being able to, you know, find patients for this clinical trial. So again, please let us know if you have any patients for for referral. Um and then sort of thinking about um in utero gene therapy, you know, if you one of the one of the things we've been learning with our discussions with the FDA. Is that um for any sort of prenatal molecular therapy it needs to be um approved in the post natal setting before you can do a prenatal clinical trial. And so if we look at currently approved FDA approved genetic therapies those are listed there. So there's you know there's two for spinal muscular atrophy. Uh there's a gene therapy the A. V. And then an anti sense all ago. Both of these work work very well. Um There are therapies for Duchenne muscular dystrophy and then an end of one therapy for um for a rare genetic disease. But then if you sort of look at the what's coming down the pike the current clinical trials for A. V. For example hemophilia G. M. One M. P. S. 123 all listed there. So you know as all as all of you know that the gene therapy world is really exploding. And so if we sort of think into the future some of those therapies may actually be available uh to enable a definitive cure because it does you know we don't really think that obviously in utero enzyme replacement therapy is going to be a definitive cure. You have to give the stuff every three months. So can we or every 2-4 weeks. So can we think of something that's going to be a single shot to cure. Uh And and and really be a more meaningful change for these families next. So obviously those are the potential benefits. But there are multiple more potential risks for the field of prenatal gene therapy. In addition to the procedural risk. We have to be incredibly careful about looking for um maternal harm off target effects and germline integration. Um and I just want to reiterate that we're not talking about embryo editing at all. We're talking about you know, second trimester fetuses um and doing gene therapy or gene editing for somatic cells only. Not not your online. A lot of ethical considerations. And actually we have a bioethicist Barbara Koenig who attends all of our weekly meetings. Um Really important for any field of fetal therapy to do non directive counselling. Uh We're learning about cultural sensitivity because there are so many um conditions where it's a specific ethnicity who's affected. Uh And then we think very carefully about should we be offering a marginal correction for a disease that's lethal in utero um to sort of you know give false hope and a prolonged um prolonged hospitalization. And of course patient representation is really critical for planning any of these therapies. And we are forming actually a patient advisory group so that we continue to have the patient representation in a real real real time fashion. In addition to the surveys that we've done. Thanks. Um Yeah and I think this sort of is a duplicate slides will go through this. Um and then the regulatory considerations um You know, we are in continued discussions with the FDA and they've been an incredible partner in terms of helping us think through the really important issues of maternal safety, fetal safety and as I mentioned, the FDA approval in the post natal setting. First. Next We are having a workshop with the FDA in case anybody is interested in learning more about prenatal somatic cell gene therapies that's going to be on October 26 seven AM to two PM our time. Just so it works out for easter time. Um And it's you know, it's registration is free. So just let us know if any of you would be interested in participating in that. So the short term goals are of course to continue the amount of prenatal genetic diagnosis we're doing. Um So carrier screening for uh of patients for currently treatable conditioning conditions. And then if that's positive testing the fetus by cBS RMDS and thesis. Uh And there's a small many of these new therapy therapies that we're able to offer, such as the stem cells or the enzyme replacement. Uh And we're actively involved in preclinical testing of somatic cell gene therapy approaches next. But the longer term vision would be a broader carrier screening and development potentially of N. I. P. T. For some of these treatable conditions uh in doing some targeted fetal therapies such as gene therapy or gene editing for a longer list of conditions. Thanks. So in terms of summary and next steps um sofitel transfusions can result in excellent outcomes. And Alcatel Major. We are continuing recruitment um actually, we're, as I mentioned, we're actually pausing recruitment for the stem cell transplantation trial of 80 M just so we can analyze the five patients, but we are recruiting for the registry um and then launching a new trial of in utero enzyme replacement therapy for life cycle storage disorders and testing prenatal strategies for gene therapy. Next and a multidisciplinary conversations. Um so it's really a billion ir representing an army of people um here where we when we talk about the work that's been done both in our fetal treatment center and in the Center for maternal fetal precision Medicine, which is kind of our research arm. Um and I went to specifically acknowledge partners on the thalassemia team, especially dr Bochenski, partners on the enzyme replacement team. Especially dr Harmatz. Um My lab members who have acknowledged and then collaborators at UCSF and around for some of the new therapies. Um So, um and the partnership of Mary Norton, who is the co director of this research arm, the precision medicine center. So, thank you so much, Really appreciate it and we'll be happy to take any questions
