Learn about exciting studies underway at the UCSF Fetal Treatment Center and how to easily refer patients who could benefit from participating in current trials. Specialists in maternal-fetal medicine and pediatric cardiology describe research on:
the link between congenital heart disease and brain development
the potential of fetal exome sequencing, particularly for hydrops
how certain in-utero interventions may have value for fetal arrhythmias, renal issues and alpha thalassemia major
Refer to Fetal Treatment Center Thank you again for joining. My name is Aaron Matsuda. I'm the director for the fetal treatment center here at UCSF. Both in san Francisco and in Oakland. Ah We are fortunate enough today to have a plethora of speakers to come and present to us next slide please. Um And we're very excited to have this opportunity to share with you all about some of the newer initiatives and research that's happening currently in the fetal treatment center. Um As you can see we have quite a Panelist here for you today. Um We're gonna be going through a lot of our studies and sharing with you where we're at and where we're going. You will have an opportunity to ask your questions, please use the Q. And a function. And all of the presenters will come online at the end to answer all of your questions and we'd love to hear from you. Um and again a lot of different studies and we'll go to the next slide here and kind of take an overview of all the studies that we're going to be reviewing including fetal heart and brain XOM high drops intervention for aortic stenosis, the raft trial in utero enzyme replacement and the Alpha Fell trial that we have opened. We're very fortunate to have a study brought to us by Doctor Shopping blonde, who is a pediatric cardio cardiologist and associate director for the UCSF fetal cardiovascular program. And on her behalf we have the political nurse christian God's will who will take us through the fetal heart and brain study. Welcome Kristen. I'd love to hear from you. Thank you. Um Good afternoon everyone. Um It's my pleasure to be prevented consenting for doctor shop a Gandhi. Um The first study actually is something you might be familiar with. We've been doing it for many years now. It's the fetal heart and brain study for complex congenital heart disease. Um This was a study launched because we were noticing that patients with complex heart disease um had both developmental and learning differences. Um So this was a study we launched um to evaluate the fetal brain by M. R. I. Prenatally. Um And it was um a approach that we not only did fetal brain M. R. I. Imaging but also administered maternal hyper oxy. A. And through diffusion. Studies were looking at oxygen uptake in the brain. Um So the inclusion criteria for this study was um neonatal forms of congenital heart disease. Where the genetics in the fetus were known to be normal. They had a fetal brain M. R. I. Usually around 34 weeks gestation. And again this was the point where the brain was as developed as possible. And mom still fit into the machine. Next slide please. Um So we I'm very excited actually to announce um just yesterday we met our enrollment criteria for this study. So we have two more patients that are going to be imaged in the prenatal period. And then the study is closed. So This consistent of about 55 patients with congenital heart disease compared to 25 controls. The main findings actually to date are that we know that patients with complex congenital heart disease have less mature brains than their control counterparts. When imaged in the third trimester, that's cerebral oxygenation and the tattle is um are impaired in these fetuses with complex heart disease. And that um through maternal hypoxia testing we may be able to identify fetus fetuses that are that are the highest risk for neurologic environment after birth. Next slide please. Three. So really the now that that study is ending our next phase is actually a new study that is funded by um the National Institutes of Health. Um It is called the transit study. So the risk of acquired new natal significant brain injury during perinatal transition for congenital heart disease. Um And this we will be launching in probably june of this year. Next slide please. Okay. Um so in this study we are looking specifically for uh fetuses that have transposition of the great arteries or extra transposition of the great arteries. Um With and without the gsd. Um there are two centers participating UCSF and sick Children in Toronto Canada. Um So the first aim of this study is actually to determine if decreased fetal cerebral oxygenation, tissue oxygenation is associated with decreased brain maturity. Um And again that is determined on fetal brain M. R. I. With maternal hyper arcoxia. And then there's two. There's a secondary or second aim that has actually two parts. Um So we're trying to look at the relationship um with brain development that happens actually in the perinatal period. So um there's a component of delayed cord clamping and how that might influence the development of white matter injury in these patients. Um So they will be followed with an echocardiogram post natally as well as nearest testing. And that's just a trans cutaneous oxygenation monitoring of the brain. Um And then finally in the second aim, we're looking with M. R. I. Again, before they go to surgery to look for signs of brain imaging injuries, specifically again white matter injury. Um So again this will be launching in june. We're very excited. Um We want to thank Kaiser for enrollment in our previous study and look forward to working with their patients on this next phase. Thank you. Mhm. Hi, I'm Billy, lino glue. I'm a genetic counselor. I worked closely with dr mary Norton and Theresa Sparks will be presenting next on the fetal xom sequencing program here at UCSF. Um One thing that's different about us is that we're really cutting edge and looking at rare genetic ideologies beyond standard of care of the micro ray and chromosome evaluation. We've been performing fetal sequencing for the last 4 to 5 years under a protocol where any patient with a structural difference and a normal micro array or carry micro array analysis is eligible to enroll and through this work we've identified in 19% of cases for any structural difference all comers we were able to identify a genetic diagnosis or explanation for that structural difference. Um with the under the auspices that potentially having an understanding of the genetic contribution to disease may help inform um perinatal management, both the management of the pregnant mother as well as the newborn. Um This is an iterative process. It's really been wonderful. Working with the the UCSF genomic medicine laboratory, we have a weekly xOM sequencing sign out call similar to a tumor board where we discuss the findings in the pregnancy. In addition to genomic variants observed. And we welcome those providers that are very referred patients to join the call um when a patient that you have referred is being presented. So you can reach out to reach out to us directly if you'd be interested. Um And we're on the cusp of beginning to offer whole genome sequencing in the near future as well. Next slide please. This is an overall um demonstration of the enrollment during our initial prenatal the program in prenatal and pediatric genomic sequencing program or pegs which was funded by the NIH. We had enrolled 301 cases. Um any fetus with one or more structural difference in a normal micro ray and in those 301 um we identified 58 definitive positive or probable positive diagnosis. So that means that um there was a variation that we think tied closely with the potential explanation for the structural variations that were observed. Um We have learned that depending on what organ system or what finding you're looking at, this positive rate will be increased or decreased um including what dr sparks will now present on non immune hydra fatalities, where we found closer to a 30% diagnostic yield next slide. Thanks so much Billy. Um so as Billy had alluded to, what's been really interesting with a lot of the sequencing work that we have done is that we have started to understand that for some phenotype stand for some disease processes. The diagnostic yield with exam sequencing is higher and high drops is a really interesting example of that. When we're talking about high drops were really thinking about this as a heterogeneous condition where there's a whole host of underlying potential causes. And specifically um when we think about the genetic causes, there's there's hundreds of different potential genetic explanations for why we see non immune high drops and also even broadening that even more so to think about things like cystic aromas and earlier presentations. Um there's a lot of things to think about. And so what we did is this slide shows our findings from the preliminary work that we did um and publish now a couple of years ago. Um and what we did is we enrolled cases of fatal infusions and high drops from across the country in order to understand on a deeper level what the genetic explanations were. And all of these cases similarly to what billy had presented. Had normal standard evaluation. So that included a standard work up for non immune high drops and included a normal microwave or carry a type. Um and when we applied exam sequencing to all of these cases, we found that in a third of cases we were able to identify an underlying genetic explanation in the pie chart here you see the different genetic contributions. And so in the yellow portion of the pie are the retinopathy. So those are things such as Noonan syndrome, Costello syndrome, cardio, facial cutaneous syndrome and many others. And those made up the largest proportion of the pie. But there were many other diagnoses as you see and those ranged from inborn areas of metabolism to musculoskeletal disorders, lymphatic disorders and many others. And it was really eye opening because this was a large cohort and it really gives us a sense of the breadth of underlying diseases and then also the relative proportions of those underlying diseases. And importantly, really underscored that we have a lot more to understand. So that way we can improve the care that we offer to our patients who encounter this challenging diagnosis. Next slide, please thank you. Um and so in terms of next steps with where we are. Now this slide here shows um the fetal phenotype, pick features of the rest of these. One area that I had alluded to is that we're really interested in understanding on a deeper level what features can give us a sense of the underlying genetic conditions. So digging deeper than just high drops and just saying there's abnormal fluid collections, What are those abnormal fluid collections? How early do they present? What other features do we see on the ultrasound or MRI that can give us a sense of the underlying diagnosis and be much more pointed in terms of how we are evaluating each case and treating each case as a unique one. And so this is work that we had presented at a conference recently that I think is just interesting because it highlights some things that we're beginning to understand about fetal phenotype types of genetic diseases that were not well understood before. Um And so for example characterizing that pleural effusions and skin edema are particularly common in cases of breast sympathies and that also we are starting to see other features emerge that were not historically associated with a diagnosis of arrest apathy such as a contracture like phenotype. Um And pretty soon as Billy had talked about two, we just received some additional grant funding from the NIH. And so we're going to be moving forward with whole genome sequencing and will be perspectively enrolling um from a few sites across the country soon and we'll be applying whole exam sequencing RNA sequencing and other functional studies in order to better understand those unsolved cases of high drops. And then we'll be delving deeper into the phenotype. Um So with that I'll turn it over to the next speaker who is Dr Moon Grady, the director of our fatal cardiovascular program and she'll talk about some interesting fetal intervention studies. Hi thank you. Um I apologize for joining late. Uh And I want to thank Kristin. Got snow for presenting the the other cardiac studies. Um I'm going to just talk very briefly about some of the multi center studies that we're currently enrolling patients. Um The first is the fast therapy trial which is the fetal atrial super ventricular feel. Atrial flutter and super ventricular tachycardia trial. Um This is actually three nested randomized controlled trials because atrial flutter, atrial tachycardia and SPT with hydra apps were considered to be three um sort of separate treatment algorithms that would be normal for for their treatment. And so each one represents a block randomization. Um As illustrated on this slide. So for atrial flutter patients are randomized to um to Jackson versus so do all for SV. T. Without high drops. Their randomized to flick inside versus to Jackson. And for super ventricular tech cardio with high drops their randomized to combination therapy of deduction plus total all versus the Jackson plus black and I'd so the patients have to be previously untreated newly diagnosed with SPT and they have to meet certain other criteria. Including risk for worsening in S. PT or a letter Greater than 80% of the time etc. So basically on initial evaluation by cardiology that's the time to think about the trial. And we our goal is to start therapy. So to randomize and start therapy within a day of receiving the referral. So patients are interested in this. They need to be referred by a provider. There's also a registry arm that were also participating in. So this is an international study being run out of Toronto with funding from the Canadian Institutes of Health Research which is similar to our NIH and UCSF was actually one of the grantees. And so we've been part of the study from the beginning. Um It ran into some hitches from covid but We're over 50% done enrolling patients in the in the biggest arm next slide. So contact me if you think you have a patient for that please. The next prospective study that we're enrolling patients in is a prospective observational cohort study. Um as opposed to the R. C. T. That was on the previous slide. Uh This one is looking at heart block instead of tachycardia and specifically heart block due to maternal autoantibodies. And we have for several years advocated home monitoring for this because treatment with dexamethasone and for I. V. I. G. Can decrease the inflammation and the baby is evolving heart block. We have been able to um to reverse block in just a small number of patients certainly once they have third degree block, there's nothing you can do. And so our goal is to catch this And within 8-12 hours of the baby starting to have an arrhythmia getting the treatment started, that's an inpatient treatment. Um if you don't treat they're going to develop heart block and not you know, not be treatable and they'll need to be referred to us here in san Francisco through the Kaiser system. The babies with heart block who are going to need pacemakers would have been placed here in san Francisco. So um so are we don't necessarily need to see the patients here. Don't need to deliver them here unless they develop heart block, but we would have delivered those here anyway. So the basic entry criteria S. S. A antibody status And a willingness to undergo a blood draw between 16 and 18 weeks to send titles to our research lab in New York. Um This is a study that is also funded by the NIH and is uh with copious lies in Denver and in new york joe bryan. If you know her name. Is is the new york P. I. And it's her lab that's doing the the tigers and we're trying to both show a net effect of the monitoring on treatment and also risk stratify patients. Next study the next slide. Uh this is just the the eligibility. I just went through uh identifying them prior to 16 weeks so that we can get them enrolled in this study. Um and get them here prior to 18 weeks for their blood draw. And I've been working and Reagan Stein and I have a smaller group of people have been working very hard to come up with algorithms to allow these patients to get most of their care still at Kaiser but to still volunteer for the study if they want to volunteer for the study. Hi I am 1 1 medicine positions here at UCSF. Um And thanks for being with us. So uh this is the raf trial that I'll be speaking about. It is um It's an R. 01. I'm looking at reno and hydra. Mommy hospital therapy. The principal the site is john Hopkins and um we're one of the co sites and we're looking at basically fetuses that are affected by bilateral renal genesis or early renal failure and the role of a serial and new infusions to achieve respiratory survival versus unexpected um management arm. And the primary outcome is looking at the proportion of neo nazis that survive to dialysis Next side. Um the next site goes into the inclusion exclusion criteria and I think I'll focus first on the inclusion criteria which are anhydrous remedios has to be confirmed before 22 weeks In cases of fatal renal failure or confirmed cobra which is a congenital bilateral renal a genesis before 26 weeks. Umm we request a normal carry a type, the mother should be over 18 years old. Um the willingness willingness to be followed at one of the rest centers, um and then also post natal care to be performed at a rap center. Um And it's um and we do a multidisciplinary uh consultation as a requirement before trial enrollment, which includes obviously maternal fetal medicine and pediatric nephrology, which we're working very closely with. And then there's some other exclusion criteria for review. Um So next I'll pass it on to Dr tippi Mackenzie. She is a professor um here at UCSF, both um a fetal surgeon and a pediatric surgeon and has the P. I. For some very exciting clinical trials. Thank you so much juan and thank you everyone for the invitation and attending. Um So I I want to talk to you guys about two. Phase one clinical trials of new fetal therapies for genetic diseases. The first is our enzyme replacement therapy clinical trial. Uh This is where we give the recombinant enzyme for some several license almost storage diseases before birth with the idea that it should improve outcomes because for many of the diseases, the organ specific damage happens in utero. So in this phase one trial, we're enrolling patients are fetuses with these diagnosis. So mps 1 to 4 A six and seven infantile onset pompe, a neuropathic Gosh and Wolman disease. And we think that um a lot of the patients will be diagnosed in families who already have an affected child or they've had previous affected pregnancies so that they will have early testing of the pregnancy by CVS or amniocentesis. And then after the diagnosis is made, we would do a video consultation and do non directive counseling. And then if they do want to participate in the clinical trial, they would come to UCSF where we would do the infusions juan Gonzales actually does the infusions. He's our a man with the magic hands, I always say. Um and so this would be done into the umbilical vein very similar to the in utero blood transfusions. That wanda's quite routinely and safely. The time period of the infusions is 18-35 weeks and they would be done every 2-4 weeks. Um again using the time interval that works for blood transfusions. And it's also the time interval that that these enzymes are given after birth. So the post natal care is standard of care. And we would be doing yearly follow up of these patients. I'm I'm really happy to say that we did just treat a patient in Canada with colleagues in Canada. The fetus had infantile onset pompe disease um in a family where they had lost two previous, excuse me, affected Children to the fatal cardiomyopathy, to the fatal cardiomyopathy. That happens sometimes in this in this disease. And after doing six infusions in utero. We had a term birth and that that patient has not had had any abnormal cardiac function and no hypertrophic cardiomyopathy. So we're really excited to partner with you in rolling patients with these diseases. And we've also partnered with the Mps society and and other international and national leaders to identify affected families and tell them about this possibility. Next slide please. Um And then I'll say a little bit more about our ongoing um in utero hematopoietic stem cell transplantation of bone marrow transplantation therapy for alpha thalassemia major. This is again at phase one clinical trial. This has been going on for several years and we have enrolled and treated five patients so far. What we're doing is we're transplanting stem cells from the mother to the affected fetus. With the idea that because the fetus and the mother are tolerant before birth, we shouldn't have to do any immuno suppression to transplant the cells. The fetus should not be rejecting maternal cells in the context of pregnancy. We are not doing any conditioning of the bone marrow to actually create space for those cells. Um And so the we expect that the in grafton of those cells will actually be low. But that potentially the in utero transplant could allow us to have tolerance to to the mother after birth so that we can do a second booster transplant this time with during the conditioning regimen to finally definitively cure the disease. Um We chose alpha thalassemia major as the first disease because these fetuses as you know, already needed in utero blood transfusion to survive a lot of them present with high drops and anemia. And so with the with our conversations with the FDA there was minimal additional procedural risk of doing the stem cell transplantation at the same time. Next slide. Um We are in the context of this trial. We are also keeping an international registry of patients with Alpha tell major as many of you know this is a this is a disease where patients have often been counseled to terminate the pregnancy because of the belief that after experiencing high drops even if they get some transfusions in utero, that there would be a poor neurologic outcome. Um But we have actually been finding from the results of the registry um and doing formal neurological testing on these survivors that those patients who get two or more in utero transfusions actually have normal neurologic testing and an excellent quality of life. So um we would we would urge you to contact us or put us in touch with families that that you you might encounter with a prenatal diagnosis of alpha thalassemia major. Next slide. And we'll just yeah. And these are the inclusion and exclusion criteria for the in Utero and stem cell transplantation trial. We are trying to do the stem cell transplant portion of it between 18-26 weeks. Um And um and we are continuing to do in utero transfusions every three weeks thereafter, next slide. And um we have been working with multiple um institutions so that although the in utero transplantation has to happen at UCSF, the subsequent care and subsequent transfusions can happen at the home institution. And I think this is kind of the same information. Next slide. Thank you so much.