#023 - Innovations in Prenatal Therapies: Insights from Dr. Tippi MacKenzie

Hello friends 👋

In this episode of the Incubator podcast, hosts David McCulley and Betsy Crouch engage with Dr. Tippi MacKenzie, a leading figure in fetal surgery and stem cell research. The conversation explores Dr. MacKenzie's journey from clinician to scientist, the challenges and innovations in fetal surgery, and the future of prenatal therapies. They discuss the importance of collaboration in research, the role of clinical trials, and the impact of genetic therapies on treating fetal conditions. The episode highlights the intersection of clinical practice and research, emphasizing the need for responsible advancements in medical science.

Link to episode on youtube: https://youtu.be/SPbYa2TthgU

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Short Bio: Tippi MacKenzie is a Professor of Surgery at the University of California, San Francisco and the Director of the Eli and Edythe Broad Institute for Regeneration Medicine. She is a pediatric and fetal surgeon who is focused on developing better ways to diagnose and treat genetic diseases before birth. She runs a translational research lab examining fetal immunology and maternal-fetal tolerance, with the ultimate goal of inventing new fetal therapies for patients with genetic diseases or pregnancy complications. She has moved two fetal molecular therapies from the lab to the clinic as phase 1 clinical trials after obtaining FDA approval: in utero hematopoietic stem cell transplantation to treat fetuses with alpha thalassemia and in utero enzyme replacement therapy in fetuses with lysosomal storage disorders. Her research has been supported by the National Institutes of Health, the March of Dimes, the California Institute for Regeneration Medicine, and the Burroughs-Wellcome Fund. Tippi has been elected to the American Society for Clinical Investigation and the National Academy of Medicine for her innovative work.

Tippi trained in classical piano at Juilliard before obtaining her undergraduate degree from Harvard College and her medical degree from Stanford University.  She completed her surgical residency at Brigham and Women’s Hospital in Boston and obtained additional fellowships in Fetal Surgery and Pediatric Surgery at the Children’s Hospital of Philadelphia.  She joined the faculty at the University of California, San Francisco in 2007 and is now a Professor of Surgery. Tippi is the co-founder of the Center for Maternal-Fetal Precision Medicine, whose mission is to accelerate the processes that link basic research to clinical trials to improve maternal, fetal, and neonatal health. This Center is testing methods to improve prenatal diagnosis of birth defects and developing new cellular and molecular therapies for definitive fetal treatment. Most recently, she is building a Center for Genome Surgery, a multi-disciplinary collaboration with the Innovative Genomics Institute, to develop methods to treat children and fetuses with genetic diseases. 

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Featured Manuscripts From Dr. MacKenzie

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The transcript of today's episode can be found below 👇

[00:00:02] David McCulley: Hello and welcome back to The Incubator: At the Bench, the neonatology physician scientist podcast where we're focusing on basic science research related to neonatal health. My name's David McCulley. I'm a neonatologist and a physician scientist at the University of California in San Diego, and I'm very lucky to be able to co-host this podcast with Dr. Betsy Crouch. Betsy, would you mind introducing yourself and our guest for today?

[00:00:29] Betsy Crouch: Happy to. Hi everyone. I'm Betsy Crouch. I'm an assistant professor at the University of California, north from David in San Francisco. I am a neuroscientist, a vascular biologist, and a neonatologist, as you all are aware. I'm very pleased to introduce today my neighbor, my very distinguished neighbor, who's also a good friend, Dr. Tippi McKenzie. Dr. McKenzie is a professor of surgery and the Benioff UCSF professor in children's health here at UCSF.

She's also the John G. Bose Distinguished Professor in Stem Cell and Tissue Biology. Recently in the past few years, she was elected as the Director of the Broad Stem Cell Center for the Institute of Regenerative Medicine here at UCSF. We have this very cool building that sits on the hill here at Mount Sutro. In addition, she was recently elected to the National Academy of Medicine. Thank you so much, Dr. McKenzie for being here with us today and we're excited to talk to you.

[00:01:43] Tippi MacKenzie: Thank you so much Betsy and David for inviting me. I'm excited to have this conversation.

[00:01:50] David McCulley: Could you start just by talking a little bit more about what your research focuses on and also what you do clinically? I think it's really exciting for our audience to hear how we've built these careers in studying the questions that we study, but also what we do as clinicians.

[00:02:08] Tippi MacKenzie: Thank you. My lab studies maternal fetal biology to understand disease onset and use that knowledge to develop therapies for patients with pregnancy complications and genetic diseases in the prenatal period. I'm trained as a surgeon. I trained as a pediatric and fetal surgeon, and I've been at UCSF for 18 years. This was my first job after fellowship.

For 14 years, I took call as a pediatric surgeon. I worked at the bedside with both of you, as you know. I love taking care of the babies, and I think it's an amazing relationship between surgeons and neonatologists to take care of these really vulnerable infants.

Four years ago, as Betsy said, when I became director of the Stem Cell Center, it just became too much to both have a surgical career and run a lab and run an institute. So for the past four years, I've stepped away from doing surgery. My clinical life right now is my clinical trials of new prenatal therapies.

[00:03:25] David McCulley: That's so exciting.

[00:03:28] Betsy Crouch: I have so much to jump in and talk about. I'll just say that, recognizing these early moments—Tippi and I together put my first baby on ECMO (extracorporeal membrane oxygenation) when I was an attending, who had a good outcome. It's these moments that you have with your friends and colleagues where you are really united in this common goal and you achieve that goal. And then you look at each other and think, "And how's your science going?" after the dust has settled at 2 AM. I'm really grateful to both of you for being able to have those clinical and scientific moments back to back.

[00:04:11] Tippi MacKenzie: Those are magic times for sure.

[00:04:13] Betsy Crouch: They are magic times, I think. One of the perks of this job is that there are these moments of inspiration that you get to capitalize on in the middle of the night when progress can be made, and it feels good.

[00:04:31] Tippi MacKenzie: It was so pure. We're just all working towards saving a child's life. That's really magical.

[00:04:43] David McCulley: Many different approaches using a lot of different skill sets. I was wondering about that, Tippi—could you describe a little bit what inspired you to focus on the questions that you're focusing on now and the research training that you had early in your career that allowed you to build your research interest?

[00:05:02] Tippi MacKenzie: Thanks for the question. My path to clinician-scientist mode was a pure MD path. I didn't take the time to get a PhD in medical school or before or after. But I'm really lucky that I've had amazing mentors that have taught me to do science along the way so that I could be successful running my own lab. To your listeners or viewers out there, you can be a clinician-scientist if you haven't gone through an MD-PhD program—you just have to be really focused and intentional about how you get that training.

In medical school, I was really lucky to work in the lab of Dr. Robert Sapolsky, who's an endocrinologist, anthropologist, biologist—just one of the most amazing human beings that I have worked with. Stanford has an interesting program where you can do your first two years in three years and do a lot of focused research. I learned in that lab just the love of science and the joy of discovery—just asking questions. He does curiosity-based research that has ended up translating. That was a really strong foundation.

When I went to surgery residency, as you guys know, everybody takes out a couple of years to do some scientific research. At the end of medical school when I was doing my rotations on my surgery rotation, I got to hear that this whole field of fetal surgery existed. Of course it was invented at UCSF in the 1980s. This was 1996. I was a surgery resident, my second to last year, four out of five. I thought to myself, "Wow, that sounds so interesting." With the freedom of being a student, I could just call the UCSF Division of Pediatric Surgery. It was before email. Somebody answered my call and was super helpful, and within a month, I was the nerdy sub-intern on Dr. Michael Harrison's surgery service.

As you guys know, he has been a pediatric surgeon here for many years and is widely regarded as the father of fetal surgery. I got to stand in a corner when Dr. Harrison did a sacrococcygeal teratoma resection on a second trimester patient. It was just the most incredible thing I'd seen. Talk about magic—20 people around the room just trying to take care of these two patients, the mother and the baby. The surgery was a success. You can imagine I was left thinking, "My God, that's literally what I want to do when I grow up."

A couple months later, I saw an article in the New England Journal that was the world's first in utero stem cell transplant in a pregnancy with severe combined immunodeficiency (SCID). That was done by Dr. Alan Flake and colleagues. All of these things kind of came together and I entered surgery residency thinking: A) I want to be a pediatric surgeon and B) I want to go figure out some of this stem cell transplantation stuff because you could tell even then that that was going to be the real future. There are the anatomic malformations that you can treat with surgery, but there are so many more genetic conditions that can benefit from scientific input into this field of surgery and obstetrics and gynecology.

I was lucky to take three years out to do research in Dr. Flake's lab. He was at CHOP (Children's Hospital of Philadelphia) by then and I really got a good foundation of flow cytometry and doing animal experiments and some of the other skills that you need, so that when I finally finished my surgery training and then my pediatric surgery fellowship—I ended up going to CHOP again—I was set up to start my lab here at UCSF.

[00:09:25] David McCulley: That is so exciting to hear. You have been inspired by so many great people whose research I followed so closely just because I have similar interests. I think it's so empowering to have the exposure that you had to be able to connect with people who are at the cutting edge of fetal surgery, at the cutting edge of prenatal treatment. That is so exciting. Because we've been really interested in how to enable more people to take this path of being a physician scientist, you mentioned that program at Stanford where you said you had more time to be able to focus on a research path. Could you just talk about that a little bit? Did you go in thinking that you might do that or how did you get introduced to that program?

[00:10:12] Tippi MacKenzie: It's just how Stanford Medical School works. I don't know if that's still how it works, but the most amazing part about it is you only pay for four years of medical school, but you can take as long as you want to finish. The majority of my classmates took five years. The usual breakdown of that was three years to do your coursework and then the standard two years to do your rotations. It also created an environment where basically everyone around you was doing some kind of research—clinical research, bench research, global health research. Because everyone is taking the two years and three years, you're not limited to your class. Your class is filled with first, second and third year students because everybody is doing a different combination of when they take immunology or genetics. It created an amazing environment. I'm sure there are other medical schools who do that, but it was a really special part of Stanford that made your MD feel like an MD-plus.

[00:11:26] Betsy Crouch: I think that's a great program to hear about. For folks who are actually pre-medical school, there are a number of more open-minded ways to consider medical school these days, thinking about the way that we practice medicine now—which is not that you have to memorize a bunch of things that are in a textbook, but that you have to know how to investigate a problem, know how to form a differential diagnosis about the patient who's in front of you, and also know how to push the field forward. To gain those two different skill sets, there's been a number of educational initiatives.

I'll just say one other program that I'm familiar with is that at Columbia, they have a three-year MD after getting a PhD. For folks who thought about being a scientist first and then decided that they wanted to go to medical school—I have a clinical fellow in my lab now who's an adult gastroenterologist who really tried hard not to go to medical school and wanted to be an educator. She did a PhD first and then realized that really taking care of people and their medical issues was her passion. Then she went and did the three-year program at Columbia. There are a number of other ways to conceptualize the traditional two and two years of medical school these days.

[00:12:48] Tippi MacKenzie: The other thing that's striking to me is in this day and age, knowledge is vast and growing at lightning speed. To think that any one person can obtain the training they need during their years of education to be successful no matter where the science and patient questions lead you, I think is a bit naive. I'm always thinking: do I have the training? When a scientific question comes up or when a patient problem comes up, it's really important to think, do I personally have the training to do this or do I need to phone a friend?

As Betsy knows, I'm always thinking about for a scientific question, who can we collaborate with? Who's got something to bring to the conversation? Because even if everybody around you has amazing training, they're all MD-PhDs, they all look at problems a little bit differently. I think it's a wonderful thing to consider working collaboratively, as Betsy and I have recently done.

[00:13:58] Betsy Crouch: Maybe that's a nice segue to getting into your research now. I was telling Tippi before we were on air that even though we're neighbors, it was a great opportunity over the weekend to really dive deep into her papers and the work coming out of the lab because I'm very familiar—to honor her for a second—about the way that she enables her trainees. There are a number of trainees who have been first author on these prominent papers that are now going on to put in a bunch of applications that I've been fortunate to support too. If you could speak a little bit about the research that you're currently investigating in the lab and where you see that going in the future, that's something that I'm very excited to talk about.

[00:14:45] Tippi MacKenzie: Thanks, Betsy. The lab really works broadly on understanding fetal biology so that we can treat genetic diseases in patients before birth. There's an enormous opportunity right now because of the convergence of three things. I mentioned Dr. Harrison invented fetal surgery in the 1980s, and now there are fetal treatment centers all over the world.

Prenatal diagnosis—it used to be you would just go get an ultrasound and we would look at, are there 10 fingers and 10 toes? Now ultrasound, MRI, everything has become more sophisticated, but there's also genetic screening. Parents are getting carrier testing before they conceive, and there's also more genetic testing even in mother's blood in the first trimester of pregnancy. There's an opportunity to diagnose genetic diseases that might not have any manifestation on the regular ultrasound screening.

Then with the invention of CRISPR by our UC Berkeley colleague, Dr. Jennifer Doudna, and additional inventions like base editing and prime editing by Dr. David Liu at Harvard, there is an amazing momentum to treat genetic diseases at their root cause. I'm really excited to put all of those things together so that we can develop programs to provide genomic therapies for patients before birth.

[00:16:32] David McCulley: That's very exciting. I have recognized the same convergence of those three things as being an incredible opportunity. It's amazing that you've been able to focus on it and really try to push it forward and try to get it ready for clinical trials, which it sounds like you're working on already. Was there a particular condition you started focusing on, or was it just thinking about, okay, what are the conditions where we could apply these approaches? How did you think about it and what's your approach right now?

[00:17:06] Tippi MacKenzie: Thanks for asking. There are a number of modalities that you can use to treat genetic diseases. The first one is the stem cell transplantation that I had read about when I was a medical student. When I started my lab, I wanted to sort of move down that path and work on stem cell transplantation. The disease we started with there is alpha thalassemia major, which is a condition where the alpha globin genes are either mutated or deleted. Patients get very sick before birth, usually in the second trimester, and they can be treated with in utero transfusions.

Initially we thought, well, maybe we can treat them with stem cell transplants. It turns out the biology isn't quite feasible for that because there's so much hypoxia in the fetus. Now we're working on a gene therapy and genome editing approach for that. Alpha thalassemia sort of came to top because you diagnose it before birth because there's an ultrasound finding. The fetuses develop fluid collections around the heart, around the liver. It's also very compelling because the pregnancy doesn't survive unless you do something, unless you do something like give blood transfusions and then there's an opportunity to do blood transfusions plus something else.

From there, we've moved on to other genetic diseases. Right now we have a clinical trial where we're giving enzyme replacement therapy to fetuses who have lysosomal storage diseases. Again, some of whom present with that hydrops finding of fluid collections around the liver usually, but also some who don't have any ultrasound findings, but we know from research for decades that there is onset of organ damage, often irreversible organ damage before birth.

The genomic approaches really have been tested only in animal models, and there hasn't been a human clinical trial of a genomic approach, either a gene therapy or genome editing, because, of course, we need to make sure that we're involving ethicists and patients and patient advocacy groups and really making sure that the genetic therapies we implement before birth are not going to be passed down over generations. There's a lot of work done in my lab and those of colleagues who are in this area to make sure that we're moving responsibly towards what might be a definitive cure for these patients.

[00:19:45] Betsy Crouch: I think about your platform, which is that you have currently—maybe these things will change—but you're thinking about stem cell therapies and then you're thinking about genetic or genomic therapies. To go back to the stem cell therapies, I think it can be educational to hear a little bit about some of the challenges that we've encountered. Do you mind telling us a little bit more about the biology of the stem cell therapy for alpha thalassemia and the lessons you've learned from that experience?

[00:20:18] Tippi MacKenzie: Of course. It goes back to that first report that I had read as a medical student where a child with severe combined immunodeficiency was treated successfully. After that, there was a lot of excitement in the field, and people came to realize that it really only works in case of immunodeficiency. That never made a lot of sense because the fetal immune system is supposed to be immature. So is it the fetal immune system that's then rejecting the cells that you're putting in in these other instances, or is it something else?

When I started my lab, a fascinating set of papers came out from Mike McCune's lab where they demonstrated that during development, fetuses develop regulatory T cells that recognize and protect against an immune response to their mother. This happens because cells cross the placenta back and forth. As you're training and educating the fetal immune system, you want to train it to recognize self and not reject its own self. These maternal cells that have been crossing into the fetus are sort of seen as self in a way, and they're developing the same kind of regulatory T cells as well as—in a mouse study we showed—that they're deleting T cells that are reactive against cells that are encountered during pregnancy.

That was a good reason to think, okay, well, if there are regulatory T cells against the maternal antigens, maybe we should be transplanting maternal cells. Looking back at the literature, people had not been transplanting maternal cells. Then there was another study, actually the first paper out of my lab, where we did a mouse study where we showed that in mice at least, the maternal immune system sort of coming in as a result of this trafficking—more cells come in and actually maternal T cells come in and they mediate rejection of other cells that you would have transplanted into fetuses. That was sort of a second reason to transplant maternal cells.

In the hubris of my youth, I was like, "I solved this decades-long problem. This is why the patients weren't engrafted. All we have to do is transplant maternal cells." At the same time, Dr. Flake's lab had actually—they were on the same path and they did an experiment in dogs where they transplanted maternal cells. Lo and behold, the dogs engrafted. They were tolerant to their moms. They got kidney transplants from their moms. All this was really exciting.

I wrote an investigational new drug (IND) proposal to the FDA to do the first clinical trial, because a true clinical trial hadn't been done in the field. I chose alpha thalassemia in conversation both with the FDA and with a set of colleagues around the world who care about this. I actually started a little society called iFetus so that we could all talk to each other so that everybody wasn't doing tooth transplants for this disease and three transplants for this other disease—different cell sources, et cetera.

We decided to go for fetuses with alpha thalassemia because they are so sick and there's this ethical rationale to try to do something. We did this trial and it was an amazingly rewarding part of my career because these patients didn't have any other options. They weren't even being given transfusions. We ended up doing a lot of outreach and public health and talking to obstetricians really all over the world and forming an international consortium. We ended up treating six patients and we just didn't get engraftment. We got very low levels of engraftment, not at all what we would have predicted based on the cell dose and what the dog study had shown.

Looking at the data more carefully, it seems like in the hypoxic environment of those fetuses, the bone marrow is so revved up, there's an expansion of red blood cell precursors and hematopoietic stem cells. If you sort of think about your donor cells playing musical chairs in the bone marrow with the host cells—because we're not doing any conditioning to wipe out the host bone marrow, the hematopoietic stem cells—it really might've been ethically the right disease, but it was biologically absolutely the worst disease probably.

I think it's a good lesson: you got to pick yourself up and figure out what you did wrong and what you're gonna do moving forward. For alpha thalassemia, we're all systems go in developing a gene therapy approach because that should work. Collaborating with Don Kohn at UCLA, who's developed lentiviral gene therapy approaches, as well as Kyle Cromer at UCSF, who's developing a genome editing approach to really try to figure out a different solution for these families because we have come to realize there are a lot of patients affected with alpha thalassemia and they have no curative options.

For the stem cell transplant, really thinking about, if alpha-thal was the worst possible disease, what's the best possible disease? That I think is Fanconi anemia, where it's a DNA repair defect. There should be a survival advantage to wild-type hematopoietic stem cells. Collaborating with Anishka Chekowicz at Stanford, who's an expert on Fanconi anemia and a close colleague and friend—she now is leading this, we're just helping. She did a fetal mouse study where she showed that when you transplant a fetal mouse, the level of engraftment goes up over time. There's a proof of concept there. She just got an IND to do a phase one trial of in utero stem cell transplantation in Fanconi anemia. You got to have resilience.

[00:26:33] Betsy Crouch: Bravo! I think that is the takeaway from the story, which is that the biology is telling you something, and it's telling you where your next step should be, even if the initial disappointment is not that the next step is, "Check, we're done. Check, we figured it out." Some more work to do on alpha-thal, but maybe for Fanconi anemia, it enabled maybe a faster acceleration of Anishka's study in that disease.

[00:27:10] Tippi MacKenzie: I hope so. I'm really excited about that trial.

[00:27:13] David McCulley: Just because we have kind of a broad audience, I was wondering, could you be even more clear about how the stem cells are given and how you know how they're engrafted or if they're not engrafted?

[00:27:25] Betsy Crouch: I want to talk a little bit about delivery as well, because I think that's also a really interesting problem when you have two patients, as we think about the prenatal baby.

[00:27:35] Tippi MacKenzie: I should preface—Dr. Harrison started doing fetal operations in the 1980s. But if you go back to the 1960s, people started giving blood transfusions to fetuses through the umbilical vein for a really common condition called Rh disease. If mom's Rh negative, baby's Rh positive, mom can develop antibodies after the first pregnancy. Those antibodies go in and chew up the red blood cells of the baby and so you can give blood transfusions. This is a really common procedure that's performed all over the world. It's technically delicate, but lots of talented maternal-fetal medicine doctors out there are doing it. It's ultrasound-based, so it's just little local numbing medicine on mom's belly, and then there's a longish needle that finds the umbilical vein and injects blood.

You can imagine that if you can inject red blood cell transfusions, then you can inject any of these medicines. That's how the stem cells are delivered. In our clinical trial and in the upcoming Fanconi anemia clinical trial, we're taking bone marrow stem cells from the mom. It is an involved procedure. Under the epidural anesthesia that you would get for childbirth, we do a standard iliac crest bone marrow harvest with the pediatric bone marrow transplant team. Then the cells are processed in the pediatric bone marrow transplant lab where they get the CD34 fraction and then spin it down to a very small volume because the fetus is tiny, and then we infuse them under ultrasound guidance.

That whole process takes about eight hours. It's always an amazingly exciting day with just a team of about 50 people touching everything along the way. That's how the stem cell transplants are done. That's also how the enzyme replacement therapy clinical trial is done, where we infuse the recombinant enzyme for the specific disease. That's how I imagine a gene therapy or genome editing approach would be done. We just submitted an investigational new drug application for an AAV (adeno-associated virus) gene therapy for a severe genetic disease called GM1 gangliosidosis.

The delivery isn't really the problem. It's the understanding of the biology and choosing the right patient population and really making sure we're working with the patients to figure out what would be a reasonable kind of therapeutic approach to then deliver.

[00:30:26] David McCulley: That's great. The other question is just—it's one thing to do these studies in mice where you can have a fluorescently labeled cell that we can follow and things like that. But when you're thinking about in a patient and in a clinical trial, how do you think about that? How do you know that you have engraftment or be able to follow the progress of the stem cells once they've been injected?

[00:30:50] Tippi MacKenzie: Great question. Thankfully there we can use the CLIA-certified lab tests that are used in the bone marrow transplant field where they are looking at genetic differences between the donor and the recipient using PCR to give percentages of engraftment. In the six patients in the clinical trial, we did two different kinds of tests because that clinical test is accurate and it's CLIA-certified, meaning you can report back results to the patient. It's only sensitive to about half a percentage point of engraftment, which of course, if you didn't engraft that half a percent, it didn't really do you any good.

In terms of the research method, we can actually go even more sensitive. For the clinical trial patients, we were also taking some blood for the research part of the test and doing flow cytometry to isolate specific cell populations and doing quantitative PCR on those specific cell populations. Then we could read out lower percentages of mother cells in the baby's blood. We did that throughout a year. We did some other research studies looking at, well, even if we had low engraftment, did we actually have tolerance to the maternal cells?

Because another part of the study, which I didn't mention, is that you don't really have to have a fully engrafted 10%, 20%, and therefore this is curative. You can actually have maybe you engraft about half a percent or 1%, but then that tolerance to the mom that the baby has before birth—if you continue to have some level of maternal cells, you can continue to make regulatory T cells to sustain that tolerance, and then you can do a booster transplant without all the immunosuppressive part of the conditioning that you usually do.

In two of the patients, we actually did see tolerance to maternal cells, even though their levels of engraftment were not in the curative range. In fact, for one of the patients, we got ready to do that booster transplant. But then the family didn't want to have another transplant. They were very happy with getting chronic once-a-month transfusions for their alpha thalassemia major. We weren't able to test that portion, sort of part B of this protocol. There are a lot of these research tests that you can also bring to play.

[00:33:30] Betsy Crouch: Is there also a way that—I mean, as we know, the definitive therapy would be a bone marrow transplant for the patient with the alpha thalassemia major. But is there a way that your prenatal transplant could make that process better or less—as we know, it's a dangerous procedure. All things being considered, there are many patients who undergo this, thankfully, without any complications. Have there been any insights into improving the current curative standard of care?

[00:34:06] Tippi MacKenzie: Great question. The current curative standard of care, as you said, it can be dangerous mainly because you have to do the conditioning of the bone marrow. For your viewers or listeners, there are two kinds of medicines you have to give to do a bone marrow transplant. One sort of wipes out the bone marrow so that there's space for your new cells. You wipe out the person's own hematopoietic stem cells in the bone marrow so that there's space. Then the second is you have to immunosuppress. You have to wipe out their T cells and B cells so that they don't reject the new cells coming in.

We're hoping—and neither of those is safe enough to do in the fetus. What we were hoping for the fetal transplant is you just give a lot of cells. Even if you haven't wiped out the bone marrow as they're playing musical chairs, they're going to sort of out-compete the host cells. We give a lot more cells than you would in a regular bone marrow transplant. Then you're transplanting from a donor that they're already tolerant to, so you shouldn't have to give the immunosuppressive conditioning. That's the hope.

What we're hoping for with the in utero transplant is even if it doesn't fully engraft, then after birth, you might still have to do that conditioning portion where you wipe out the bone marrow, but you don't have to do the immunosuppressive part of the conditioning because they're already tolerant to their mom or the donor that you've used. In terms of how to do, if they haven't had fetal therapy, how to do a regular bone marrow transplant safer, I think one of the things that's been helpful is just shining a light on this long-neglected disease and asking all of our colleagues around the world: How many patients with alpha thalassemia have you transplanted? What protocol did you use? Are there things we can learn from each other?

[00:36:08] Betsy Crouch: Thank you for that. I'll say that I get the benefit of walking in every day as I walk to my office. There are two sort of artistic pieces in the hallway that are present as I walk to my office. One is, Tippi has a map across the world of her patients who have enrolled in her clinical trials with little pushpins. I think it's really exciting to see where these patients are coming from, how they're hearing about this exciting research, to feel like we're—to be honest about it—like we're kind of a beacon of hope for certain long-neglected diseases. Then there's a picture of all of these babies or children who have been treated.

It's quite inspiring, I think, just to remember that the world is a big place and that there are collaborators—and I say that in terms of the scientists, but also the patients and the families. Tippi's done a lot of great work in collaborating with the patients and the families and understanding what are their goals and then in designing her both basic science and clinical trials towards the most important collaborators potentially, which is the patients. I'm grateful to you for putting those mementos and those signs up to remind us how we do our science matters. Thanks.

There are so many exciting directions to go in our last couple of minutes. Maybe industry collaborators, I think, is an exciting direction that our listeners would appreciate. I think getting some tips from you and your experience.

[00:38:02] Tippi MacKenzie: Thanks for the question. We've had some really fruitful collaborations with industry for testing some of the products that have been developed for patients after birth to determine whether or not they would be safe and effective to use before birth. For example, the lysosomal storage disease in utero clinical trial I mentioned. You can't do a clinical trial, of course, without doing some of the initial animal studies. We did a mouse study in collaboration with the industry partner who makes the postnatal enzyme for—in this case, we used MPS7 (mucopolysaccharidosis type 7), which is known as Sly syndrome. That was a really nice collaboration. From that, we were able to obtain data about the safety and efficacy for in utero enzyme replacement therapy so that we could present that to the FDA.

We've worked with industry partners to test various gene therapies, AAV gene therapies, and right now we're doing a lot of work in lipid nanoparticle delivery of genome editors in mouse models, prenatally in mouse models. We've also worked on antisense oligonucleotides, again, with the lead industry partners there to determine whether the product is safe and effective, even in a large animal study. I think it's hard to think about developing a therapy like purely academically to then take that all the way to the patient. That's where industry partnerships and collaborations can be so helpful. I've been really fortunate to be able to participate in those.

[00:39:50] Betsy Crouch: And how do you meet your industry partners? You put out an ad on a...

[00:39:55] Tippi MacKenzie: Great question. In some cases, at conferences probably, or through word of mouth, or through other academic collaborators. There have been a couple instances where I sort of cold emailed somebody. I think it's compelling to want to develop a treatment for patients before birth. We all have the same goal. We all have the goal of helping human beings. I think that people in general want to work together.

[00:40:38] Betsy Crouch: Cheers to that. I think it's compelling to want to cure, right? To truly cure diseases and to give a child a trajectory that they never would have had before when the opportunity is there prenatally that might not be there postnatally.

[00:40:55] Tippi MacKenzie: Exactly. The biological opportunity.

[00:40:59] David McCulley: I do think that's one of the most exciting things about our job—that as a physician scientist, we get to help promote these bridges that connect people who are inspired and interested to be able to do things for patients that don't otherwise have an effective therapy or treatment. I think it's such a unique opportunity to be able to see the patients as we do in the clinic or in the hospital and then be able to apply the research techniques that we've learned how to use and then be able to use our collaborations with other researchers who don't not necessarily have the same contact with patients but have a really incredible skill set or inspiration to be able to bring new therapies for patients who don't have otherwise effective treatment. That's an inspiring story that your research has been able to tell. So exciting to talk with you.

[00:41:50] Tippi MacKenzie: Thank you so much, David.

[00:41:53] Betsy Crouch: Should we wrap up with our traditional end-of-the-show question, which is: How do you and your team relax? What do you do when you're not investigating cutting-edge prenatal therapies?

[00:42:08] Tippi MacKenzie: Well, one of the traditions we have is our weekly tradition, which is we start lab meeting with Rosebud Thorn. Everybody—we go around the room: What's the best thing that happened to you last week? What's the worst thing that happened? And what are you looking forward to? It becomes a really nice check-in about what are people bringing to work that they would like to talk about. There's life celebrations. One of my grad students got married over the weekend. But then there are also challenging situations where that experiment didn't get done because this was happening in this person's life and what we look forward to. I started doing that with my children 10 years ago and it's sort of improved the dinner table conversation and I feel like it's been a really rewarding tradition we have in the lab now.

[00:43:15] Betsy Crouch: Can I say one other thing that I know about Tippi? Because I walk into her office almost every day is that she has a piano in her office. Tippi is also a Juilliard-trained pianist and she has headphones like this. To give a little bit of personal insight, she has this beautiful piano that she has invited my children to sit and play at when we're juggling different things. There's also some beautiful music that takes place in her office and around this Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Institute, thanks to her classical music training.

All righty, well, thank you so much, Dr. McKenzie, for being with us today, for sharing your insights on really prenatal cures, which I think should be hopefully an important tool in our toolbox moving forward. It's been beautiful to imagine this brave new world with you. David, anything further?

[00:44:14] David McCulley: No, that was great. It was so great to see you, Tippi. Your work is so inspiring. I think among the neonatology physician scientists that are listening to this and our trainees who are inspired to do work like you're doing, it's so empowering to hear how you built your career, what inspired you early on, and the questions you're asking now, and how you've been able to do the work that you're doing. Thank you so much for taking time to talk with us. We really appreciate it. And now it's time for your lab meeting. So hopefully you have another good Rose, Thorn, and Bud session.

[00:44:40] Tippi MacKenzie: Thank you so much, Betsy and David. I really appreciate the invitation and thank you for having this podcast. It's a really wonderful effort. Really appreciate the privilege of being on. Thank you.

[00:44:53] David McCulley: Excellent. Thank you so much, Betsy, and thanks to our audience for tuning in. We will be back in the new year with a new interview. Thank you so much and have a good day.

[00:45:04] Betsy Crouch: Stay tuned for more. Take care.