Melanie (Host): Welcome to the podcast series from the Specialists at Penn Medicine. I'm Melanie Cole, and today we're highlighting the Sickle Cell Program at Penn Medicine. Joining me is Dr. Nadia Don Ali. She's the director of the Sickle Cell Program at Penn Medicine and Dr. Scott Pesak. He's the Gene Therapy Lead and adult Thalassemia program Director at Penn Medicine.

Doctors, thank you so much for joining us today, Dr. Ali. I'd like to start with you, speak briefly about the causes of sickle cell disease. Who it affects, it's not just a children's disease, is it? Tell us a little bit about it.

Dr. Ali + Dr. Peslak: Absolutely. And first off, thank you so much for inviting us to be here today and to speak to our colleagues. So sickle cell anemia or sickle cell disease is a congenital. Mutation in the hemoglobin gene and alters the production of adult hemoglobin in all people, individuals. So what actually happens is that the mutation leads to hemoglobin.

Forming rigid polymers in deoxygenated red blood cells. I like to say like the red blood cells are like the bags, that carry oxygen throughout our body. And the hemoglobin is really important in delivering oxygen to our muscles and organs and allowing us to function, in people who have sickle cell anemia or sickle cell disease.

What ends up happening is that. When the red blood cell goes through the body and goes into areas with oxygen, content is lower. The hemoglobin That is mutated ends up forming these long lines that make the red blood cells change in shape. So they get stuck in places in our body.

They, often, do not survive very long and. You end up with chronic breaking apart of the red blood cells. This leads to the overall hemoglobin or blood cell level being lower, And then it also leads to periodic pain. Episodes and over time affects all parts of the body. So it's a congenital disorder that occurs in lots of people, millions of people, and it causes lots and lots of morbidity and mortality.

Melanie (Host): Well, thank you for that. So, Dr. Ali, sticking with you for just a second, how are the sickle cell programs at Penn Medicine And the Children's Hospital of Philadelphia reaching their respective patient populations for information and treatment? Tell us a little bit about the programs And the unique advantages that they hold.

Dr. Ali + Dr. Peslak: Well, at, Penn Medicine as well as the Children's Hospital of Philadelphia, we are very close to each other. I'm specifically working with the adult program here at Penn Medicine and. We do have multiple ways that we reach out to individuals living with sickle cell disease as well as specific programs for our patient's.

For example, we have a social worker in our program who meets with all of our patient And also has individual sessions for peer support where patient's can come together, allies of patient's can come to learn more about sickle cell and just living with the disease and. Speak with one another.

another newer initiative is that we at Penn Medicine have a community advisory board where we touch base and talk directly with our members about things that are ongoing in our program such as research, and get information from the community about what more programs we can have. In the past, we've also had events, like educational events in partnership with other community programs, community-based organizations to help deliver education to the community.

I'll also ask, Dr. Pesak has been with Penn Medicine longer than me, and he has participated in many of these programs and these outreach programs. Thank you, Dr. Ali, and it's a pleasure to be here as well, and really excited to be able to talk to the, the entire physician community about our sickle cell program here, at Penn.

I have been here at Penn for about 10 years or so. I, Study sickle cell disease in the lab as well as thalassemia. but I've been really involved in trying to, promote and educate our patient's and connect them with both the Children's Hospital of Philadelphia And the community. I will say our nursing team and our sickle cell coordinator team is really fantastic at the transitions.

From the pediatric to the adult phases of life, we have an excellent, embedded psychologist in our program that provides much of the mental health, coordination and care, for patient's, which is a, a major, burden of health in many of our sickle cell patient's. we have an excellent research team and we've have several different research registries that we're trying to understand how sickle cell disease affects patient throughout their lifespan, as well as developing new, interventional and Observational trials for sickle cell patient's, across the lifespan.

and, we have many connections with community organizations in Philadelphia, most notably the Crescent Foundation, as well as the Sickle Cell Disease Association of America, both of which really help to bring in patient's that are maybe outside the health system into our clinic, and to really receive comprehensive multidisciplinary care that allows them to not only survive, but thrive throughout, their young adulthood and into the later years of their life.

Melanie (Host): Dr. Ali, tell us about the approved drug therapies for the treatment of sickle cell disease and describe how those medications work and when they are indicated when they should be considered.

Dr. Ali + Dr. Peslak: unfortunately, we don't have very many, drugs in our toolbox currently there are only three drug modifying therapies that are FDA approved. the oldest and most well, Studied, is hydroxyurea. So hydroxyurea is actually a, traditionally a chemotherapy drug, that was initially used for, acute leukemias. but it has been studied, very thoroughly and found to.

Alter the production of hemoglobin in the bone marrow, And we can use this to our advantage And in people who are living with sickle cell anemia. Remember, anemia is a big part of the disease And the induction of fetal hemoglobin, which is a type of hemoglobin That is made in.

Before birth and really in the first six months of life. So after the first six months of life, we start to make adult hemoglobin, and that's where the sickle mutation causes problems. and you get sickle hemoglobin rather than adult hemoglobin. So hydroxyurea. Leads to the persistence and production of fetal hemoglobin.

we now have evidence to show that it is helpful to give as, as young as nine months of age. now that's not something I am doing, but That is where it is considered for patient's who have traditional sickle cell, anemia with two copies of the mutation. We say hemoglobin SS or s.

Beta thalassemia zero, which means that they only make sickle hemoglobin. this drug can help increase. Levels of fetal hemoglobin, which can help increase blood levels overall, it can help decreased ongoing hemolysis, and it's really been the longest studied medication that we have. It was originally approved back in 1995 after the multicenter, study of hydroxyurea.

MSH trial, it doesn't have a fancy acronym, but MSH trial came out, in New England Journal of Medicine in 1995, And we have a lot of good follow-up data, and particularly in adults, it helps. With longevity and decrease of morbidity and mortality. And most importantly, and how it originally got approved, it, decreases the amount of vasal occlusive events, including acute chest syndrome.

So hydroxyurea is really our number one tool that we have, and it has been well approved and well studied in children and adults. a couple of caveats is that. As I mentioned at the very beginning, it is a traditional chemotherapy drug And so we have to be very cautious about it because of potential, alterations that could be harmful in pregnant women or at the time of conception, so we are careful about that.

There are two other drugs that, I'll briefly mention. So, but Hydroxyurea is our number one and really is indicated for everyone with the classic sickle cell disease, hemoglobin SS and hemoglobin S beta zero, which clinically presents very similarly, at least in terms of hemoglobin levels. there are other types of sickle cell disease, hemoglobin sc.

And other combinations of this, of sickle hemoglobin, S beta TH plus, or sd. So other types of hemoglobin out there. Hydroxyurea is definitely indicated in everyone with the classic sickle cell anemia. The two other's are glutamine. And so both of Those are a little newer, but we have pretty good, not as good data, but, we have some and l-glutamine, was actually approved first in 2017.

L-Glutamine is an amino acid and it helps decrease oxidative stress within the red blood cell. Remember I said the problem with sickle cell anemia is that when there's deoxy oxygenation, you get rigid polymers forming, you get chronic hemolysis. So part of the. pathology in sickle cell disease is that there is susceptibility to oxidative stresses.

So, l-glutamine works by decreasing and fighting back against that oxidative stress That is ongoing in the red blood cells. And so this medication's a little. More difficult to take. It's a powder twice a day, but it can be mixed with a lot of things. And it has shown in original studies to decreased pain and how frequently there are pain episodes.

So, and This is something That is another tool that we can reach to, to see if it will help. And in my experience, it has been very beneficial. The third one, which is. Completely different, is, uh, cri, CRI for short, and it is an IV infusion And it's targets P selectin.

So, it is not specific to the red blood cells. Rather, it works on decreasing stickiness, inside the vessels. And this one is a little more mixed and nuanced. there's been some mixed study outcomes. It's a little harder to sometimes, think about prescribing because it is an infusion and patient's have to come to the infusion center.

But in that sense, some people actually do prefer it because it's not an everyday medication, but it is an infusion initially given once every two weeks just for two doses, And then monthly. This also. Did show decrease, time to first pain crises And the development of multiple pain crises in follow-up data.

It had mixed results, but it's still approved in the United States and I have found it to be very beneficial in some patient's. And if I could just add, two other points. one with, with Hydroxyurea, This is a medication That has been shown to be safe really all through childhood as well as adulthood.

One of the big questions was, do we use this only in patient's who have severe pain? And we've found through several studies, including something called the Baby Hug Study, it was published in 2011 that, hydroxyurea is safe. And effective in children starting at the age of two, all throughout their lifespan.

So really, I think with this drug, we're gonna change a natural history of sickle cell disease in a very positive way. And we're gonna see, patient's with much fewer, complications as they come into their adult life that are just becoming, adults and, and moving from the pediatric setting right now.

The other point I will say is that many patient's who have certain kinds of complications, including a history of stroke, something called acute chest syndrome, which is an inflammatory disease of the lungs or increased pressures in the heart, pulmonary hypertension, sometimes start regular red blood cell transfusions. Something called exchange transfusions in which we take.

Sickle cell blood out and transfuse in nons sickle cell blood. And this can really help to reduce the risk of recurrent stroke or other major complications or even severe pain, longer term. But I think the important point to make with all This is this can be very complex and, talking to, a comprehensive program like the one here.

At Hopin Penn Medicine, it is really critical. You know, we have five physicians and we're all excellent and a really excellent nurse practitioner as part of our practice where we, in addition to the entire team that we mentioned earlier, that helps to understand which treatments are right for which patient's, and being able to offer either established therapies, more advanced therapies and trials, or, even gene, the, which I know we'll get to in just a few minutes.

Melanie (Host): Thank you, both of you in such a comprehensive program with a multidisciplinary approach, and Dr. Pesak your work in the laboratory And the clinic is focused on the development of new therapies in sickle cell disease. Give us a little update on new and ongoing developments in your lab And the sickle cell field in general, because I think it's a pretty exciting time in your field.

Dr. Ali + Dr. Peslak: Absolutely. so my laboratory here at Penn, focuses on studying this fetal form of hemoglobin, as Dr. Ali mentioned before, the one That is changed and increased in the setting of hydroxyurea. We know that this works in many patient's, but sometimes even with the maximal dose of Hydrea in many patient's, we don't.

Achieve the effects that we want, which is really reducing as best we can and minimizing the amount of pain episodes that patient's experience, minimizing their, time in the hospital, maximizing their productivity, and ensuring they live productive lives. And so to do that, we are pursuing many different therapies. in my lab I study.

Switch from the fetal to the adult form of hemoglobin. So we use a variety of different techniques in the lab using animal models, using primary patient samples, using genetic CRISPR based screens to try to understand, what are the newest ways to be able to advance our therapies. And my colleague, Dr. Liz Traxler also works on this in the lab as well.

And, and, just recently published on a, beautiful genetic screen understanding many new targets that we can look at in the lab as a field. My laboratory is working on two things in particular. One is looking at a pathway involving a phosphatase, which is a, chemical that helps regulate the, activity of certain cells.

And we're trying to understand the mechanism of this. This is something called PP six C. the other is looking at, repurposing other medications that are used for other blood disorders, something called IMiDs to try to understand how this works, how the mechanism works, for you, a variety of high dimensional techniques, including looking at.

Something called proteomics. All the proteins that are changed transcriptomics, all the different, RNA that are changed And the messaging that's changed to really be able to not only use these in a safe way, but also potentially to be able to, develop new and better drugs, through engineering in our lab and many other's through the field And in collaboration with our industry partners, to be able to move this forward.

beyond fetal hemoglobin, which is what I focus on in lab. Many, other researchers throughout the country are trying to understand other ways to, change the effectiveness of red blood cells in a way that these are more durable, less likely to break down. There's a newer therapy that's being studied, something called mid pivot, which helps increase energy levels in red blood cells, and helps reduce the risk of these cells of sickling that's being studied in a large phase three trial that we have participated in here at Penn.

there's many other's that are trying to understand how do we change the individual risk of cells, to reduce the amount of sicking and to improve the health of these red blood cells. Again, to really allow our patient's to have the best quality of life possible. one of the things that we as a field are trying to figure out is how do we measure this?

how do we understand. What is best for patient's to be able to design clinical trials that are effective And then we can achieve appropriate endpoints. That's something we're really working on as a field to understand that better. but, one of the things that we know is, the most effective for achieving better outcomes in patient's is fetal hemoglobin.

And that's why I studied in my lab And we're excited to be able to, present much of this work at, uh, next year's American Society hematology meeting. well as the work that's been going on both at University of Pennsylvania And the Children's Hospital of Philadelphia, where I collaborate with many other, physicians including Dr. Garrett Global and Dr. Eugene Kross, as well as Dr. Abdu Malik and Stefano Revella.

All phenomenal physician scientists, that are working on sickle cell disease and thalassemia in a really, I think, comprehensive and unique, and creative way.

Melanie (Host): That's fascinating. And Dr. Pesak, along those lines, over the past several years, two new gene therapies have been approved for the treatment of sickle cell in adults. Describe a little bit about the clinical trials and research that led to these therapies And the link between this research And the sickle cell programs at the University of Pennsylvania and Children's Hospital of Philadelphia.

Dr. Ali + Dr. Peslak: Absolutely. so, there has been a, I would say a 20 five-year journey or more to try to. bring gene therapy based approaches, to patient's with both sickle cell disease and a related disorder that I take care of. Thalassemia, which is instead of a genetic change in the quality of the red cells, it's a decrease in the amount of, hemoglobin that's present.

And so there are similar gene therapy approaches for both of these disorders, but we'll focus on sickle cell disease today. both of these approaches, essentially require us to, what's called mobilize or move stem cells out of the bone marrow into the blood, using a a specific set of drugs.

And this case a sickle cell disease. We use something called PLE four or, uh, mossville, to be able to get these cells outta the bone marrow and to collect them using an apheresis procedure. We then can partner with one of, several different, industry partners to, change these stem cells in a way that provides benefit to patient's.

So the two approved, stem cell therapies. Or something called lovo cell, which is a gene addition therapy in which we add a nons sickling hemoglobin to, instructions to make a nons sickling hemoglobin to hematopoietic stem cells. or, um, something called exo cell, which is a gene editing approach in which we, change and decrease the amount of this repressor of fetal hemoglobin, something called BCL 11 A. So it's almost like taking BCL 11 A when it's there.

Prevents fetal hemoglobin from being expressed. If we take that break off, we take that BBC 11 A off, we can increase the levels of fetal hemoglobin. So either of these, either increasing fetal hemoglobin or expressing a non sickling hemoglobin, can significantly reduce in 90 to 95% of patient's that receive this therapy, the risk of acute pain episodes.

And so they're equivalent in terms of their effectiveness. it is a very long process. Once we collect these cells, um, they have to be sent to the company. It takes about. Three to four months to manufacture in addition to the five to six months before that when we had to collect these cells.

And then patient's have to be admitted to the hospital for what is essentially an autologous transplant. We're giving them UL and chemotherapy and infusing in these edited or gene edition cells, and allowing them to engraft and make new non sickling hemoglobin. I think it's, it's transformative, therapy. but we still are in early days, so we're really excited about offering this at Penn.

we have, now infused two thalassemia patient's with, the beta cell product, which is similar to Lobo cell and is a gene addition product. and they're doing great. we are, discussing our first sickle cell patient right now. Who will be, collecting stem cells and doing gene therapy in 2026. And we're excited about offering this broadly to the community.

But the caveats to This is that it's, it is a very long process. We need to make sure patient's are ready from a social perspective, from a psychological perspective, from a medical perspective, make sure their iron levels are good, make sure they understand the process. it does require fertility preservation, as patient's.

Getting UL and chemotherapy, need to preserve, their fertility, either their eggs or their sperm prior to the, chemotherapy being administered. and there is a small but significant risk of cancers related to the busulfan, And we know that the risk is higher in sickle cell patient's. And This is just, recent data at ASHRM that suggests that the risk of cancer in general is higher in sickle cell patient's.

So it's further augmented by these therapies. We're trying to reduce that by getting better ways to condition the bone marrow to remove The stem cells that make sickle hemoglobin, And in the field. And eventually we're going to be have the approach where we, we call in vivo gene therapy, where we can essentially give an infusion with the instructions to change the stem cell to make non-sick hemoglobin without the need for mobilization and chemotherapy and everything else.

But we are a few years away from that. We're excited for that as a field. but again, I think it's early days. It's a great option for a subset of patient's. It is one in which requires a significant discussion, and comprehensive evaluation, for patient's that might be interested in these cellular therapies.

Melanie (Host): Well, along those lines then, Dr. Ali, can you expand upon the treatment process, what it's like? In these therapies, as Dr. Pesak was mentioning, some of the complications and, prophylactic actions and initiatives that are taken, when these therapies are considered, do some of them have advantages in efficacy, safety, long-term effects?

Speak a little bit about what This is like for the patient's.

Dr. Ali + Dr. Peslak: Absolutely. and Dr. Pele also, he has much more experience with this than I do. however, like he mentioned, This is a transformative therapy. however, it is a very long process and one of the. Things that we need to think about initially is the busalan, which is the conditioning regimen that prepares your body's, bone marrow to receive the new, cell.

Product, which is your own cells, but still, they've been modified. So we, we want your body to take them in that conditioning process. Receiving the busalan we're basically wiping out your immune system. We are putting you at-risk for infections. We're wiping out all of your rapidly growing cells in your body.

So that's why fertility preservation is so important. Other rapidly growing cells include your uc mucosa, so having nausea, having sores in the mouth, mucositis, which is, uh, inflammation of the mucosa, especially in your mouth. So sores in the mouth, pain in the mouth, trouble eating and drinking in the first few weeks of getting this, it's a very, very long process and there can be a lot of.

Morbidity going through this process in itself. And then the engraftment period of these stem cells, your own stem cells, autologous, meaning they came from you, they belong to you, but they have to go back. They have to go find their home in your bone marrow again, And that process takes time.

And in the meantime, we support you with blood transfusions. Every time you get a blood transfusion, there is a small, very small risk of infusion reactions So, It takes time. We can support your red blood cells and platelets, but platelets take longer to come up than white blood cells.

So supporting you through this process with giving you platelet transfusions, blood transfusions, it is quite a lot. Dr. Paek, what else would you like to add? Yeah, I would say that That is, certainly the case. we rely and partner with, our really excellent colleagues, in the cell therapy and transplant center and on the gene therapy side, Dr. Allison, Lauren and Dr. David Porter, have been our, really close partners in ensuring that our patient's understand this whole process and are supported through the entire journey, particularly.

during the inpatient admission and during recovery. as your listeners know, Penn been a, a haven for cell therapy for many years, including CAR T therapy and bone marrow transplants. We were pioneers in many years in the field, so, you know, even though gene therapy. In sickle cell disease is relatively new to Penn.

We are very well-versed as an institution, as it is a hospital in taking care of patient's receiving cellular therapy. And our, physicians, our staff, our, cell transplant coordinators, our nursing staff, on the floors, really understand these side effects, how best to support patient's from a symptomatic perspective, and how to get them through this difficult period during admission to where they can be in the vast majority of the cases.

Without significant recurrent pain episodes, And in a really transformative way.

Melanie (Host): Dr. Ali, do you have some final thoughts on how someone would contact the sickle cell program at Penn Medicine? If they needed to refer a patient or just want more information, I'd like you to offer up a summary as well.

Dr. Ali + Dr. Peslak: Absolutely. and I don't have the clinic number off the top of my head. Dr. PE does, but yeah, it's, it's 2 1 5 6 1 5 6 5 5 5 is our main number. so That is the contact number for anybody That is interested in, referral to the Sickle Cell program, either for a one time consult visit for a comprehensive visit for advanced therapy discussion.

we currently do not have any open. Clinical trials right now, but we will in 2026 and we're working on that. And so happy to, discuss in any way with patient's. But That is the number 2 1 5 6 1 5 6 5 5 5. And so if you call the clinic line, that will, um, be redirected to our nurse navigator who will, assess, all the information given, um, give.

The person, patient, referring provider, anyone a call back to clarify. And That is going to be the best way to, refer a patient into our practice for evaluation, either a one-time consult or for continuous care. so we're very lucky that we have, Antoinette Lemon is our nurse navigator with our program.

in summary, we have a comprehensive sickle cell program. We have multidisciplinary care. We have very well trained physicians, physician scientists who are actively involved in research. We also partner with, psychologists, social workers, as well as many other medicine subspecialists throughout the Penn medicine. Healthcare organization to give our patient's the best care possible.

we're very excited for, the future of sickle cell disease And the future of care of our patient's at Penn Medicine. So, thank you, Dr. Ali, for your, your leadership in this, in this realm. It's, it's, uh, it's really an exciting time, I think for the program here And for, improving care for our patient's.

Absolutely.

Melanie (Host): Thank you both so much for joining us today and telling us about such a comprehensive approach at Penn Medicine for sharing your expertise. Thank you again for joining us and to refer your patient to Dr. Ali or Dr. Pesak at Penn Medicine, please call our twenty four seven provider only line at 8 7 7 9 3 7 Penn.

Or you could submit your referral via our secure online referral form by visiting our website@pennmedicine.org slash refer your patient. That concludes this episode from the Specialists at Penn Medicine. I'm Melanie Cole.