Dr. Mike Smith (Host): This is Pediatric Insights: Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. I'm Dr. Mike. And with me are Dr. Saima Kayani, a pediatric neurologist at Children's Health and Associate Professor at UT Southwestern, and Dr. Victor Aquino, pediatric hematologist oncologist at Children's Health and professor at UT Southwestern.

Welcome to the show. I'm excited to have you guys on today. We're going to dive into gene therapy, specifically Skysona, and examine, you know, which children this can help, how it's delivered, what kind of care is involved, and kind of what is the future impact on pediatric gene therapy.

So again, welcome to the show. Dr. Kayani, I want to start with you. Can you tell us a little bit about Skysona and who it treats, how this is administered.

Saima Kayani, MD: Skysona is a cell-based gene therapy that was recently approved by FDA for patients with adrenoleukodystrophy, specifically the cerebral form of adrenoleukodystrophy. So when we talk about adrenoleukodystrophy, it's a very rare X-linked genetic disorder, which is caused by a defect in ABCD1 gene. As I said, it's a rare disorder. So, the prevalence is one in 15,000 newborns. The reason it has become more important to know about adrenoleukodystrophy, specifically the cerebral form of adrenoleukodystrophy, is because Texas state started newborn screening for ALD in 2019. So, these patients are diagnosed very early on in life, and the idea is that, with efficient diagnosis, we can bring efficient access to the treatment options that are available for ALD, and Skysona being one of those.

Host: Dr. Aquino, you know, it's my understanding that Children's Health is one of a limited number of centers in the US that offers this type of gene therapy. Why is this so limited to so few centers?

Victor Aquino, MD: So, it's difficult to make the gene therapy. It's also needed to be administered in a center with expertise in gene therapy. And so, we're one of the centers that has, over the years, built a gene therapy program that can provide these therapies to people.

Host: Dr. Kayani, prior to the gene therapy, what was the treatment like for these patients?

Saima Kayani, MD: This is a loaded question. So, let me give you a little bit of context for adrenal leukodystrophy. Being a rare brain disorder, this was not diagnosed appropriately or within a timeframe where we could provide therapy for these kids. adrenal leukodystrophy, when diagnosed early, the kids they are referred to a bone marrow transplant center where they can get bone marrow transplant.

But before newborn screen was implemented in Texas, most of these kids, they were not diagnosed within the timeframe where we had the window of treatment. So unfortunately, their disease was advanced enough to where we could not offer them any treatment options. But bone marrow transplant is one of the treatment options. But now, keeping in mind, there are some patients with ALD who will not have a perfect match for bone marrow transplant. And when that happens, first of all, they have to be diagnosed within the timeframe where we can offer the treatment.

Secondly, they have to have a perfect match for bone marrow transplant. And if there was no match, then unfortunately we didn't have any options for treatment for this horrible disease.

Host: Dr. Aquino, can you lay out a little bit just how this works, this specific gene therapy works to improve the patient outcome?

Victor Aquino, MD: So, the patient's lack a gene, as Dr. Kayani said. And so, what we do is we actually have a way to make bone marrow cells come out into the blood by giving a medicine called GCSF. And then, we can collect those up in a machine through an IV. We then send those cells to the company. They then do the gene therapy, which is inserting the defective gene into the cells, and then they send them back to us, and then we infuse them into the patient.

Host: How long does that take from start to finish?

Victor Aquino, MD: Yeah. So, it usually takes about eight to 10 weeks to process the cells and return them back to us. Sometimes we don't collect enough cells or the cells don't get enough of the gene in them and we have to repeat that. So, you're looking at about two to three months before we can start the process of doing the gene therapy.

Host: How do you know when a patient is going to respond here? How do you know it's good to move forward with this therapy?

Victor Aquino, MD: So, we usually offer it to all patients. We do screening to make sure they're healthy enough to go through the gene therapy. That's absolutely the only requirement. Also, it only works for children early in their disease process. And so, we do an MRI to make sure that their adrenal leukodystrophy hasn't progressed. So as long as that MRI looks okay, then we can proceed with gene therapy.

Host: And Dr. Kayani, how do you know when this is working? Are there early signs that signal this is, "Okay, we're stabilizing the disease here"?

Saima Kayani, MD: Yeah, absolutely. So, again, in order to properly answer this question, let's understand this disease. Adrenoleukodystrophy, it can present with either adrenal gland insufficiency. But in 30 to 40% of the boys, it will start affecting the white matter of the brain. It slowly causes destruction of the white matter of the brain to where these patients can develop early-onset dementia-like picture, right? They start losing their developmental skills. By the time they have clinical symptoms, most of the time, it is too late for us to treat. So, years and decades of research in this disease has given us a very good biomarker, which is MRI. Early signs of the disease can be seen in the form of inflammation, that can only be seen on the MRI.

So, here at Children's, we have a program where, when they are referred to our center, we have this sort of like a virtual multidisciplinary clinic between genetics, neurology, endocrinology, and Dr. Aquino's bone marrow transplant clinic, where these patients, when they enter our centers, we diagnose them. After confirming the diagnosis, they come to my clinic for neurologic surveillance, and they go to endocrinology clinic for adrenal gland monitoring.

So, neurologic brain disease monitoring starts very early on in life for these kids. We get serial MRIs. They get MRI once a year until they turn three years of age. And after three years of age, we get MRIs every six months. So as soon as we see that there is early signs of disease in the MRI. So, when we do the MRI, there is a scoring system which we call it low score. It assesses or it gives us the disease burden, right? So, the score can go anywhere from one to thirty-four, but we cannot treat if the score is above nine, right? So as the disease progresses, we see signs of inflammation. The first sign of inflammation when I see that this is happening, we refer these kids to Dr. Aquino's clinic right away. And they have been really amazing in getting our patients in within a few days.

And when they're diagnosed at birth with adrenoleukodystrophy, now these kids are already have a tissue typing to where we start looking for their bone marrow match. If bone marrow match is not there, then Skysona is an option. So, these kids, they come into the clinic at first sign of brain inflammation or brain disease. And they get a prompt consultation with our bone marrow transplant team, which leads to either, you know, bone marrow transplant or Skysona, which is great considering that most of these kids were never diagnosed in a timely way where we could offer them any treatment.

Now, with early diagnosis, we have this efficient monitoring system for them at Children's, which leads to very early detection and timely treatment options are provided to these families and that's, you know, our mission. And we are glad to be part of that team. So, this is how these kids are detected now based on the MRI.

There will be other options of like monitoring. We are trying to discover more like, you know, biomarkers in the blood, which may help us detect the brain disease, maybe in future without doing MRI. But at this point, we are doing MRIs and blood testing as an exploration to kind of find some blood biomarkers for disease.

Host: Early on, what are the outcomes we're looking at? What are we measuring here? And what are those outcomes that we're following over time?

Victor Aquino, MD: So, the main things we look at is we do have ways to tell if the gene is in the cells in the patient. So, we do send testing to the company to make sure that they see the gene product in the patient. And then, like Dr. Kayani said, then the second thing is we measure to make sure there's enough of the enzyme. And then, the third and the most important thing is to make sure the MRI isn't showing progression of the lesions in the brain on MRI.

Saima Kayani, MD: Once MRI starts showing early signs of inflammation, this disease is relentless. It never stops until it affects the whole brain. So, halting the progression of the disease in MRI is a very important sign that this treatment is working. And in early phase, you know, one of the most important things that we are monitoring in addition to efficacy assessments is safety.

Host: Well, tell us a little bit about that. Like, when a patient goes through this, what kind of safety record are we looking at?

Victor Aquino, MD: So, the gene therapy works almost all the time. So usually, when we do it, we see the gene is working. There are some risks to the gene therapy. The main risk is the development of leukemia. There have been some children who when they receive gene therapy have developed leukemia. So, we have a way to watch for that. And if it occurs, we can offer treatments. Usually, it's a regular bone marrow transplant.

Host: Now, this question is for both of you. We'll start with Dr. Kayani. What have you learned from all of this? And what do you think can be applied to future gene therapy?

Saima Kayani, MD: First of all, I mean, I'm a clinician, and then, you know, if I wear my clinician hat, I think this early screening, and getting these patients to early therapy and treatment, a few years ago, five years ago, if you asked me, like, you know, how do we diagnose and treat ALD, we probably wouldn't know much, right? But at this point, we have a cohort of close to 50 patients that are being monitored in our clinic. And we have treated a few patients with bone marrow transplant, and one patient received Skysona last year. So we have learned a lot about this disease.

We have learned, being at center, one of the six centers, in the nation who provide the Skysona, the monitoring, the safety monitoring of these patients, learning about how the long-term follow-up. So every time a patient gets Skysona, they are enrolled into a long-term follow-up study.

We are part of that, so we are learning the long-term impacts, because the knowledge is just not based on our own patients, right? So, we have access to everybody else, their data, like everybody else who has gotten Skysona and how they are doing and what stage, they are at and how these kids are thriving.

We do neuropsych assessments for these kids at yearly intervals. And we are seeing that this gene therapy really works as efficiently as bone marrow transplant does. And just becoming the expert in this rare disorder, not only from the diagnostic standpoint, but from the treatment and long-term management is something that, I think, is a very valuable thing. So for our community, we can provide the care, and our patients don't have to travel like to East Coast or West Coast to get this treatment that is life-saving.

Host: Dr. Aquino, I'd like to hear what you've learned. And also, if you could answer how can physicians refer patients to you?

Victor Aquino, MD: Yeah, what I've learned is it takes a lot of infrastructure to do this that we have built out over time for our various gene therapy products that we offer. And basically, we've built a multidisciplinary team that includes endocrine and neurology and us, because you really need more than just one type of physician to take care of these patients.

So, how can they be referred to us? Certainly, most of the patients are now identified on newborn screening. Dr. Kayani sees them. If people are interested in referring patients, we have a gene therapy website that you can go to at childrens.com. And there's a number to refer them to our center, so that we can start the process.

Host: This has been fantastic information. So many more questions. I'd love to have you guys come back on. I know there's so much more, that we could have talked about, but this was fantastic. Thank you so much for your time today. You can find more information at childrens.com. And if you found this podcast helpful, please rate, review, and share the episode and follow Children's Health on your social channels. This is Pediatric Insights: Advances and Innovations with Children's Health. I'm Dr. Mike. Thanks for listening