Lysosomal Storage Disease Program

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances at Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Rabi Hanna, Chair of Pediatric Hematology, Oncology and Blood and Marrow Transplantation at Cleveland Clinic Children's and Dr. Angelika Erwin, a medical oncologist at the Center for Personalized Genetic Healthcare at Cleveland Clinic. So welcome, Rabi. Welcome, Angelika.

Rabi Hanna, MD: Thank you so much, Dale. I'm so excited and happy to be here.

Angelika Erwin, MD: Thank you for having us.

Dale Shepard, MD, PhD: Absolutely. So maybe to start, you can tell us a little bit about your roles at Cleveland Clinic. So Angelika, maybe we'll start with you.

Angelika Erwin, MD: Sure, yeah. So I'm a medical geneticist and I started at the Cleveland Clinic in 2014. I also have a background in internal medicine, but in genetics we do treat all different age groups. So really, I see patients from infancy on up to adulthood. So I do see patients with all different kinds of rare conditions, different rare diagnosis, and for all kinds of indications. But really my expertise is in the area of the lysosomal storage disorders, which is what we're going to talk about today. So I'm very excited to be here.

Dale Shepard, MD, PhD: Excellent. Rabi, tell us a little bit about what you do here.

Rabi Hanna, MD: So I am a pediatric oncologist and I lead the Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation. What it is so unique about BMT in pediatrics, that almost 40% of it, it's done for nonmalignant diseases, including diseases like lysosomal storage disease, few of them, and that's how I really developed this interest in many of the genetic diseases, that they are lifelong and they can really severely affect both the patient health and their quality of life. And that's how I came to interact with Dr. Erwin, and so happy to be here today to talk about lysosomal storage disease.

Dale Shepard, MD, PhD: Excellent. So we have a somewhat diverse group that might be listening. So lysosomal storage diseases... What exactly are we talking about? Give us some examples of these disorders. Rabi, maybe I'll have you cover that.

Rabi Hanna, MD: I think that's a fantastic question because it is really a heterogeneous group of diseases. Think of this lysosomes as the enzymes that are inside the cells. They are the digestive system of our cells. They help to break down proteins, fats. And if there is a deficiency in them, this substrate, either protein or fats or polysaccharides, would accumulate in the different cells, either bone, brain, heart, and different organs. And it can lead to really very variable manifestation that some of them can be very severe, and that affect the life and they can die quickly. Some of them can be more progressive and late onset that they can be only seen in adulthood. And there is more than 50 types of diseases. And there is always a new development of this discovery of metabolites and metabolism diseases. I usually really interact with the ones that are the more severe, and they start earlier in life, in either childhood.

And I'm so excited also that our healthcare system, states, has paid attention to the prognosis of this disease and that some of them can be potentially cured. So few of them are actually are incorporated into the newborn screening for pediatrician and others, that they may see some of that tests on this sample test that they do on the pricker from the fingers or the heels, that they could come up couple of weeks later, it will show maybe that there is a risk for developing mucopolysaccharidosis, or Krabbe or adrenoleukodystrophy. Those are three of the very severe diseases that if we could diagnose them early, probably could offer them some lifesaving therapy. And that's the importance of why we need to do that in the newborn screen. And I hope that the whole United States soon would be screened for many of these diseases.

Dale Shepard, MD, PhD: Give us an idea for perspective, how prevalent are these, how many patients are affected by these diseases? So Rabi, I'm going to let you take that one. And then we'll talk about the program with Dr. Erwin.

Rabi Hanna, MD: It is really very rare diseases. And I think collectively, all of these risks will lead to seeing probably, depending on where the size of the center that you practice, it will be still few. But speaking of hematologist, actually, I will tell you that there was a patient who come to us frequently, has been diagnosed as a chronic ITP, thrombocytopenia. And she turned to be a Gaucher disease because this patient will have this cells affect the bone marrow, and it will lead to less production and their spleen will be big too. So she was treated for many years as a chronic ITP, with different biologics and steroid, and others that by checking the enzymes, we quickly diagnosed her and we were able to treat her and help her.

We have a different patient with Niemann-Pick. They are very rare, one per million, but collectively all of these diseases together, it would really lead to probably seeing a few patients every year here and there collectively. I think it's going to depend on how big is the center. But especially for hematologists or even an oncologist who may see a huge liver, spleen, I think it's important to think about this lysosomal storage disease that could mimic with hepatosplenomegaly and some other hematological manifestation.

Dale Shepard, MD, PhD: So, Angelika is a medical geneticist. How did you get interested in lysosomal storage disorders, and tell us a little bit about the program.

Angelika Erwin, MD: Sure, yeah. So all of those disorders are hereditary in genetic conditions and that's where the geneticists comes in. We usually see those patients when there is, either a suspicion or if they have already been diagnosed by another specialist, to often to confirm the diagnosis, either via biochemical or molecular testing, and then also to make sure that we educate the family about recurrence risk or identify additional family members. Almost all of those conditions have recessive inheritance. So we often don't see a family history, but then there are a few that have excellent inheritance. And so we may detect other family members, either a parent or a sibling, or other family members in those X-linked disorders who also require treatment and medical management.

And so I am quite interested during fellowship because I did my genetics training at a large lysosomal center where there was lysosomal disease program. And so I really was exposed to a broad variety of these lysosomal storage disorders. And what really fascinated me is that there is treatment, at least for some of those disorders. And so we can really help the patient especially if we identify them early and diagnose them early. And you also don't just see the patient one time, which often is the case in genetics. We diagnose them and then often, there's nothing else to do. And so then they go on and are followed by other specialists. But in those lysosomal storage disorders, you really do follow them a longer time and build this very close patient-physician connection. And so that really fascinated me and I really enjoyed working with the patients. And so when I started at the Cleveland Clinic, I took on the patients who were already followed in the department who had lysosomal storage disorders.

And then in a pretty short period of time, I grew the program. I grew that patient population through outside referrals through the newborn screen that was implemented in Ohio. And as Rabi mentioned, that while the individual disease may be rare, the collective is actually not that rare. And so we do find a good number of patients every year who are newly diagnosed.

So all of these disorders are multisystemic disorders. So without exception, every single disorder affects multiple different organ systems. And so those patients have a multitude of medical needs and all of them are followed by several subspecialists. And I noticed that whenever a patient was newly diagnosed, it was always on top of the new diagnosis, a burden for the patient to identify a subspecialist in whatever disease area they needed care for, who had expertise in their rare disorder.

And so after having worked with these patients for a while, I formed pretty close connections with other subspecialists at the Cleveland Clinic, who had already patients with lysosomal storage disorders that they were following and who had expertise in the area, such as Rabi. And so at some point I decided, or we decided to just pull this group of specialists together and form a lysosomal storage disease program.

This way, newly diagnosed patients can be referred to subspecialists within our team. And this really ensures that first of all, the patient is referred to a subspecialist who is familiar with their rare disorder and can provide the most up to date. And it also, I think, improves their healthcare because there is very good communication between us lysosomal storage disease experts.

And that takes off the burden of the patient to have to make sure that all of their physicians are on the same page because we really communicate with each other, especially when we have, and just as an example, we are following some patients with a rare storage disease, which is called mucopolysaccharidosis, and they have neurologic involvement. They needed an MRI of their brain. At the same time, they needed an MRI of the spine. They also needed dental work. And so we really worked hard together to make sure that sedation had only to be done once. And all of those imaging, as well as the dental work and whatever will be done could be done at the same time. And so I think it's, it's extremely important to improve or optimize those patients' healthcare and medical care as we're working together as a group. So it's really important to optimize, to work together as a group to optimize these patients' medical care.

Dale Shepard, MD, PhD: Now, in terms of working together, certainly you have a collection of specialists at the clinic that you're working with. What does that look like in terms of collaboration with community providers, because as a rare disease, I can imagine that a lot of patients come from a distance. How does that collaboration work?

Angelika Erwin, MD: I think that's an excellent question, because you are right. We do have patients who come from pretty far away sometimes. And again, here we have, as a group we have the advantage of trying to coordinate their appointments, to try to coordinate their care so they don't have to drive it back and forth multiple times. We really try to fit all of their appointments for as many as possible in their one visit. And sometimes they only have to come up once per year and we do all of their appointments at that time.

Sometimes, it's more often depending on what kind of disorder and what is needed. We also reach out and we also work closely with community providers in patients who need ongoing treatment. And so for patients who are close to the Cleveland Clinic, it is a little bit easier because Dr. Hanna is doing infusions and other treatments in his infusion center, and so those are treated on site. But then if a patient lives three hours away, we don't want them to have to drive three hours every other week to come and get treatments. So we do work closely also with community providers to either enable that they get or make sure that they get their infusions in the treatment locally. Or sometimes we have patients in home infusions, but they always have to start in a hospital setting when they start on treatments.

So I think having this core group at the Cleveland Clinic that can take care of all of the subspecialty needs is very important. And I think having that close connection to their community providers is another important part of their medical care, and we really do try to work with them very closely.

Dale Shepard, MD, PhD: So Rabi is a programmatic big picture thought. How have you been able to leverage virtual second opinions and telemedicine, and things like that into managing these patients?

Rabi Hanna, MD: It has been really very helpful. I think if you put the patient at the center of the care, and going back to your question about collaboration with the community, we have to work with the community and number one task for us, I feel it is actually increasing awareness and education. And we just recently have a patient where we got really a compassionate use for a new enzyme therapy for them. We had to work with a pediatrician to be able to get some of the screening, some of the tests done locally and to really educate the physicians about that, because the family lives three hours, those are very rare. They don't all live in Northeast Ohio. And we did as much as possible and we incorporated that in our evaluation with IMT that they will allow us to do virtual visits for the screening and some of the follow up.

Unfortunately, I wish we could have done more of the enzyme therapy even there. But I think at this moment that there are phases, some therapies, they would be required to come. And then we work with them. Hopefully later, as Dr. Erwin mentioned, we have patients now that are on home infusion. So we work with different home care services to educate them about not only pediatrics, but also these rare diseases, these rare enzymes. And that's where I feel that the benefit of having the program, it becomes a resource for the community to educate and to help address any problem, and learn from each other. Because sometimes, we hear from what nephrologists were able to do or others that could help us even as a hematologist. And I wear one of the hat as the medical director of our infusion. So it helps us to even learn new ways to be able to deliver the care to the patient instead of just trying to make that a burden for them, because this are lifelong diseases, and we really have to keep that in mind.

Dale Shepard, MD, PhD: Dr. Erwin, when you think about awareness, how closely do you work with patient support groups and advocacy groups for these rare diseases?

Angelika Erwin, MD: I think you have to work very closely with them. Sometimes, obviously we have to keep up the boundaries from pharmaceutical companies, and patient advocacy groups and the treating physicians. But I think overall in these rare diseases, we have to work closely together. You know, I participate in patient outreach events. I speak to patient groups. I also do physician education to really make sure that we don't forget about those rare diseases, that we raise awareness, and that the physicians who are often the ones to see those patients first, because I'm not the one who sees the patients first.

Usually, they're seen by somebody like a hepatologist because they have enlarged liver, or by a hematologist because they have very low platelet counts. And so we really have to make sure that we continue raising awareness, educating so that the physicians who are the first contact with the patient, that they have these rare disorders on their screen, and that they include those in their differential diagnosis. We do work closely together with the goal to diagnose patients early so that we can reach our goal and treat them, get them on treatment early if treatment is available.

Dale Shepard, MD, PhD: And I guess in terms of treatments, Rabi, you mentioned bone marrow transplants. Tell me a little bit about that and what kind of diseases might be best applicable for that patient selection. That's always seems to be a big issue with transplants, and sounds like sometimes these patients might have a lot of multi-system problems. So how do you address a transplant and a complex patient like this?

Rabi Hanna, MD: Excellent question, and I think that's really challenging. Because luckily now, we are in a different situation than 20 years ago, to be honest, when first bone marrow transplant was offered for a patient with Hurler's syndrome, which is a mucopolysaccharide type one.

So Hurler's disease is really the prime example of a disease that will benefit from bone marrow transplant because the enzyme deficiency will lead to an increase in the substrate. And that will precipitate in the different cells, including the bones, including the heart. It will lead to heart defect, mitral valve or others also. And the longer you go without therapy, there is more effect on these organs, especially also the brain. So it is critical to diagnose early because the bone marrow transplant, this hematopoietic cells have the ability to produce this enzyme and prevent any further damage. But it doesn't go back in the time. It will not go back and correct what it is, that damage has happened and occurred to either the brain or the heart or others.

So that's the benefit of it really, and there has been studies to show if you do bone marrow transplant in the first year of life. So infants, we are talking about them, the outcome, especially from cognitive, it is much better compared if you do a bone marrow transplant for them later, as they are toddlers, which is what has been in the past because there was a delay in diagnosis. And there are a few other diseases like adrenoleukodystrophy, that sometimes doesn't manifest until a little bit later. And when they are symptomatic, unfortunately, the damage has happened at so much to the brain that even if you do bone marrow transplant, you are not going to help prevent any further progressing.

So it is important to really... Back to your question, about how do we make that decision, that's back to the benefit of having a program. So we usually have our neurologist to make an assessment. If that neurocognitive is at the stage, we have neuropsych testing. We will have even sometimes bioethics involved. If we really... Sometimes we feel the parents are pushing and we are trying to weigh that, is there a true benefit, or if this is going to be a futile care. But I think with a newborn screen, hopefully we are going to detect more earlier patients and be able to offer them bone marrow transplant. And I do hope really that the therapies are going to continue to evolve and we are excited.

Also one of the benefit of having a program, we could attract pharma to be able to open studies here. So we are proud that we are able to offer many enzyme therapies that are FDA approved, or are in a research phase, including now, an enzyme therapy for patient with Hunter disease, where we are injecting it in the spine through a pump to see if we could overcome the neurocognitive. Because this enzyme, they are big proteins. They don't cross the blood-brain barrier. So we're trying to inject them directly and see if we could have and achieve really reasonable outcomes that could lead to approval of this medication. So that's the other benefit of really having a big center.

Dale Shepard, MD, PhD: Excellent. So what's exciting on the horizon? What are you excited about in the field? What are the areas of progress that you're enthused about? And Dr. Erwin, we'll start with you.

Angelika Erwin, MD: So, as Rabi mentioned, there is ongoing development, treatment modalities, treatment approaches. So we already have enzyme replacement therapy for some of those disorders. They are not perfect. There are still options under development that hopefully, maybe will cross the buffer and barrier or will get better access to the organs where they need to get to. So it's exciting that there are still ongoing development in the area of enzyme replacement therapy.

There are also substrate reduction therapy approaches, where we often have an all treatment available or where... Not often, we have only a few of those available, but there are more in development. So hopefully, we'll see more development in that area. One marrow transplant is also looked into for other disorders. And then I think the most exciting is really the gene therapy approach that is under development for a number of those lysosomal storage disorders. Most of them are in the early phases of clinical trials. So phase one, phase two, there are some phase three chart that are coming up now, or that have just been started. So I'm really curious and excited to see those results and to see if we can use those for our patients, because I think that is where we'll see the most impact on patients' quality of life, and also longevity.

Dale Shepard, MD, PhD: Looks like Dr. Hanna is agreeing with that. Any other areas of enthusiasm for you?

Rabi Hanna, MD: I just want to expand on the gene therapy. I think that is really exciting that the technology has advanced and we are using the ability to use the stem cell from the patient themselves, and then correct the gene using newer technology like the CRISPR, or earlier studies that they were actually using gene addition using lentiviral to deliver the normal gene. It is still, I would say, suboptimal because it relies on the fact that we have to give some chemotherapy to be able to create enough space in the bone marrow to get the new cells to engraft and produce. But there are really ongoing trials and still are in a preclinical that they will avoid the fact to give chemotherapy. There are studies for some other disease that could be just giving the correct gene and they can, using higher doses of the lentiviral or adenovector, that could deliver the enzyme then to the liver, without the need also for chemotherapy.

So it's exciting because I wanted to remind that this is really long life. And if we could find out that a drug, that it is a living drug, that could continue to produce a high level of this enzyme. So without having the fact that they need to come so frequently, weekly, or every other week for infusion and achieve higher level, that would really make a big difference. Because even that bone marrow transplant can help, it is not without side effect. In transplant, or as I have seen a lot of side effect when we use a different person, that could cause some other complication like Graft-versus-Host disease, to name the least, and we don't want to switch a disease with another, and having your own cells to be the donor and correct them. That would be the ultimate goal.

Dale Shepard, MD, PhD: That's great. Well, Dr. Erwin, Dr. Hanna, I appreciate all your insights on this topic and thank you for being with us.

Rabi Hanna, MD: Thank you so much for having us.

Angelika Erwin, MD: Yeah. Thank you so much.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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