Pediatric Oncologist at Cleveland Clinic Children’s, Rabi Hanna, MD, talks about a possible solution for sickle cell disease.
Interview conducted by Ivanhoe Broadcast News in 2023.
Is it fair to say that sickle cell is a life long debilitating disease?
Hanna: Yes.
Can you explain what patients with this disease go through?
Hanna: Sickle cell disease is referenced by some people as anemia, and I feel that’s a misnomer because they think it is just a blood disease. I think about this as a vascular disease. It affects every place that your blood is going to. If you aren’t familiar with sickle cell disease, what happens in the body is a malfunctioning in the growth of red cells. Instead of a person’s red blood cells being round and flexible (which allows them to squeeze through vessels) a sickled cell has a mutation in the gene that causes the cell to become rigid and changes its shape to that of a crescent. When that happens, the cells get stuck to each other, and that leads to injury in the vessels and the formation of small blood clots. Basically, the blood doesn’t go where it should. Therefore, oxygen doesn’t flow to potential parts of the body, and that can be any part. The bone is the most common place that can get affected because it has very narrow and small vessels. This is why the most frequent manifestation of sickle cell disease is pain, it’s literally crushing the bone. It goes in the bone, but the same thing can happen in the brain. In turn, patients can have a stroke, specifically kids who are toddlers. It presents itself as a silent stroke and can affect their intelligence and performance in school. It also can affect the eyes, the heart, and the lungs. Patients who have a severe form of sickle cell can be in and out of the hospital so much that it doesn’t make for a normal life.
How is it treated?
Hanna: Sickle cell disease was discovered more than 100 years ago. Until the ’60s, most of the patients, including children, would die from infection. Now, through newborn screening, we discovered that we can diagnose the patient very early and put them on protective antibiotics. We treat the disease by really addressing the manifestation. The first one being antibiotics for the first few years of life and vaccination. But then in the ’90s we discovered that there is a medicine called hydroxyurea, which seemed to decrease the severity of the disease. That was the only medicine we knew that could help sickle cell, until new medications were introduced in 2019. L glutamine, Voxelotor and Crizanlizumab were the three medications that seemed to help lessen hospital admission rates for sickle cell patients by 75% once taken. However, the organ damage that happens as a result of this disease was left unmanaged. Problems with the hear, the lung and the pulmonary, hypertension, and the kidney greatly affected life expectancy. The life expectancy for patients with sickle cell is around 38-43 years old, which is many decades less than what’s projected for those living in the U.S.
There’s a new therapy out called “gene therapy”, can you tell me what that is?
Hanna: Yes, I do want to preface by saying that this is a clinical trial and there are now many ongoing clinical trials focusing on gene therapy. Since the 1990s, we knew that we could cure sickle cell by performing a bone marrow transplant with a suitable match, but that has much more complications and runs the risk of experieincing graft rejection. Unfortunately, the donor can “attack” the patient and cause another disease called the Graft-Versus-Host Disease. Also, many times we can’t find an appropriate donor so it’s never been the ideal plan of action. Luckily, now with advanced technology, we have gene therapy and I’m excited Cleveland Clinic Children can be apart of it. Gene therapy has gone into different phases and different versions of it. In the past, there’s always been a concern that adding a gene to our normal coding structure can cause potential integration in a harmful way and could lead to leukemia or some other neoplasm. Thankfully, this newer phase of gene therapy is built on a more improved discovery of Crispr and Caspase 12. It’s very precise, like a scissor. We can guide it and it goes directly to the portion that’s being coded. We’ve learned from nature that there are some patients with sickle cell that are healthy. Those are the ones who have persistent fetal hemoglobin. In our clinical trial, we see high production of the fetal hemoglobin and it seems to protect against all sickling.
Is it stem cells that are used in this treatment? Where do they come from?
Hanna: Yes, we take them from the patient’s blood. We give medication to the patient, it’s called Plerixafor and it’s different from some other medications typically used for stem cell mobilization. Another medicine, called Filgrastim or G-CSF, can cause a problem for sickled cells. It needs to be dealt with differently. However, with plerixafor, the medicine aids the stem cell in detaching from their niche inside the bone marrow. It’s then released into the blood and we attach the patient to an apheresis machine that separates the stem cell from the red blood cells from the plasma. It takes a couple of times to collect enough stem cells from the patient. Sometimes one cycle works, sometimes it can take up to three cycles.
How many stem cells do you need?
Hanna: We need 15 million per kilogram to guarantee we have enough to edit.
Is that 15 million per kilogram according to the weight of the patient?
Hanna: Yes.
That’s a lot of stem cells!
Hanna: It’s a large amount, but some patients, again, they can do it in one day. Sometimes it will take us more than almost three cycles. It depends on their health, the iron overload, and their age. There are variable factors affecting that.
Does this gene editing happen one time?
Hanna: Yes, so after we take the stem cells we send them to a company called Editors. This company will be able to select the stem cell specifically and insert them using the CRISPR-Cas12. This is a very sensitive procedure. The promoter of hemoglobin G1 and G2 is then changed to produce new stem cells that create red blood cells rich in fetal hemoglobin – which prevents sickling. It takes about a month to produce, and another month to perform quality checks. However, once given the green light we bring in the patient. It’s important to know that this phase of the process does involve chemotherapy, but it’s not extensive. It’s in the form of a medicine called Busulfan, and it’s given daily for four days and then there’s three days of rest. After that time, the blood cells are then infused and it works like a standard blood transfusion. The cells go through the patient’s veins and seep into the bone marrow where they produce new white and red blood cells. The new red blood cells will play a vital role in the prevention of sickling. We have a few patients at the European Hematology Association and one has reported it’s been more than a year, no pain crisis. I can’t tell you how exciting it is to have a patient tell you that.
After the clinical trial, are there still sickled cells evident in the patient’s body?
Hanna: The patient will still produce a little bit of sickled cells, it’ll range around 30-40%. They’ll biologically identify as a carrier of sickle cell trait, but they usually don’t experience pain. Since the majority of the hemoglobin present is fetal hemoglobin, it’s protective and typically downgrades the status from disease to trait.
Are there any dangers or risks that come with this therapy?
Hanna: That’s what we’re trying to find out. This is a clinical trial resource, so we are still assessing the safety, feasibility, and efficacy of this. We need to finish the trial but it’s been encouraging. We don’t see any side effects beyond what we usually see for chemotherapy. Certain side effects are to be expected due to that. The patient will spend some time in the hospital and remain monitored every 1-3 months for two years to catch any relevant side effects we weren’t aware of.
Do you think this infusion process is a one and done? Or will they have to come back in five years?
Hanna: That’s a fantastic question. I really do think it will be a one and done. The reason why is because those are stem cells. Stem cells live long lives and they come from your own body. Usually, there’s no chance of rejection and we haven’t seen that in this study or other gene therapy trials that have gone on much longer. Ideally, this should be a one and done.
This is exciting because there’s patients like Danielle, 30 something years old, who lived in pain her entire life and for the first time ever, she’s not.
Hanna: Yes. It is very rewarding when you can hear a patient say the words “I finally feel free”. It really opens your mind and puts you in their shoes. Can you imagine how many limitations were on their life? Danielle lived in such fear of going into a pain crises she couldn’t travel. Even being admitted to other hospitals were a concern for her because she didn’t want them to dismiss her pain and label her as a drug seeker. She has necrosis in several of her bones, so to finally not feel those limitations and to “feel free” was an eye opener for me as a provider and I’m so happy that I was apart of enabling her and other patients with sickle cell to experience this. I hope this will be accepted and approved by the FDA so that more patients can benefit from it.
So do I! How many were in the trial?
Hanna: There are six patients now and we’re aiming to enroll 20 patients. The enrollment is happening very rapidly.
Have all six of them seen improvement?
Hanna: Yes.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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