Patrick McGann, MD, MS, Cincinnati Children’s Hospital  

 What else is out there? We have hydroxyurea. We have voxelotor, crizanlizumab, Endari, transfusions. What’s next? There’s a plethora of treatment options to treat the variety of patients who have who have sickle cell disease. We’re stuck with 4 or 5 options. What else is in the pipeline to treat sickle cell disease?

 If we had this conversation 5 years ago, it wouldn’t be much of a conversation. It’s a good time to be in sickle cell, and the future is bright. Gene therapy, despite the issues, is there. There are many ways to do that. As someone had mentioned, science will prevail with time. The curative options are there, but it’s important to recognize that they’re not going to be there tomorrow, and they’re not going to be there next year for the masses.

There are a number of other therapies out there. Fetal hemoglobin is out there. Fetal hemoglobin is a good target. We know about BCL11A. There are groups trying to make fetal hemoglobin higher using a medication that is in development, and I’m sure there are many ways that’s being tried. There’s a class of medications, called PKR activators, that were designed for pyruvate kinase deficiency. It’s is a very small population, but they can be repurposed to reduce hemolysis in sickle cell disease in ways not too unsimilar to voxelotor. Crizanlizumab is medicine that targets P-selectin.

Several other medications in that class are in development or are being repurposed to see if they can address pain. Because even though we’re trying to address the root cause, when a patient comes with pain, what can you do to abort that pain? We have nothing, except for opiates, which are not the solution. It’s a tough battle, but there are efforts trying to do that with P-selectin and all selectins, and many ways with inflammation. But there are many classes. This is a bigger conversation than it could have been even a couple of years ago. It’s an exciting time, and we’ll get to a point where sickle cell disease treatment is a cocktail approach. You take a couple of things, and as long as we can work on it, if we can address things from different angles, then we’ll make our patients have better lives.

Absolutely. Well, thank you so much. This has been an amazing conversation. I want to thank Abdullah, Wally, and Pat. Before we close, tell the audience your 1 big dream, or 1 final thought, that you want everybody who sees or hears or takes care of patients with sickle cell disease to know as a takeaway message from this conversation. I’m going to start with Abdullah. Your 1 final word that you want them to know about?

As you said, this has been a really exciting conversation. Wally, you, and Pat contributed greatly. Considering this discussion, there are 2 things. It’s important, scientifically, to pursue curative options like gene therapy. I’ll repeat that science will prevail. We will have to overcome the risks, understand them better, and remedy them. That’s 1 thing. 

Coming back to Wally’s point, we need more disease-modifying agents that we can use in Africa or India. The typical approach would be—I agree with Pat—new F-inducing agents or a combination of F-inducing agents. Maybe a combination of F-induction with some downstream modifications like anti-inflammatory or antiadhesion therapies. These are going to be important, and I believe these have to be pursued in sickle cell, along with these high-tech, higher-source modalities. This includes swallowing a pill, which can easily be conveyed to Africa or low-resource countries.

Thank you so much, Abdullah. I’m going to follow up with Wally. Wally, what are your 1 or 2 big-picture, take-home thoughts?

 I’d like to put my public health hat on. I want our audience to know about a report that came out in November from the National Academies of Sciences, Engineering, and Medicine. Ify, you and your colleagues did wonderful preparing 512 pages about all that is wrong in sickle cell care in the United States and what needs to be done to make sickle cell care better. There were 7 pillars that you pointed out, and they had to do with education and social policy. They had to do with patient empowerment and disparities. You declared sickle cell to be a disparities disease, as Pat said earlier. They had to do with therapy as well. But it wasn’t just therapy that you focused on. You focused on social determinates of health, you focused on policy, racism, and changes in the fabric of the health care system, especially for adults with sickle cell. We don’t even have an adult sickle cell disease health care system. We have a shack instead of a home for adults with sickle cell disease. That’s the 1 thing I want to take away. None of this discussion we just had will matter is there’s nobody to care for the patients. And in many parts of the country, there’s nobody—doctor, nurse, or other—to care for these patients.

Very well said. Thank you so much, Wally. 

I’m going to add to that because it’s so important. The names of the medicines don’t matter. Whether you live in Cincinnati, or Angola, or India, if we have good therapies, they should be available. We need to leverage that equity to global treatment of sickle cell disease. Hydroxyurea was developed in the 1980s and ’90s and is only now becoming available in Africa. Not really, even. I don’t want to give a talk when I’m retiring in a few decades telling patients about all these new therapies that we’re using in the United States and how sickle cell disease is history, except in Africa, where 90% of kids are still dying before they’re adults. That can’t happen. As these therapies are developed, by Bill Gates or whomever, we’re going to need a lot of people. We need to be sure that these are truly equitable in a timely manner, or we’re doing a huge disservice to the global sickle cell community.

Thank you so much. I’m going to give my thoughts. The first thing I want the audience to recognize is that sickle cell disease is a lifetime genetic disorder. It doesn’t go away when you become a teenager or when you leave pediatrics. It doesn’t disappear when you get married. It’s there for the rest of your life. It does shorten your life span. 

The second thing is pain with sickle cell disease. It’s important, but it’s not the only important thing. Organ damage, that chronic, slow slump of devastation to the organs is a reality, and no patient will die because of pain. They will die from strokes, kidney disease, pulmonary hypertension, infection, heart problems, lung problems. It’s important to look at them as treating not just pain but the entire person. That entire person will also involve their quality of life. Ask them how they’re doing, how are they functioning. Do they get up and go to work? If not, why not? When you’re giving treatment, look at the impact of treatment. Not just on their pain, as we talked about, but on their overall quality of life. 

We talked about screening for sickle cell disease at birth, screening for complications following the guidelines, and early intervention. For example, retinopathy picked up early can prevent blindness, treating hyposthenuria early prevents ESRD [end-stage renal disease], and picking up pulmonary hypertension can prolong life by putting the right treatment in place. But there’s also supportive care. And let’s not forget the role of the primary care provider. The last time I checked, having sickle cell disease does not protect you from getting breast cancer, colon cancer, high blood pressure, diabetes, or diverticulitis, or any other thing that anybody else gets. My patients have all this, and they deserve whole care—not sickle cell care but all-around holistic medical care.

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Experts look into what is next for sickle cell disease and provide key thoughts on the space. 

What’s Next and Final Thoughts in SCD 

 I’m going to pose this question to Wally: What is the real-world potential? If gene therapy works, what does it look like for America, Europe, and Africa?

 Let’s start with Africa. We can’t even get hydroxyurea to Africa. How in the world is Bill Gates going to get enough money so that Africans can get access to a therapy that takes a year out of your life and has all the things you must do that we just got through talking about? How in the world are they going to do that? You can see the handwriting on the wall. We’re producing Ferraris here. We’re not producing Chevrolets. You can make only so many Ferraris per year. Maybe even Rolls-Royces, where you hand-paint everything and sew the fabric by hand. You cannot manufacture enough of these procedures per year to cure everybody in Africa. Only the elite in the United States will get their hands on a Ferrari or a Rolls-Royce, which is what we’re talking about, to get their disease treated. 

This is never going to be a production-line procedure. This is going to be 1 at a time. What you just said—take my cells out, ship them. It’s a tailor-made suit. It’s a Ferrari. It’s a Rolls-Royce. It’s not buy it off the rack, take a pill, take an infusion. We should not overblow the potential of these therapies in terms of getting to the masses, and we should talk more about disease-modifying therapies. We should talk about prevention. I’m just going to go ahead and say it: genetic counseling. That’s not a dirty term. It’s not genocide to tell an at-risk couple, if both mom and dad have sickle cell trait, “Look, if you have a baby, there’s a 1 in 4 chance that Junior could have sickle cell disease. This is what sickle cell disease looks like. Take a look.” I don’t think that’s bad.

They can make their own choice, right? They can make the choice. But a lot of times, the choice is accidental. They had no idea. I saw a teenager, whom I asked, “Do you want to have a child right now?” “No.” You might want to ask if she has sickle cell trait. “I don’t know.” Then we had that conversation. “You have a choice about whether you have a child at age 21, or if you have a child with sickle cell disease at age 21.” That’s part of the whole informed decision-making, so that the young people who are thinking about making babies have a chance to choose if they go down that road.

 I try to explain to people, because when they hear 1 in 4, they go, “Oh, I’m not going to be 1 of the 4. I’m not going to be the 1.” No, it’s every time you have a baby. Every time you have a baby, there’s a 1 in 4 chance. I have families. I take care of families in which 3 of 5 siblings were born with sickle cell disease after mom and dad had the first child with sickle cell disease. They took a chance and had another 1. Then they took a chance and had a third 1. And they go, “But they told me it was a 1 in 4 chance.”

Yes, that’s very common. “I already had 1, so I’m not going to a second 1 with sickle cell disease.”

Key opinion leaders dive into global challenges in sickle cell disease while focusing on treatment access.

Challenges in Global Access to SCD Treatments  

Pat, can you describe the steps people go through to do a bone marrow transplant to gene therapy? Set the stage to help people understand why busulfan and why we’re talking about mutations. Can you walk us through the whole gene therapy process?

 With transplant or gene therapy, the term transplant could be autologous, meaning your own cell gene therapy transplant. It’s not as if you’re transplanting a solid organ or a kidney. Sometimes patients get confused about this. It’s looks like a blood transfusion hanging when it eventually goes in. For a bone marrow transplant, the donor—whoever that is—either gets a bone marrow aspiration, where they get bone marrow cells taken from their bone marrow, or a medicine to rev up their blood cells and get blood taken just from their vein. The patient needs to get prepared because they need to get rid of all their sickle cells. They need to suppress their immune system, so they don’t reject this foreign cell, which is someone else’s.

We use strong chemotherapy. If you have leukemia, as a comparison, you need to kill every last leukemia cell, and you get blasted with really strong chemotherapy agents and strong immunosuppressive agents. This is usually a week or so before; the days are counted backward. The cells that go in your body are most vulnerable to infection to everything. It’s a dangerous time. That’s when complications come in. If it’s a transplant, you get infused with that donor’s bone marrow cells and hope it takes. It takes some weeks’ time for your body to take those new cells, and you’re often receiving antibiotics and getting transfused and sustaining it, because your bone marrow is still not working. Basically, your immune system is suppressed. It’s a tough time.

Transplant conditioning, as this regimen is called, has gotten a little less toxic—reduced conditioning is the term. But that’s still serious conditioning. Even though it’s reduced from what it used to be, it’s a relative term. Gene therapy is a little different because you’re giving back your own cell. The way gene therapy happens is it’s ex vivo, meaning they take it out of your body. There are different ways that this is being done. Many patients need to have a bone marrow aspiration or many procedures to take enough cells out of their bone marrow to take them to the lab to fix them. There have been new ways to do this with peripheral blood and a medication called plerixafor, which is much better than going to the operating room for these horrible procedures. 

Those cells are then taken to the lab and edited, or whatever the mechanism of gene therapy is. You still need to ablate your bone marrow to get rid of all your sickle cells. Because if you have any or many sickle cells in there, when you give back your edited gene cells, those will just take over. You still need to suppress that bone marrow. Because it’s your own cells, the immune suppression isn’t as much of a problem as it is with transplant. Still, it’s a week of pretty serious medicine—busulfan, traditionally—and you’re in the hospital for less of a period of time than transplant. It’s quite an ordeal. Similarly, it takes or doesn’t, and you monitor over time if that gene therapy has worked and whether it’s sustainable—cross your fingers—in the long term.

Basically, you have 2 options. The first option, you have to kill off their own bone marrow cells using chemotherapy. Then you give them somebody else’s bone marrow, like a blood transfusion. The stem cells from the other person finds its way into their bone marrow and then grows. Then you wait and see what happens. Do you fight it? Do you accept it? We know if it takes or not. For gene therapy, we take out the patient stem cells, take it to a laboratory. It’s usually in New Jersey—don’t ask me why. They manipulate it to pick out the gene they don’t want. Then they give that patient back their own modified stem cells and wait for it to grow. But you still have to wipe out that person’s bone marrow, so you don’t have this fight going on. Even though they’re your cells, they’re a little different with the new gene change that has been made. It’s a complicated process, and it’s really the only way to cure your disease. Either stem cell or gene therapy. We have had some setbacks in the past and more recently, but I believe that science is going to prevail. Over time we’re going to get to the point where we figure out the way to do this in the safest way to make it available to the most people with sickle cell disease and other blood disorders.

A discussion of the course of gene therapy compared with stem cell therapy.  

Stem Cell vs Gene Therapy Processes in SCD 

 There are other gene therapy approaches. One is using CRISPR-Cas9, which has been used for 2 purposes. There are trials that use CRISPR-Cas9 to inactivate BCL11A in red blood cells. As you know, BCL11A is the main factor in this switch. It decreases the fetal hemoglobin expression and switches to the adult. If you disrupt this in red blood cells only, and you can do that by deleting an enhancer, then the fetal hemoglobin expression continues to be high. That’s the approach used by David Williams at Boston Children’s Hospital.

There was a publication of 7 patients with thalassemia and 2 patients with sickle cell with the same approach. It was a plenary session paper, and it showed early-stage efficacy. Now there’s another gene therapy approach that attempts to correct the sickle cell mutation. It’s being developed by investigators at Stanford University. What they try to do is correct the sickle mutation. What I have been able to find out, the study has not started. But in vitro, they have found that 70% of the CRISPR-Cas9 export cells have a correction, some correction of both alleles. In other words, you take an SS and turn it to an AA, which is the most desirable thing. For the remainder, there’s a single correction, which means you turn an SS to an AS. It remains to be seen how effective it is. Certainly, the occurrence of these malignancies in gene therapy trials cast some doubt. I don’t know what the outcome will be. Certainly, that’s a much-needed therapeutic approach. Hopefully, some safety measures will be able to be put in place, because they work. 

She looked at 40 patients and put us on a roller coaster, right? She showed us that 25 of 40 had been treated and followed for 12 months. And their hemoglobin count was really good, an 11 g/dL. With 5 of 11 coming from that new hemoglobin that you just got through talking about. 

The other thing that I didn’t mention, Wally, is that she looked at the crisis numbers. These patients had a median VOC [vaso-occlusive disease] and acute chest syndrome of 4 per year in the previous 3 years. And after that it was 0.

 Everybody got excited. You’ve turned an SS into a sickle cell trait, essentially. It was a whole bunch of patients, and we got excited. And what you said happened just a couple of weeks ago. It’s as if they’re running to the exit. Everybody’s going off; forget that. But at this point, we don’t know whether it was the Busulfan, the conditioning agent, or if it was something else that caused these problems. The jury is still out.

Experts review data around emerging gene therapy approaches in sickle cell disease. 

Patrick McGann, MD, MS, Cincinnati Children’s Hospital

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