Stephanie Cherqui, PhD, Assistant Professor in the Department of Pediatrics at University of California San Diego Health, talks about her clinical trial for the treatment of Cystinosis.
What is Cystinosis?
Stephanie Cherqui: Cystinosis is due to a genetic defect that leads to the abnormal accumulation of cystine in all the cells of a body. So progressively, the organs start to be injured, and eventually, they will fail. And because of that, the patients require kidney transplantation. They can have blindness, muscle weakness, diabetes – I mean, so many complications occur with time.
Let’s walk through this treatment that you’ve developed. How long you’ve been working on it, all the steps and exactly what is it.
Stephanie Cherqui: I started this project in 2007. My goal was always to do a gene therapy (to develop gene therapy strategies for rare diseases). And when I was doing my PhD on Cystinosis, we’d just found the gene, so we didn’t know too much about this disease at the time. But it was always in my mind to just go from gene to gene therapy. So, when we found the gene, we realized that it was expressed everywhere, in every single cell. And it was not a protein that was secreted, so it was even more complicated for gene therapy. And when I came here to train in America, to train on stem cell and gene therapy, I realized that after my postdoc, when I became faculty, I want to go back to Cystinosis and develop a gene therapy approach. This was particularly challenging. And so to be able to bring a healthy gene to every single tissue in the body, I was thinking that the only solution is to use our bone marrow stem cells because that’s the natural vehicle that can travel all around your body and try to fix an injury in your body if you have one. I tried several type of bone marrow stem cells. But against all odds, we realized that the cells that worked to prevent Cystinosis was the blood cells, the hematopoietic stem cells. So, what we realized is that if we use hematopoietic stem cells in a mouse model, we could prevent the injury of the other organs and dramatically decrease the cystine content in the tissues. That by using hematopoietic stem cells is equivalent to a bone marrow transplant. Bone marrow transplant can be very risky to do when you take stem cell or bone marrow from foreign donor. You know, in contrast, when you use the patient’s own stem cells, and you do what we call autologous transplantation, then it’s much less risky. But obviously, the patient’s stem cells are also defective of a gene. So, what we do is we gene-correct the cells in a dish using our vector to bring the functional gene to the cells. So, we gene-correct the cells. Then, once the cells are gene-corrected, we transplant them back to the patient. Then after the stem cell, we’ll will reconstitute the bone marrow of a patient. So, first we must do what we call a needle myeloablation, i.e. We remove the stem cells from the patient’s body, and we transplant the corrected one. They will go and travel to the bone marrow, multiply there, reside there for the life of a patient. So, then this becomes a source of healthy stem cells for the rest of the patient’s life. And when we have another tissue injury occurs because of the disease, the stem cells will travel to the tissues and provide this healthy protein to all the diseased cells around. And that’s what we found in the mice. And we are now trying it for the first time in a patient.
Tell me a little bit about Jordan Janz, your first patient. How has the process gone for him?
Stephanie Cherqui: I knew Jordan for several years. We met Jordan at a family event. He has always been very interested in the stem cell program. When we opened this clinical trial, he responded and volunteered and quickly expressed a lot of interest. And he got in touch with our clinical investigator, who talked to him several times about the study. He has been very intelligent and rationale about this process, understanding everything, understanding the risks but still wanted to do it. And he realized that he might be the first, and so being the first is the scariest part because you don’t know what you are going to go through. You don’t even know if you will have any benefits from this novel therapy. So, it’s very brave of him to be the first in this kind of clinical trial. We are very lucky that we have Jordan in the study because he has been very brave but also very strong and never complains. It was nice to be able to talk to him in a scientific way to try to understand how we could improve things, how we could do things differently. So, it has been a great learning curve for both of us. They help us a lot. I’m saying they because his mama has been very helpful also.
How is it going so far? Do you have any evidence that the gene-modified stem cells are expanding and differentiating the way that you expected from the mouse model?
Stephanie Cherqui: The preliminary results we have from this study so far show that it’s going as expected in terms of reconstitution of the bone marrow. And the preliminary efficacy results are very promising. But I cannot say more at this point.
What’s next for the trial? Are you enrolling more patients?
Stephanie Cherqui: Yes. We are. It’s a phase 1-2 clinical trial, so we want to show safety and efficacy. We will enroll a total of six patient for this phase. We’ve already enrolled patient Number 2, and we are working on getting his stem cells gene-corrected.
What would success look like and how would this change a person’s life if they could have this?
Stephanie Cherqui: A patient with Cystinosis has to take 40 to 70 pills a day around the clock, even at night, to compensate for all the nutrients they lose and for all the clinical complication they have. So, it’s a difficult quality of life for them. The drug, that allows release of the cystine from the cells called cysteamine, has a severe effect. And so what we expect and what we would like, is that the bone marrow stem cell transplantation would be a one-time, lifelong treatment for Cystinosis that would avoid the long-term complications and would allow to actually decrease the number of drugs the patients have to take and improve the clinical outcome because these patients still die from the disease. So, they have a treatment, but they don’t have a cure.
What has it meant to work all these years and take something from your very initial discovery of the gene all the way to testing this in clinical trials?
Stephanie Cherqui: At the beginning, Cystinosis was a model. As I said, for my PhD, I was in a lab where they are looking for the gene responsible for cystinosis. That would be a good place to be because at the time, I couldn’t work on a gene therapy right away. It was way too science fiction at the time, so I didn’t do a PhD on that. I thought cystinosis was a good disease model to work on do. And, you know, you read and when you read about Cystinosis and about all the complications, it’s just words, you know? You don’t put face to it. It’s just words. But after I met all the families – and, as I said, it’s been 18 years that I’ve been working on cystinosis. I’ve met the kids. I’ve seen them grow up. So now it’s a very personal fight. We have ups and downs, you know? Sometimes it’s great, or sometimes it’s not. And every day, I really took it personally because I just see all these families that are expecting and hoping for a better treatment. So, it was personal. It’s my family.
Are you feeling hopeful?
Stephanie Cherqui: I am feeling hopeful. I’m scared and stressed because it’s something that I’ve always wanted and that you work very hard at. But now that it’s true and happening, it’s, like, what if it’s not working? What if something bad happens? I mean, it would be terrible. So, it’s stressful. Last October, the cystinosis community lost three patients. One was 23, 39 and 24. I remember Nancy Stack of the Cystinosis Research Foundation sending me this email saying we lost three patients. And thank you for the hope you are giving us because we are scared for our children. And so, this just helps me to continue even if sometimes I’m, like, oh, why did I do that? I mean, why am I giving myself so much stress. But I think at one point, we need to take the risk and try. And if it works, it will be wonderful. If it doesn’t, we will be all disappointed. But at least I can say that I tried. I mean, we all try because it takes a village to do this kind of research and clinical trial. I mean, you have no idea how many people are working so hard to do that to reach that point. The family, the Cystinosis Research Foundation, the research team, the clinical staff, the patients who volunteer, I mean, it’s really a village.
Is there anything else you want to add, or that I didn’t ask?
Stephanie Cherqui: The only thing is that all this research is academic research that is grant funded. We were lucky to be able to start this project because of funding received from the Cystinosis Research Foundation – because at the time, it was kind of a crazy idea to think that blood cells could treat tissue degeneration. And I’m so thankful that we got this first funding, and that allowed us to generate all these preliminary data that showed really promising therapeutic potential. And then we got NIH funding and some funding from California Institute for Regenerative Medicine. So, all this funding allowed us to reach the point where we are today. So, I also want to have big thank you to all these institutions.
Interview conducted by Ivanhoe Broadcast News.
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.
If you would like more information, please contact:
Heather Buschman
Assistant Director, Communications and Media Relations
UC San Diego Health
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
