StemBook in conversation with Joanne Kurtzberg about cord blood transplantation, cerebral palsy, and metabolic diseases

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StemBook in conversation with Joanne Kurtzberg about cord blood transplantation, cerebral palsy, and metabolic diseases

Lisa Girard

Joanne Kurtzberg, MD is a Professor of Pediatrics and Professor of Pathology at Duke University Medical School. Additionally, she is the Chief Scientific Officer and Medical Director of the Robertson Clinical and Translational Cell Therapy Program, Director of the Pediatric Blood and Marrow Transplant Program, Co-Director of the Stem Cell Laboratory, as well as Director of the Carolinas Cord Blood Bank. Dr. Kurtzberg’s research and clinical interests include using cord blood transplants for the treatment of metabolic diseases and cerebral palsy. She spoke to StemBook editor, Lisa Girard, recently about progress in these areas.


Can you tell StemBook readers a little about your background, your area of research, and what projects are going on in your lab?

I’m trained in pediatric hematology-oncology. I completed my fellowship in 1983 and joined the faculty of Pediatrics in the Division of Pediatric Hematology-Oncology at Duke at that time. Then, because of the ongoing interest I had in stem cells initially based on work with a patient that had biphenotypic leukemia, I moved into the transplantation field and started the pediatric bone marrow transplant program here at Duke in 1990. In that program, we focused on treating children with both malignant and genetic conditions with generally allogeneic hematopoietic stem cell transplantation.  Along the way, we became interested in using cord blood as an alternative donor source for hematopoietic reconstitution after myeloablative therapy.


This was the patient’s own cord blood at this point?

 Initially, and during the first 10-15 years of cord blood transplantation, cord blood was predominantly used as a source of allogeneic donor cells. It was found to be more immunologically tolerant of a new host than bone marrow-mobilized blood cells and early on we learned that we could use it without full HLA matching. Partial matching is required but when you can give up matching of one or two of the six or eight loci typically required for matching, you can provide access to stem cell donors for a lot more patients. In spite of mismatching, cord blood cells cause less graft versus host disease (GVHD) than adult cells. Therefore, long-term outcomes with cord blood transplantation, particularly in children, are associated with less GVHD, a major advantage for stem cell transplantation.  Also in my background I should mention that I created and run the Carolinas Cord Blood Bank, an FDA licensed public cord blood bank that is located at Duke. We started that bank in 1998 and currently collect donated cord blood from sites all around the country including Brigham and Women’s Hospital in Boston and we offer a kit program that moms can use donate from places all over the United States.


Are cord blood transplants more tractable for children than for adults in terms of the amount of cord blood that’s needed for a transplant relative to other stem cell sources?

 One of the limitations of cord blood transplantation is that not every unit of cord blood that’s collected has enough cells to transplant an adult or larger-sized individual. We’ve learned a lot about what the minimum cell doses required for cord blood transplant are and roughly 10-12% of cord blood units that are collected have enough cells for the average-sized American adult. For the other adult patients that might still benefit from a cord blood donor, either two cord blood units are combined for a single transplant, or more recently, there are some exciting new graft engineering technologies that are emerging to expand stem or progenitor cells in the laboratory before infusion or modify the cells in some way to make them more potent at the time of transplant.


I’m also familiar with some of the work and clinical trials you’ve been doing using cord blood transplants with cerebral palsy (CP) patients and those with inborn errors of metabolism diseases. I’m not really familiar with how that works and I was wondering if you could tell us about that?

 This really started because once it was realized that cord blood could serve as an alternative donor for transplant, and also that it could provide access to people that needed a transplant but didn’t have a match, it was logically used in children that were undergoing transplant to correct metabolic diseases and didn’t have a bone marrow donor. Back in the mid-1990s we performed what might have been the first cord blood transplant for a child with Hurler’s Syndrome. Basically what was happening when you use a hematopoietic stem cell to correct an inherited metabolic disease is that through engraftment of that cell you are allowing that cell to become the replacement source for the missing enzyme or other factor-almost like a cellular form of gene therapy or, as I call it, “poor man’s gene therapy”. However,even though these patients don’t have a blood problem, vis a vis these diseases typically affect brain, heart, and or other organs, they have to undergo myeloablative chemotherapy so their body doesn’t reject the donor cells. That’s a drawback of the procedure. One positive effect of the procedure is that cells are the only vehicle to get enzyme into the brain. You can give enzymes in the blood, but it won’t cross the blood brain barrier; but if you give cells, or a transplant, then it will engraft in the brain as well and produce enzyme, or the other factors that are missing.


Could you explain how the transplantation for CP is therapeutic?

 Once we had experience in treating children with brain disorders that were due to inherited metabolic conditions, we learned that when we gave cord blood cells they migrated and engrafted in the brain on a permanent basis. We also learned that many of the cells that went to the brain were in the family of microglial cells, which is a cell in the myeloid lineage. We then had the idea that maybe in the case of an injury, not a genetic condition but an acquired condition, a child’s own cord blood cells might also go to the brain and repair the injury. Further, if you can use the child’s own cells, or autologous cells, you wouldn’t have to give chemotherapy to prevent rejection and the cells would be accepted because they are the same genetic material as the child.


These cells that end up in the brain have proneurogenic capability?

 We have learned a fair amount from the neurologic genetic diseases, but we and others also studied these cells in the laboratory as well as in animal models of brain injury. What we found was that the cells make cytokines that are anti-inflammatory, pro-neurogenic, and pro-angiogenic and they constitutively produce these cytokines. In response to injury, they increase the amount of cytokines they create and in either animal or in vitro models they reduce inflammation and promote healing. In some cases, that may be vascular healing and in other cases it may be promoting neurons to either recover or repair. In other settings it’s just providing cytokines or paracrine factors that influence the behavior of the endogenous cells. Then, in animal models of stroke and CP, it has been shown that human cord blood cells in an area of injury decrease the consequence of injury, and that’s for traumatic brain injury, hemorrhagic stroke or ischemic stroke.


This is in clinical trials now?

 Yes. We have taken this into clinical trials and have recently published the results of the first phase one safety trial involving babies with hypoxic ischemic encephalopathy in which they receive their own cord blood back in the first two days of life. We did show both safety as well as better survival and function at a year of age; although this was a safety study and not really powered to look at efficacy, so we are taking that into phase two. We also have a study in children with cerebral palsy that is ongoing right now that is a randomized placebo-controlled trial. This is to see if cord blood infusion, and again this is their own cord blood, lessens the symptoms of CP. We are planning to develop a product that would be an allogeneic, or donor-derived product, that could be used for similar indications in children and babies who don’t have their own cell store.


Regarding the first clinical trial you described involving autologous cord blood transplantation shortly after birth, once a patient was identified to have been born with that type of trauma were they then enrolled, or how was that aspect of the trial managed since cord blood has to be collected at birth?

 We started the trial in our own center where we also have cord blood collectors for moms that want to donate to the bank. What we evolved to was that when a baby was born with this condition, and usually this condition is identified in a term baby either right around the time of birth or shortly before birth, meaning an hour or so; the mom was asked by the obstetrician or midwife delivering the baby for verbal assent to collect cord blood. We provided and continue to provide collection bags for cord blood in all the delivery rooms of hospitals in which we have cord blood donation going on so the obstetricians already have a bag and know how to collect. With the mom’s verbal assent, they do the collection right after the baby’s born and then the baby’s condition is sorted out. If the baby has the condition and qualifies for the trial, then the parents are approached to hear more about it and sign a written informed consent if they want their baby to participate.


My last question is if you could speak to the survival rates due to stem cell transplants in the last ten years, given the associated risk factors with transplants such as GVHD. What has been the incremental gain?

Stem cell transplantation in general, using donor cells from either bone marrow, mobilized blood, or cord blood has become a more common practice over the last twenty years. It’s applied to more patients with more diseases at an earlier phase of their disease. A lot more is understood about how to match donors, how to prevent GVHD, and how to support the patient through the risky phase of the procedure. There have been many multifactorial changes over time. Having said that though, outcomes have improved. Just in cord blood transplantation, if you look back at the early days of the late-80’s to mid- 90’s and compare those survival rates say in children with leukemia to survival rates today, you’ll see an overall improvement in disease-free survival of about 20%. That can mean many things. There are more cord blood units being added to patients and they are better quality because banking practices have improved. There are a number of reasons why the numbers are better, but they are about 20% improved over the last couple of decades.


Dr. Kurtzberg, I really appreciate your time. Thank you for talking with StemBook.