Topics of On-Going Research in Cord Blood Transplantation

Summary of Topics below

Also, abstracts for medical research articles on any topic can be found from the on-line search engine of the National LIbrary of Medicine: PubMed .

• 1. Is it better to collect cord blood before or after delivery of the placenta?

  Answer: This is a close call.

  • Solves P, et al. 2003; Bone Marrow Transplant. 2003 Feb;31(4):269-73
    In a sample of 569 vaginal deliveries, a larger volume and a higher number of stem cells were harvested from the in utero collection group.
  • Lasky, LC, et al. 2002; Transfusion Oct;42(10):1261-7
    They say that, in terms of sample volume and cell count, there is "no advantage of either method".
  • Surbek, DV, etal. 2000; Am J Obstet Gynecol Jul;183(1):218-21
    They prefer in utero collection for cesarean delivery

  Example: One bank which collects ex utero has a slide show of the collection process .

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• 2. What is the optimum cord blood collection method , gravity drip versus syringe?

  Answer: Studies have shown that pulling the blood out with a syringe tends to draw a bigger sample than simply letting the blood drip by gravity into a bag.

  • Bertolini F, et al. (1995) J Hematother Feb;4(1):29-36
    "Comparative study of different procedures for the collection and banking of umbilical cord blood."
  • Elchalal U, et al. (2000) Am J Obstet Gynecol. Dec;183(6):1587-8.
    These authors advocate flushing all the blood out with saline, which is a more aggressive method than simply pulling out blood, and is not in routine use.

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• 3. What is the optimum cord blood storage container , bags or vials?

  There is no clear answer:

  • Existing scientific studies do not show a significant difference between blood storage in bags versus syringes.

  • A given bank will use only bags or vials, not both, because their freezer is equipped with racks for holding either one or the other. Also, the loading of the racks should be balanced for mechanical and temperature stability.

  • On the one hand, those banks that use bags like to point out that they are a "closed system", in which the blood does not have to be transfered from one container to another. This lessens the chances of contamination if the transfer is not done with proper sterile technique. Of course, blood labs are not supposed to be hiring employees who don't know how to transfer blood properly.

  • On the other hand, those banks that use vials like to point out that frozen bags are prone to shattering if they are not handled very carefully. Of course, they should be handled very carefully.

  • A bank which uses vials has the option of separating the cord blood into multiple vials. If the sample is stored in multiple portions, then the family has the option of using it one portion at a time, should medical research develop new therapies in which this is desirable. (However, multi-compartment bags can achieve the same purpose)

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• 4. What is the long-term viability of frozen cord blood?
  (Actually, all the studies of cord blood viability have been done on samples of separated Mono-Nuclear Cells, not whole blood.)

  Answer: So far, recovery of viable stem cells from cord blood is over 90% at 15 years.

  References:
  Kobylka, P., et al. 1998, Transplantation, 65(9):1275-1278.
  Mugishima, H., et al. 1999, Bone Marrow Transplant, 23(4):395-396.
  Broxmeyer, H. E., et al. 2003 pnas.0237086100

  Background information:

  In theory, it should be possible to store cells for millenia at -196 C, the temperature of liquid nitrogen. Below -130 C, no liquid water exists in cells. Thus, no molecules dissolved in water can contact each other for a biochemical reaction. Furthermore, at -196 C there is not sufficient thermal energy present to drive any biochemical reaction. The only degradation that can occur at this temperature is reactions caused by background radiation and cosmic rays. It can be calculated, that at normal terrestrial conditions, it would take about 2000 years before a considerable amount of damage was caused by such reactions.

  References:
  Mazur P. 1988, Ann NY Acad Sci. 541:514-31.
  "Stopping biological time. The freezing of living cells"
  Mazur P. 1984, Am J Physiol. 1984 Sep;247(3 Pt 1):C125-42
  "Freezing of living cells: mechanisms and implications."

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• 5. How long does it take to search for a cord blood donor?

  Answer: At least a month less than to find a bone marrow donor.
  
  Median time to chose a cord blood unit is 13.5 days (range, 2-387), compared to median time to approve an unrelated bone marrow donor of 49 days (range, 32-293), in a summary of 171 donor searches over the course of a year at the University of Minnesota. The "additional time taken to obtain a BM donor was predominantly due to the additional 30-day interval (range, 10-101 days) required to clear the donor".
  Reference:
  Barker, JN et al. (2002) Biology of Blood & Marrow Transplantation vol.8(issue 5):257-260

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• 6. How long does it take cord blood to engraft in a transplant recipient?

  Answer: At least a week longer than it takes bone marrow to engraft.
  
  Median engraftment times for bone marrow and cord blood are typically 18 and 26 days.
  References:
  Rocha, V., et al. (2000) NEJM 342:1846-54
  Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647

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• 7. How does Graft Versus Host Disease (GVHD) from cord blood compare to other sources of stem cells?

  Answer: GVHD is less severe with cord blood than with bone marrow
  
  In a study where all patients received an HLA-matched transplant from a sibling, and the results were controlled for age, the relative risk of cord blood versus bone marrow was 0.41 for acute GVHD and 0.35 for chronic GVHD
  Reference: Rocha, V., et al. NEJM 2000;342:1846-54

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• 8. Does cord blood carry a Graft-Versus-Leukemia effect?

  Answer: Apparently very little, if any.

  Graft-versus-Tumor effect is known to be correlated with Graft-Versus-Host Disease (GVHD). Both are mediated by T-cells. While the T-cell content of umbilical cord blood is lower than bone marrow, it is not low enough to be the sole factor explaining the lower incidence of GVHD in cord transplants. Apparently the types of T-cells, their maturity, and their activity also differ. This is a frontier of on-going research.
  References:
  Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647

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• 9. What is the minimum dose of stem cells from cord blood needed for engraftment of a new immune system?
  This is the same as asking, what is the maximum patient size that can be transplanted with a single cord blood collection?

  Answer: The optimal dose is about 20 million nucleated cells per kilogram of body weight.
  "patients who received no more than 10 million nucleated cells per kilogram had a 75 percent probability of death, whereas recipients of at least 30 million nucleated cells per kilogram had a 30 percent probability of death."
  Reference: Editorial by Gluckman, E. NEJM 2001;344:1860

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• 10. Can the use of cord blood for adults be enhanced by expanding the number of stem cells in vitro?

  Answer: Yes.
  Several biotech companies are developing techniques to rapidly grow stem cells in a laboratory environment. These methods are being used in clinical trials.

  Example:
  Blood & Marrow Transplant Newsletter issue #51 reports on the first adult to survive a cord blood transplant with expanded stem cells. Published by Pecora et al. 2000 Bone Marrow Transplantion 25:797-799.

  References:
  MJ Laughlin et al, 2001; NEJM 344(24):1815-22
  Retrospective study of 68 adults who received cord blood; 90% engrafted.
  EJ Shpall et al. 2002; Biology of Blood & Marrow Transplantation vol.8:368-376
  "Transplantation of Ex Vivo Expanded Cord Blood"
  Reports on a clinical trial conducted at the U. of Colorado on 25 adults & 12 children with high-risk diagnosis.
  J Jaroscak et al, 2003; Blood 2003 101:5061-67
  Phase I trial on 28 patients of conventional UCB transplants augmented by ex vivo-expanded cells.

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• 11. Can the use of cord blood for adults be enhanced by combining multiple, mis-matched, cord blood units?

  Answer: Yes. See the next question.

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• 12. What is the maximum degree of patient-donor incompatibility (mismatched HLA types) that can be tolerated in cord blood transplants?

  Answer: Apparently quite large
  Examples:

  • Report on an adult patient who received two partially matched cord blood units and both engrafted (called a "double chimera")
    Reference: NEJM 2001;344:1870
  • Several clinical trials presented at the 43rd annual meeting of the American Society of Hematology in Dec. 2001 were transplanting adults with multiple (from 2 to 6) mis-matched cord blood units. Surprisingly, although these patients initially show a mix of HLA types ("chimerism") from the different units, over time most survivors display a single dominant cord blood type.
    Reference: Cord blood transplants: Making do with less by M.D. John Wingard
  • Report on an adult patient in Britain who recovered after receiving a transplant of 7 cord blood units; one perfect match and 6 mis-matched
    Reference: The Guardian newspaper 7/9/2002

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• 13. How does long-term survival compare among recipients of bone marrow transplants versus cord blood transplants?

  Answer: They are comparable.

  Among pediatric patients, the overall survival rates are comparable for the two transplant types, but the causes of death differ with each. Among cord blood transplants, the most common cause of death was complications during the long wait for engraftment. Among bone marrow transplants, more patients died of severe Graft-Versus-Host Disease. Despite the fact that cord blood seems to lack graft-versus-tumor activity, cord blood transplants were not associated with higher rates of patient relapse.
  Reference:
  Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647

  More in-depth answer: Cord blood stem cells may hold an advantage in telomere length.

  Telomeres are like molecular caps that tie off the ends of chromosones. As cells replicate, their telomeres get shorter. Literally, telomere shortening is the aging process at the cellular level. For example, when Dolly the sheep was cloned from a six year old cell, she was born with shortened telomeres, as if she was already six years old.

  Some researchers have suggested that telomere shortening in hematopoietic stem cell transplantation (ex: giving an old person's stem cells to a young patient) is a potential mechanism for late graft failure.
  References:
  Awaya, N. et al. (2002) Biology of Blood & Marrow Transplantation vol.8(issue 11):597-600

  Another in-depth answer: Cord blood is more effective in repopulating the stem cell "reservoir"

  Although it is well known that cord bood takes longer than bone marrow to engraft after transplant, a recent study indicates that in the long run (after one year) the cord blood does a better job of re-populating the body's reservoir of blood stem cells. Apparently, the stem cells in cord blood would rather multiply than differentiate into more evolved blood cells. This also implies that "expanding" the number of stem cells in transplants will not speed engraftment; it is more important to get them to differentiate sooner.
  References:
  Francesco Frassoni et al. 2003 Blood First Edition Paper:
  prepublished online 4/10/2003 DOI 10.1182/blood-2003-03-0720

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• 14. Which poses less risk of passing an inherited disorder, adult bone marrow or infant cord blood?

  Answer: This is a toss-up

  More and more diseases are now recognized to have a genetic basis. We have always known that some diseases are passed by recessive inheritence. We now also recognize that some genetic mutations confer a predisposition to disease. For example, the "Philadelphia chromosome (translocation)" is associated with a predisposition to developing leukemia at some point in life. Many of these inherited predispositions do not manifest until adulthood. Plus, the very drugs that are used to suppress cancer in transplant patients can trigger malignancy in predisposed cells from the donor.

  On the one hand, the older the donor of stem cells, the more reliable is the donor's clean medical history showing an absence of inherited mutations. On the other hand, the older the donor, the greater the likelihood that the donor cells have an acquired mutation. At this time, it is not clear whether older or younger donors are better.

  It is possible to test donor cells for inherited mutations, which would be present in every cell. But with hundreds of known mutations, only a limited number can be screened with a reasonable amount of blood.
  References:
  McMilin, K., 4/1/2002 Transfusion vol.42(issue 4):495

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• 15. Are there more primitive types of stem cells hidden among blood stem cells, awaiting discovery?

  Answer: Probably
  Examples:

  • Press Release 11/1/2000 from StemCells, Inc. (Nasdaq: STEM)
    "First Identification of Purified Blood Stem Cells as a Source of Mature Liver Cells; Published in Nature Medicine
  • Nature 6/20/02 vol.417
    Catherine Verfaillie of the U. Minnesota Medical School and her team have extracted "multipotent adult progenitor cells" from adult bone marrow which can turn into every type of tissue in the body, just like embryonic stem cells.
  • Stem Cells: Dreams or Reality? (original requires free registration; copy here ).
    Medscape reports on a review talk given by Dr.Catherine Verfaille at The American Society of Hematology 44th Annual Meeting. Can adult stem cells compete with embryonic stem cells in the categories of Plasticity, Clonality, and Reprogramming?

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• 16. Can cord blood stem cells be used for gene therapy?

  Answer: Yes.

  Traditionally, patients with severe hereditary disorders of the immune system were given a stem cell transplant to replace the defective gene. This is kind of like fixing a broken transmission by replacing the whole car. Plus, while the patient's hereditary disorder may be fixed, there are new medical problems associated with a transplant that is not a perfect match.

  The more sophisticated approach is to transplant the patient's own stem cells after they have been genetically engineered to fix the defective gene. The genetic engineering is done with a virus. The patient's own cord blood is an ideal source of matching stem cells.

  Example:
  Transplants of genetically engineered cord blood have been successfully used to cure some forms of "bubble boy syndrome", or SCID . Initially, the SCID results were touted as the first success story of gene therapy. Unfortunately, this clinical trial was halted in 2003 when two of the children subsequently developed leukemia. It is not clear at present if the leukemia was triggered by the gene insertion process, or if the SCID patients simply had a greater predilection towards leukemia than the population at large.

  References:
  Parkman R, et al. 2000, Annual Rev Med 51:33-47 (ADA-SCID)
  Salima Hacein-Bey-Abina, et al. 2002, NEJM 346:1185-1193 (X-linked SCID)
  Antoine C, et al. 2003, Lancet 361(9357):541-2
  "Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99."
  Sara M. Mariani 2003, Highlights of the 2003 meeting of the American Association of Immunologists, reported by Medscape 6/3/03

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• 17. Can cord blood stem cells be used to treat diseases of the Central Nervous System?

  In the lab, stem cells from umbilical cord blood can be induced to develop into nerve cells. When neural cells derived from stem cells are transplanted into lab mice, the cells have been shown to survive and function. The hope is that, eventually, there will be established procedures to infuse cord blood into human beings, get the stem cells to turn into nerve cells, and have those nerve cells function in the body to fix the patient's problem.
  But the leap from where we are to that goal is a long one.

  Disorders of the Central Nervous System (CNS) which might be treated with stem cells:

  • degenerative diseases: Parkinson's, Alzheimer's, Multiple Sclerosis
  • traumatic damage: post-stroke, spinal cord injuries
  • hereditary diseases: Huntington's, Leukodystrophies
  
  Clinical trials which are currently recruiting patients in the United States can be found by searching the web site ClinicalTrials.gov

  Research Report: Multiple Sclerosis

  Stem cell transplants as a therapy for Multiple Sclerosis have been in clinical trial for the past three years. These trials are using autologous stem cells from the patient, not cord blood. The transplants seem to have slowed the progression of MS in some patients. But the transplant itself carries a significant risk of mortality, about 10%, and thus was only tested in patients with severe MS who were not responding to other treatments.

  References:
  press release 4/16/2002 from the American Academy of Neurology annual meeting.
  Nash RA, et al. 5/22/2003 Blood
  A team led by George Kraft of the Fred Hutchinson Cancer Research Center, Seattle, WA, tried autologous stem cell transplants on 26 MS patients, followed over a period of three years.
  Fassas A, et al. 8/2002, J Neurol. 249(8):1088-97
  Researchers in Italy and Greece performed a retrospective study of stem cell transplants in 85 MS patients.

  Research Report: Amyotrophic Lateral Sclerosis (ALS; or "Lou Gehrig's Disease")

  Cord blood transplants as a therapy for ALS are currently in clinical trial. The ALS Therapy Development Foundation issued a review of "Human Umbilical Cord Blood Therapies in ALS" in Dec. 2002, followed by an update on cord blood ; subsequently the Muscular Dystrophy Association opened a clinical trial of cord blood transplant for ALS in 2003.

  Research Report: Inherited Metabolic Disorders

  Some hereditary disorders cause the metabolism to gradually destroy the nervous system. One class of hereditary disorders is leukodystrophies, in which the cells sheathing nerves are improperly developed or maintained, and gradually break down. Another class of hereditary disorders is storage disorders , in which cells are damaged by the abnormal accumulation of waste products. There are different types of storage disorders: Mucopolysaccharidoses (MPS) Storage Diseases (includes Hurler's Syndrome, Sanfilippo Syndrome) and Lysosomal Storage Diseases (includes Gaucher Disease, Tay-Sachs).

  The team lead by Joanne Kurtzberg, M.D., at Duke University, is conducting trials of cord blood transplants for various inherited disorders. They have presented some results at the Dec 2003 meeting of the American Society of Hematology and put out a press release in Jan 2004.

  References to Laboratory Studies:
  Cairns, K, & Finklestein, SP 2003: Phys. Med. Rehabil Clin N Am 14(1 Suppl):S135-S142
  "Growth factors and stem cells as treatments for stroke recovery"
  Savitz SL, Malhotra S, Gupta, G, & Rosenbaum DM 2003: J Cardiovasc Nurs 18(1):57-61
  "Cell transplants offer promise for stroke recovery"
  Sanchez-Ramos, JR 2002: J Neurosci Res 69(6):880-893
  "Neural cells derived from adult bone marrow and umbilical cord blood"
  Zigova, T, etal. 2002: Cell Transplant 11(3):265-274
  "Human umbilical cord blood cells express neural antigens after transplantation into the developing rat brain"
  Bicknese, AR, etal. 2002: Cell Transplant 11(3):261-264
  "Human umbilical cord blood cells can be induced to express markers for neurons and glia"

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• 18. Can cord blood stem cells be used for organ regeneration?

  Possible Answer: Cellular Cardiomyoplasty

  This is a brand-new field of medicine in which stem cell transplantation is used to repair or regenerate damaged heart muscle. Animal studies have shown that stem cells from bone marrow can survive in dead heart muscle and improve its ability to contract. As of late 2002, this technique has entered phase I clinical trials with human beings.

  In the trials, the stem cells are injected into the perimeter of the dead muscle. Most studies have harvested the stem cells from bone marrow, although blood stem cells have also been harvested by apheresis of the circulating bloodstream. The bone marrow is sometimes injected fresh, or sometimes filtered to increase the percentage of stem cells. So far, many different approachs are being attempted because this field is still in its infancy.

  The first molecular evidence that stem cells from cord blood can repair heart damage in transplant patients was announced by researchers at Duke University in Feb 2004.

  References:
  Stamm, C. et al. (4Jan2003) The Lancet 361:45-46
  Tse, H.-F. et al. (4Jan2003) The Lancet 361:47-49
  News reports about study results presented at the American Heart Association meeting: CNN 10Nov2003
  Press releases from the American Heart Association: AHA 11Nov2003
  Press release from Duke University, to be presented at the International Association of Bone Marrow Transplantation Research meeting 12-17Feb2004 in Orlando, FL: IBMTR Feb2004
  Web page from the FDA’s BRMAC (Biological Response Modifiers Advisory Committee), dated 15Mar2004, on the clinical development of cellular products to be used in the treatment of heart diseases.

  Possible Answer: Kidney repair

  References:
  Several research groups (example: U. of Queensland, Australia ) are working to take stem cells from bone marrow and elicit them to grow into renal cells. Moreover, donor stem cells are being infused in combination with kidney transplants to reduce patient need for immunosuppressive drugs that prevent organ rejection.

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• 19. Are there charlatans claiming phony cures with cord blood?

  Answer: YES

  Examples:

  • Using a child's own cord blood to treat cancer
    Almost every private cord blood bank suggests that cord blood can be used to treat the baby if s/he develops cancer. This is extremely unlikely. Adult cancers seem to arise from acquired cell mutations, and doctors believe it is usually safe to transplant patients with their own stem cells. But pediatric cancers seem to arise from inborn genetic abnormalities, which means the abnormality is present in the stem cells too. Prevailing medical opinion holds that children with cancer should receive donated (allogenic) transplants, not (autologous) transplants of their own stem cells. Thus, your baby's cord blood may save a sibling from cancer, but not the baby from which it came.
    References:
    Backtracking leukemia to birth
    Rowley, Janet D. 1998 Nature Medicine vol.4, issue 2, p.150-151
    Highlights From the 2003 Annual Meeting of the American Association for Cancer Research
    "Cancer is the most common genetic disease: 1 in 3 people in the western world develops cancer, and 1 in 5 dies from it"
    Mariani, SM, Deputy Editor, Medscape General Medicine 5(3), 2003

  • The Parkinson's "cure" in India
    Dr. Dinesh Garg achieved reknown in the United States by founding a private cord blood bank, LifeCord USA, which turned out to be a mailing address with no lab. (No relation to other banks named "Lifecord" in Gainesville, FL, Graz, Austria, and Korea.) After that scam was exposed, he fled the country for India, where the Times of India reported that Dr. Garg has "cured" Parkinson's patients with cord blood transplants. The report claims that brain cells "derived by modification of discarded umbilical cord blood stem cells" were infused into the cerebrospinal fluid while cooling the brain and spinal cord. The Indian news reports have been repeated uncritically by the American media.

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