Senate Commerce Subcommittee on Science, Technology, and Space – Testimony by David A. Prentice

Date: 09/29/2004

 

September 29, 2004

David A. Prentice, Ph.D.

Senior Fellow for Life Sciences, Family Research Council;
Affiliated Scholar, Center for Clinical Bioethics, Georgetown University Medical Center

Mr. Chairman, Distinguished Members of the Committee, thank you for the opportunity to provide testimony on this important subject.

Mark Twain noted that “There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.” This is certainly true regarding the hype and emotion surrounding the stem cell issue.

We should start with some biological definitions, to provide a common scientific frame of reference.

“Almost all higher animals start their lives from a single cell, the fertilized ovum (zygote)… The time of fertilization represents the starting point in the life history, or ontogeny, of the individual.”1The quotes below are from internationally preeminent human embryologist Ronan O’Rahilly in his latest textbook. Dr. O’Rahilly originated the international Carnegie Stages of Human Embryological Development, used for many decades now by the International Nomina Embryologica (now the Terminologica Embryologica) Committee which determines the scientifically correct terms to be used in human embryology around the world.

“Although life is a continuous process, fertilization…is a critical landmark because, under ordinary circumstances, a new, genetically distinct human organism is formed when the chromosomes of the male and female pronuclei blend in the oocyte. This remains true even though the embryonic genome is not actually activated until 2-8 cells are present, at about 2-3 days… During the embryonic period proper, milestones include fertilization, activation of embryonic from extra-embryonic cells, implantation, and the appearance of the primitive streak and bilateral symmetry. Despite the various embryological milestones, however, development is a continuous rather than a saltatory process, and hence the selection of prenatal events would seem to be largely arbitrary.”2

“Prenatal life is conveniently divided into two phases: the embryonic and the fetal…[I]t is now accepted that the word embryo, as currently used in human embryology, means ‘an unborn human in the first 8 weeks’ from fertilization. Embryonic life begins with the formation of a new embryonic genome (slightly prior to its activation).”3

Thus whether within the body or in the laboratory via In vitro fertilization or other assisted reproductive techniques, the first stage of development of a new individual begins with fertilization. Because it has become an area of interest, it is useful to point out that biologically the process of cloning (somatic cell nuclear transfer; SCNT) also produces a zygote as the starting point for development. As the President’s Council on Bioethics has noted, “The first product of SCNT is, on good biological grounds, quite properly regarded as the equivalent of a zygote, and its subsequent stages as embryonic stages in development.”4  The National Academy of Sciences noted the following:

“The method used to initiate the reproductive cloning procedure is called nuclear transplantation, or somatic cell nuclear transfer (SCNT). It involves replacing the chromosomes of a human egg with the nucleus of a body (somatic) cell from a developed human. In reproductive cloning, the egg is then stimulated to undergo the first few divisions to become an aggregate of 64 to 200 cells called a blastocyst. The blastocyst is a preimplantation embryo that contains some cells with the potential to give rise to a fetus and other cells that help to make the placenta. If the blastocyst is placed in a uterus, it can implant and form a fetus. If the blastocyst is instead maintained in the laboratory, cells can be extracted from it and grown on their own.”5

Embryonic stem cells can be isolated from a blastocyst-stage embryo early in human development, whether produced by fertilization or by cloning (SCNT):

“[A]n embryonic stem cell (ES cell) is defined by its origin. It is derived from the blastocyst stage of the embryo. The blastocyst is the stage of embryonic development prior to implantation in the uterine wall.”6

A first question we might address is, “Why use stem cells?” The short answer is to treat degenerative diseases. In the past, infectious diseases were the scourge of mankind; antibiotics, vaccinations, and sanitation have dealt with these as killers. Today degenerative diseases, such as heart disease, stroke, chronic lung disease, Parkinson’s disease, and diabetes are our main concern. These leading causes of death in the U.S. are common to all developed nations and are becoming more prevalent in developing nations. In degenerative diseases, it is usually only part of the organ or tissue that is damaged, rather than the entire organ. Stem cells are proposed to treat these diseases by repairing and replacing the damaged tissue.

A stem cell has two chief characteristics: (1) it multiplies, maintaining a pool of stem cells, and (2) given the correct signal, it can differentiate into other specific cell types for use by the body. There are several sources of stem cells (see figure above). The two types which have generated the most interest are embryonic stem cells derived from the early embryo (5-7 days after conception), and so-called adult stem cells which reside in most, if not all, tissues of the body. Embryonic stem cells were first isolated in mice in 1981, and in humans in 1998; adult stem cells were first identified in bone marrow in the 1960’s, and in recent years have been found in a wide range of tissues throughout the body. Adult stem cells are actually present in the tissues of the individual from the moment of birth, and could more properly be termed tissue stem cells, post-natal stem cells, or non-embryonic stem cells, and include umbilical cord blood stem cells and placental stem cells.

Embryonic stem cells are derived by removing the inner cell mass of the early human embryo (the blastocyst); in this process, the embryo is destroyed. The cells are placed into culture, and their purported advantages are that they can proliferate indefinitely, and can form any tissue. Scientific publications support the claim that they can proliferate for long periods of time in culture. In theory they can form any tissue; however, the experimental basis of their potential to form any tissue relies on the cells being within the normal developmental context of the embryo, where they form the range of tissues and organs of the human body during normal development.

While embryonic stem cells might seem to have a theoretical advantage over adult stem cells, the published literature shows that the claims for embryonic stem cell advantages over adult stem cells are thus far unsubstantiated. Indeed, the National Institutes of Health has noted that: “Thus, at this stage, any therapies based on the use of human ES cells are still hypothetical and highly experimental.” 7And also “Whether embryonic stem cells will provide advantages over stem cells derived from cord blood or adult bone marrow hematopoietic stem cells remains to be determined.”8

There are no current clinical treatments based on embryonic stem cells, and there are in fact only few and modest published successes using animal models of disease. Those who work with embryonic stem cells even have difficulty obtaining pure cultures of specific cell types in the laboratory dish. For example, an Israeli group reported in 2001 that they had obtained insulin-secreting cells from human embryonic stem cells.9  While this report was seized on by the press as a potential treatment for diabetes, what was not reported, and what was revealed by the scientific paper, was that only 1% of the cells in the culture dish supposedly made insulin. The remaining 99% of the cells were a mixture of other cell types, including nerve, muscle, a few beating heart cells, and also cells which continued to proliferate. In fact, those growing cells point out another problem with embryonic stem cells—the potential for tumor formation.10 Embryonic stem cells have a distinct tendency to run out of control.

Embryonic stem cells are actually difficult to establish and maintain in culture. James Thompson, who originated the first human embryonic stem cells in 1998, required 36 human embryos to finally obtain just 5 stem cell lines. Each stem cell line derives from one embryo. The Jones Institute in Virginia, in the summer of 2001, used 110 human embryos to derive 3 stem cell lines. And in the spring of 2004, a Harvard group used 342 human embryos to obtain 17 stem cell lines. In addition, embryonic stem cells face a significant risk of immune rejection. Tissue formed from embryonic stem cells will thus be rejected like most organ transplants without a precise tissue match. Indeed, a group from the Whitehead Institute reported that embryonic stem cells are actually genomically unstable, meaning that the expression of their genes is unstable: “The epigenetic state of the embryonic stem cell genome was found to be extremely unstable.”11  This might in fact explain why there is such difficulty in obtaining pure cultures and why they tend to form tumors. This may also explain the problems in achieving true functional differentiation of embryonic stem cells. This has been particularly troubling with regards to diabetes. While some reports have suggested that a fraction of embryonic stem cells could be stimulated to produce insulin, those reports were called into question by a Harvard study that indicated the embryonic stem cells were not making insulin themselves, but were imbibing it from the culture medium in which they were grown and then releasing it.12 Another recent study found that supposedly differentiated insulin-expressing embryonic stem cells were not actually true beta cells, and when injected into animals caused tumors.13 Human embryonic stem cells (even new lines) have been found to accumulate chromosomal abnormalities in culture as well.14, 15

It is illustrative to examine some quotes from proponents of embryonic stem cell research. In a review paper co-authored by James Thompson,16 the following statements are noteworthy:

“Rarely have specific growth factors or culture conditions led to establishment of cultures containing a single cell type.”

“Furthermore, there is significant culture-to-culture variability in the development of a particular phenotype under identical growth factor conditions.”

“[T]he possibility arises that transplantation of differentiated human ES cell derivatives into human recipients may result in the formation of ES cell-derived tumors.”

“[T]he poor availability of human oocytes, the low efficiency of the nuclear transfer procedure, and the long population-doubling time of human ES cells make it difficult to envision this [generation of human embryos by nuclear reprogramming] becoming a routine clinical procedure…”

Other researchers have noted similar problems with embryonic stem cells:

“The work presented here shows that none of the eight growth factors tested directs a completely uniform and singular differentiation of cells.”17

“Transplanted ES cells spontaneously differentiate into any of a variety of ectodermal, endodermal and mesodermal cell types—sometimes into a disorganized mass of neurons, cartilage and muscle; sometimes into teratomas containing an eye, hair or even teeth.”18

A commentary in the journal Science included the following: 19

“[M]urine ES cells have a disturbing ability to form tumors, and researchers aren’t yet sure how to counteract that. And so far reports of pure cell populations derived from either human or mouse ES cells are few and far between—fewer than those from adult cells.”

“Bone marrow stem cells can probably form any cell type,” says Harvard’s [Douglas] Melton.

And a commentary in the New England Journal of Medicine noted the significant problems still facing potential utility of embryonic stem cells:20

“There are still many hurdles to clear before embryonic stem cells can be used therapeutically. For example, because undifferentiated embryonic stem cells can form tumors after transplantation in histocompatible animals, it is important to determine an appropriate state of differentiation before transplantation. Differentiation protocols for many cell types have yet to be established. Targeting the differentiated cells to the appropriate organ and the appropriate part of the organ is also a challenge.”

Furthermore, the theory that cloning (SCNT) will produce matching tissues for transplant that will not be rejected has already been shown incorrect. When tested in mice, 21the ES cells from the cloned mouse embryo were rejected by the genetically-identical host:

“Jaenisch addressed the possibility that ES clones derived by nuclear transfer technique could be used to correct genetic defects… However, the donor cells, although derived from the animals with the same genetic background, are rejected by the hosts.”22

As noted above, Dr. James Thomson has stated that cloning is unlikely to be clinically significant. Other leaders in the embryonic stem cell field have also published similar views, including Australia’s Alan Trounson:23

“However, it is unlikely that large numbers of mature human oocytes would be available for the production of ES cells, particularly if hundreds are required to produce each ES line… In addition, epigenetic remnants of the somatic cell used as the nuclear donor can cause major functional problems in development, which must remain a concern for ES cells derived by nuclear transfer. …it would appear unlikely that these strategies will be used extensively for producing ES cells compatible for transplantation.”

The evidence from animal studies indicates that it will indeed require a tremendous number of human oocytes to produce even one ES line from cloned embryos. Dr. Peter Mombaerts, who was one of the first mouse cloners, estimates that it will require a minimum of 100 eggs.24The reported first cloning of a human embryo in South Korea this year actually required 242 eggs to obtain just one ES cell line.25

There are in truth few actual positive published scientific reports regarding the claims put forth for embryonic stem cells, and a significant number of negative characteristics. At present embryonic stem cells have shown modest success in repairing spinal cord damage26and Parkinson’s disease,27though the latter experiments showed significant tumor formation in the animals. The theoretical potential of embryonic stem cells to treat diseases, and the theoretical ability to control their differentiation without tumor formation, is wishful thinking.

The relative lack of success of embryonic stem cells should be compared with the real success of adult stem cells. A wealth of scientific papers published over the last few years document that adult stem cells are a much more promising source of stem cells for regenerative medicine. Adult stem cells actually do show pluripotent capacity in generation of tissues, meaning that they can generate most, if not all, tissues of the body. In a paper published in May 2001, the researchers found that one adult bone marrow stem cell could regenerate not only marrow and blood, but also form liver, lung, digestive tract, skin, heart, muscle.28Other researchers have found pluripotent ability of adult stem cells various sources including from bone marrow, 29,30peripheral blood,31inner ear,32and umbilical cord blood.33

The chart attached as Appendix A shows examples (not all-inclusive) of tissues from which adult stem cells have been isolated, as well as some of the derivatives from those stem cells. Bone marrow stem cells seem particularly “plastic”, potentially with the ability to form all adult tissues. Even liposuctioned fat has been found to contain stem cells which can be transformed into other tissues. In point of fact, any time someone has looked in a tissue for stem cells, they have found them.

Many published references also show that adult stem cells can multiply in culture for extensive periods of time, retaining their ability to differentiate, and providing sufficient numbers of cells for clinical treatments. More importantly, adult stem cells have been shown to be effective in treating animal models of disease, including such diseases as diabetes,34stroke,35spinal cord injury,36Parkinson’s disease, 37and retinal degeneration.38

Moreover, adult stem cells are already being used clinically for many diseases. These include as reparative treatments with various cancers, autoimmune diseases such as multiple sclerosis, lupus, and arthritis, anemias including sickle cell anemia, and immunodeficiencies. Adult stem cells are also being used to treat patients by formation of cartilage, growing new corneas to restore sight to blind patients, treatments for stroke, and several groups are using adult stem cells with patients to repair damage after heart attacks. Early clinical trials have shown initial success in patient treatments for Parkinson’s disease and spinal cord injury. An advantage of using adult stem cells is that in most cases the patient’s own stem cells can be used for the treatment, circumventing the problems of immune rejection, and without tumor formation.

The mechanism for these amazing regenerative treatments is still unclear. Adult stem cells in some cases appear capable of interconversion between different tissue types, known as transdifferentiation. In some tissues, adult stem cells appear to fuse with the host tissue and take on that tissue’s characteristics, facilitating regeneration. And in some studies, the adult stem cells do not directly contribute to the regenerating tissue, but instead appear to stimulate the endogenous cells of the tissue to begin repair. Whatever the mechanism, the adult cells are successful at regenerating damaged tissue. As Robert Lanza, a proponent of embryonic stem cells and cloning has noted, “there is ample scientific evidence that adult stem cells can be used to repair damaged heart or brain tissue… if it works, it works, regardless of the mechanism.”39  The citations given above for adult stem cells are only a sampling, including some more recent references. A representative list of diseases currently in patient clinical trials with adult stem cells is given as Appendix B. A more complete review of the recent adult stem cell literature is appended at the end, as a paper prepared for the President’s Council on Bioethics in 2003 (see: bioethics.gov/reports/stemcell/appendix_k.html).

In summary, adult stem cells have been shown by the published evidence to be a more promising alternative for patient treatments, with a vast biomedical potential. Adult stem cells have proven success in the laboratory dish, in animal models of disease, and in current clinical treatments. Adult stem cells also avoid problems with tumor formation, transplant rejection, and provide realistic excitement for patient treatments.

Mr. Chairman, Distinguished Members, thank you once again for allowing me to present testimony on this issue.


Appendix A

Post-Natal (non-embryonic) Stem Cells and their Known or Possible Derivatives
(not an all-inclusive list)

(From the peer-reviewed scientific literature; for placenta by company press releases)

Appendix B

CURRENT CLINICAL APPLICATIONS OF ADULT STEM CELLS
(not a complete listing)

ADULT STEM CELLS—HEMATOPOIETIC REPLACEMENT

CANCERS

BRAIN TUMORS—medulloblastoma and glioma

Dunkel, IJ; “High-dose chemotherapy with autologous stem cell rescue for malignant brain tumors”; Cancer Invest. 18, 492-493; 2000.

Abrey, LE et al.; “High dose chemotherapy with autologous stem cell rescue in adults with malignant primary brain tumors”; J. Neurooncol. 44, 147-153; Sept., 1999

Finlay, JL; “The role of high-dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors: a reappraisal”; Pediatr. Transplant 3 Suppl. 1, 87-95; 1999

RETINOBLASTOMA

Hertzberg H et al.; “Recurrent disseminated retinoblastoma in a 7-year-old girl treated successfully by high-dose chemotherapy and CD34-selected autologous peripheral blood stem cell transplantation”; Bone Marrow Transplant 27(6), 653-655; March 2001

Dunkel IJ et al.; “Successful treatment of metastatic retinoblastoma”; Cancer 89, 2117-2121; Nov 15 2000

OVARIAN CANCER

Stiff PJ et al.; “High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: An autologous blood and marrow transplant registry report”; Ann. Intern. Med. 133, 504-515; Oct. 3, 2000

Schilder, RJ and Shea, TC; “Multiple cycles of high-dose chemotherapy for ovarian cancer”; Semin. Oncol. 25, 349-355; June 1998

MERKEL CELL CARCINOMA

Waldmann V et al.; “Transient complete remission of metastasized merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation”; Br. J. Dermatol. 143, 837-839; Oct 2000

TESTICULAR CANCER

Bhatia S et al.; “High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer”; J. Clin. Oncol. 18, 3346-3351; Oct. 19, 2000

Hanazawa, K et al.; “Collection of peripheral blood stem cells with granulocyte-colonystimulating factor alone in testicular cancer patients”; Int. J. Urol. 7, 77-82; March 2000. 12

LYMPHOMA

Tabata M et al.; “Peripheral blood stem cell transplantation in patients over 65 years old with malignant lymphoma—possibility of early completion of chemotherapy and improvement of performance status”; Intern Med 40, 471-474; June 2001

Josting, A; “Treatment of Primary Progressive Hodgkin’s and Aggressive Non-Hodgkin’s Lymphoma: Is There a Chance for Cure?”; J Clin Oncol 18, 332-339; 2000

Koizumi M et al.; “Successful treatment of intravascular malignant lymphomatosis with highdose chemotherapy and autologous peripheral blood stem cell transplantation”; Bone Marrow Transplant 27, 1101-1103; May 2001

ACUTE LYMPHOBLASTIC LEUKEMIA

Ohnuma K et al.; “Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies”; Br J Haematol 112(4), 981- 987; March 2001

Marco F et al.; “High Survival Rate in Infant Acute Leukemia Treated With Early High-Dose Chemotherapy and Stem-Cell Support”; J Clin Oncol 18, 3256-3261; Sept. 15 2000

ACUTE MYELOGENOUS LEUKEMIA

Ohnuma K et al.; “Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies”; Br J Haematol 112(4), 981- 987; March 2001

Gorin NC et al.; “Feasibility and recent improvement of autologous stem cell transplantation for acute myelocytic leukaemia in patients over 60 years of age: importance of the source of stem cells”; Br. J. Haematol. 110, 887-893; Sept 2000

Bruserud O et al.; “New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients”; Stem Cells 18, 343-351; 2000

CHRONIC MYELOGENOUS LEUKEMIA

Ohnuma K et al.; “Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies”; Br J Haematol 112(4), 981- 987; March 2001

JUVENILE MYELOMONOCYTIC LEUKEMIA

Ohnuma K et al.; “Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies”; Br J Haematol 112(4), 981- 987; March 2001

ANGIOIMMUNOBLASTIC LYMPHADENOPATHY with DYSPROTEINEMIA

Lindahl J et al.; “High-dose chemotherapy and APSCT as a potential cure for relapsing hemolysing AILD”; Leuk Res 25(3), 267-270; March 2001

MULTIPLE MYELOMA

Laughlin MJ et al.; “Hematopoietic engraftment and survival in adult recipients of umbilicalcord blood from unrelated donors”, New England Journal of Medicine 344, 1815-1822; June 14, 2001

Vesole, DH et al.; “High-Dose Melphalan With Autotransplantation for Refractory Multiple Myeloma: Results of a Southwest Oncology Group Phase II Trial”; J Clin Oncol 17, 2173-2179; July 1999.

MYELODYSPLASIA

Ohnuma K et al.; “Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies”; Br J Haematol 112(4), 981- 987; March 2001

Bensinger WI et al.; “Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers”; New England Journal of Medicine 344, 175-181; Jan 18 2001

BREAST CANCER

Damon LE et al.; “High-dose chemotherapy and hematopoietic stem cell rescue for breast cancer: experience in California”; Biol. Blood Marrow Transplant 6, 496-505; 2000

Paquette, RL et al., “Ex vivo expanded unselected peripheral blood: progenitor cells reduce posttransplantation neutropenia, thrombocytopenia, and anemia in patients with breast cancer”, Blood 96, 2385-2390; October, 2000.

Stiff P et al.; “Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer”; Blood 95, 2169-2174; March 15, 2000

Koc, ON et al.; “Rapid Hematopoietic Recovery After Coinfusion of Autologous-Blood Stem Cells and Culture-Expanded Marrow Mesenchymal Stem Cells in Advanced Breast Cancer Patients Receiving High-Dose Chemotherapy”; J Clin Oncol 18, 307-316; January 2000

NEUROBLASTOMA

Kawa, K et al.; “Long-Term Survivors of Advanced Neuroblastoma With MYCN Amplification: A Report of 19 Patients Surviving Disease-Free for More Than 66 Months”; J Clin Oncol 17:3216-3220; October 1999

NON-HODGKIN’S LYMPHOMA

Tabata M et al.; “Peripheral blood stem cell transplantation in patients over 65 years old with malignant lymphoma—possibility of early completion of chemotherapy and improvement of performance status”; Intern Med 40, 471-474; June 2001

Josting, A; “Treatment of Primary Progressive Hodgkin’s and Aggressive Non-Hodgkin’s Lymphoma: Is There a Chance for Cure?”; J Clin Oncol 18, 332-339; 2000

Kirita T et al.; “Primary non-Hodgkin’s lymphoma of the mandible treated with radiotherapy, chemotherapy, and autologous peripheral blood stem cell transplantation”; Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 90, 450-455; Oct. 2000

Yao M et al.; “Ex vivo expansion of CD34-positive peripheral blood progenitor cells from patients with non-Hodgkin’s lymphoma: no evidence of concomitant expansion of contaminating bcl2/JH-positive lymphoma cells”; Bone Marrow Transplant 26, 497-503; Sept. 2000 14

HODGKIN’S LYMPHOMA

Josting, A; “Treatment of Primary Progressive Hodgkin’s and Aggressive Non-Hodgkin’s Lymphoma: Is There a Chance for Cure?”; J Clin Oncol 18, 332-339; 2000

RENAL CELL CARCINOMA

Childs R et al., “Regression of Metastatic Renal-Cell Carcinoma after Nonmyeloablative Allogeneic Peripheral-Blood Stem-Cell Transplantation”, New England Journal of Medicine 343, 750-758; Sept. 14, 2000

Childs, RW; “Successful Treatment of Metastatic Renal Cell Carcinoma With a Nonmyeloablative Allogeneic Peripheral-Blood Progenitor-Cell Transplant: Evidence for a Graft-Versus-Tumor Effect:; J Clin Oncol 17, 2044-2049; July 1999

VARIOUS SOLID TUMORS

Nieboer P et al.; “Long-term haematological recovery following high-dose chemotherapy with autologous bone marrow transplantation or peripheral stem cell transplantation in patients with solid tumours”; Bone Marrow Transplant 27, 959-966; May 2001

Lafay-Cousin L et al.; “High-dose thiotepa and hematopoietic stem cell transplantation in pediatric malignant mesenchymal tumors: a phase II study”; Bone Marrow Transplant 26, 627-632; Sept. 2000

Michon, J and Schleiermacher, G. “Autologous haematopoietic stem cell transplantation for paediatric solid tumors”, Baillieres Best Practice Research in Clinical Haematology 12, 247-259, March-June, 1999.

Schilder, RJ et al.; “Phase I trial of multiple cycles of high-dose chemotherapy supported by autologous peripheral-blood stem cells”; J. Clin. Oncol. 17, 2198-2207; July 1999

SOFT TISSUE SARCOMA

Blay JY et al.; “High-dose chemotherapy with autologous hematopoietic stem-cell transplantation for advanced soft tissue sarcoma in adults”; J. Clin. Oncol. 18, 3643- 3650; Nov 1 2000 15

ADULT STEM CELLS—IMMUNE SYSTEM REPLACEMENT
AUTOIMMUNE DISEASES

SCLEROMYXEDEMA

A.M. Feasel et al., “Complete remission of scleromyxedema following autologous stem cell transplantation,” Archives of Dermatology 137, 1071-1072; Aug. 2001.

MULTIPLE SCLEROSIS

Mancardi GL et al.; “Autologous hematopoietic stem cell transplantation suppresses Gdenhanced MRI activity in MS”; Neurology 57, 62-68; July 10, 2001

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

Burt, RK and Traynor, AE; “Hematopoietic Stem Cell Transplantation: A New Therapy for Autoimmune Disease”; Stem Cells17, 366-372; 1999

Burt RK et al.; “Hematopoietic stem cell transplantation of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus”; Cancer Treat. Res. 101, 157-184; 1999

CROHN’S DISEASE

Burt RK et al., “High-dose immune suppression and autologous hematopoietic stem cell transplantation in refractory Crohn disease”, Blood 101, 2064-2066, March 2003

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

Hawkey CJ et al.; “Stem cell transplantation for inflammatory bowel disease: practical and ethical issues”; Gut 46, 869-872; June 2000

RHEUMATOID ARTHRITIS

Burt RK et al., “Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism”, Arthritis & Rheumatism 50, 2466-2470, August 2004

Verburg RJ et al.; “High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy”; Arthritis Rheum 44(4), 754-760; April 2001

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

Burt, RK and Traynor, AE; “Hematopoietic Stem Cell Transplantation: A New Therapy for Autoimmune Disease”; Stem Cells17, 366-372; 1999

Burt RK et al.; “Hematopoietic stem cell transplantation of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus”; Cancer Treat. Res. 101, 157-184; 1999

Burt, RK et al., “Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: sustained response in two of four patients”, Arthritis & Rheumatology 42, 2281- 2285, November, 1999. 16

JUVENILE ARTHRITIS

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

Burt, RK and Traynor, AE; “Hematopoietic Stem Cell Transplantation: A New Therapy for Autoimmune Disease”; Stem Cells17, 366-372; 1999

SYSTEMIC LUPUS

Wulffraat NM et al.; “Prolonged remission without treatment after autologous stem cell transplantation for refractory childhood systemic lupus erythematosus”; Arthritis Rheum 44(3), 728-731; March 2001

Rosen O et al.; “Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells”; Arthritis res. 2, 327- 336; 2000

Traynor AE et al.; “Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study”; Lancet 356, 701-707; August 26, 2000

Burt, RK and Traynor, AE; “Hematopoietic Stem Cell Transplantation: A New Therapy for Autoimmune Disease”; Stem Cells17, 366-372; 1999

Burt RK et al.; “Hematopoietic stem cell transplantation of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus”; Cancer Treat. Res. 101, 157-184; 1999

Traynor A and Burt RK; “Haematopoietic stem cell transplantation for active systemic lupus erythematosus”; Rheumatology 38, 767-772; August 1999

Martini A et al.; “Marked and sustained improvement 2 years after autologous stem cell transplant in a girl with system sclerosis”; Rheumatology 38, 773; August 1999

POLYCHONDRITIS

Rosen O et al.; “Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells”; Arthritis res. 2, 327- 336; 2000

SYSTEMIC VASCULITIS

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

SJOGREN’S SYNDROME

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

BEHCET’S DISEASE

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

MYASTHENIA

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

RED CELL APLASIA

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

AUTOIMMUNE CYTOPENIA

Rabusin M et al.; “Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune disease”; Haematologica 85(11 Suppl), 81-85; Nov. 2000

Papadaki HA et al.; “Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with autoimmune cytopenias”; Blood 96, 3272-3275; Nov 1 2000

IMMUNODEFICIENCIES

Banked unrelated umbilical cord blood was used to reconstitute the immune system in 2 brothers with X-linked lymphoproliferative syndrome and 1 boy with X-linked hyperimmunoglobulin-M syndrome. Two years after transplantation, all 3 patients have normal immune systems. These reports support the wider use of banked partially matched cord blood for transplantation in primary immunodeficiencies.

Reference

Ziegner UH et al.; “Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies”; J Pediatr 138(4), 570-573; April 2001

Eight children with severe immunodeficiencies treated by adult bone marrow stem cell transplants. Six of 8 showed relatively normal immune systems after 1 year.

Reference

Amrolia, P. et al., “Nonmyeloablative stem cell transplantation for congenital immunodeficiencies”, Blood 96, 1239-1246, Aug. 15, 2000.

SEVERE COMBINED IMMUNODEFICIENCY SYNDROME-X1 (ASC gene therapy)

Cavazzana-Calvo M et al.; “Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease”; Science 288, 669-672; April 28, 2000

ANEMIAS

SICKLE CELL ANEMIA

Gore L. et al.; “Successful cord blood transplantation for sickle cell anemia from a sibling who is human leukocyte antigen-identical: implications for comprehensive care”, J Pediatr Hematol Oncol 22(5):437-440; Sep-Oct 2000

Steen RG et al.; “Improved cerebrovascular patency following therapy in patients with sickle cell disease: initial results in 4 patients who received HLA-identical hematopoietic stem cell allografts”; Ann Neurol 49(2), 222-229; Feb. 2001

Wethers DL; “Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment”; Am. Fam. Physician 62, 1309-1314; Sept. 15, 2000

SIDEROBLASTIC ANEMIA

Ayas M et al.; “Congenital sideroblastic anaemia successfully treated using allogeneic stem cell transplantation”; Br J Haematol 113, 938-939; June 2001

Gonzalez MI et al.; “Allogeneic peripheral stem cell transplantation in a case of hereditary sideroblastic anaemia”; British Journal of Haematology 109, 658-660; 2000

WALDENSTROM’S MACROGLOBULINEMIA

Anagnostopoulos A et al.; “High-dose chemotherapy followed by stem cell transplantation in patients with resistant Waldenstrom’s macroglobulinemia”; Bone Marrow Transplant 27, 1027-1029; May 2001

APLASTIC ANEMIA

Gurman G et al.; “Allogeneic peripheral blood stem cell transplantation for severe aplastic anemia”; Ther Apher 5(1), 54-57; Feb. 2001

Kook H et al.; “Rubella-associated aplastic anemia treated by syngeneic stem cell transplantations”; Am. J. Hematol. 64, 303-305; August 2000

AMEGAKARYOCYTIC THROMBOCYTOPENIA

Yesilipek et al.; “Peripheral stem cell transplantation in a child with amegakaryocytic thrombocytopenia”; Bone Marrow Transplant 26, 571-572; Sept. 2000

CHRONIC EPSTEIN-BARR INFECTION

Fujii N et al.; “Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active epstein-barr virus infection”; Bone Marrow Transplant 26, 805-808; Oct. 2000

Okamura T et al.; “Blood stem-cell transplantation for chronic active Epstein-Barr virus with lymphoproliferation”; Lancet 356, 223-224; July 2000

FANCONI’S ANEMIA

Kohli-Kumar M et al., “Haemopoietic stem/progenitor cell transplant in Fanconi anaemia using HLA-matched sibling umbilical cord blood cells”, British Journal of Haematology 85, 419-422, October 1993

DIAMOND BLACKFAN ANEMIA

Ostronoff M et al., “Successful nonmyeloablative bone marrow transplantation in a corticosteroid-resistant infant with Diamond-Blackfan anemia”, Bone Marrow Transplant. 34, 371-372, August 2004

THALASSEMIA

Tan PH et al., “Unrelated peripheral blood and cord blood hematopoietic stem cell transplants for thalassemia major”, Am J Hematol 75, 209-212, April 2004

STROKE

Meltzer CC et al.; “Serial [18F]Fluorodeoxyglucose Positron Emission Tomography after Human Neuronal Implantation for Stroke”; Neurosurgery 49, 586-592; 2001.

Kondziolka D et al.; “Transplantation of cultured human neuronal cells for patients with stroke”; Neurology 55, 565-569; August 2000

CARTILAGE AND BONE DISEASES

OSTEOGENESIS IMPERFECTA

Horwitz EM et al., “Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone”, Proceedings of the National Academy of Sciences USA 99, 8932-8937; 25 June 2002.

Horwitz EM et al., “Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta”, Blood 97, 1227-1231; 1 March 2001.

Horwitz, EM et al.; “Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta”; Nat. Med. 5, 309-313; March 1999.

SANDHOFF DISEASE

CORNEAL REGENERATION

Anderson DF et al.; “Amniotic Membrane Transplantation After the Primary Surgical Management of Band Keratopathy”; Cornea 20(4), 354-361; May 2001

Anderson DF et al.; “Amniotic membrane transplantation for partial limbal stem cell deficiency”; Br J Ophthalmol 85(5), 567-575; May 2001

Henderson TR et al.; “The long term outcome of limbal allografts: the search for surviving cells”; Br J Ophthalmol 85(5), 604-609; May 2001

Daya SM, Ilari FA; “Living related conjuctival limbal allograft for the treatment of stem cell deficiency”; Opthalmology 180, 126-133; January 2001

Schwab IR et al.; “Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease”; Cornea 19, 421-426; July 2000.

Tsai et al.; “Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells.”; New England Journal of Medicine 343, 86-93, 2000.

Tsubota K et al.; “Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation”; New England Journal of Medicine 340, 1697-1703; June 3, 1999

OCULAR CORNEAL REGENERATION

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Matthes-Martin S et al.; “Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis”; Blood 96, 3997-3999; Dec 1, 2000

PRIMARY AMYLOIDOSIS

Sezer O et al.; “Novel approaches to the treatment of primary amyloidosis”; Exper Opin. Investig. Drugs 9, 2343-2350; Oct 2000

LIMB GANGRENE

Tateishi-Yuyama E et al.; “Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial”; Lancet 360, 427-435; 10 August 2002.

SURFACE WOUND HEALING

Badiavas EV, “Participation of Bone Marrow Derived Cells in Cutaneous Wound Healing”, Journal Of Cellular Physiology 196, 245-250; 2003.

HEART DAMAGE

Wollert KC et al., “Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial”, Lancet 364, 141-148, 10 July 2004

Britten MB et al., “Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction”; Circulation 108, 2212-2218; Nov 2003

Perin EC et al.; “Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure”; Circulation 107, r75-r83; published online May 2003

Stamm C et al.; “Autologous bone-marrow stem-cell transplantation for myocardial regeneration”; The Lancet 361, 45-46; 4 January 2003

Tse H-F et al.; “Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation”; The Lancet 361, 47-49; 4 January 2003

Strauer BE et al.; “Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans”; Circulation 106, 1913-1918; 8 October 2002

Strauer BE et al.; “Myocardial regeneration after intracoronary transplantation of human autologous stem cells following acute myocardial infarction”; Dtsch Med Wochenschr 126, 932-938; Aug 24, 2001 21

Menasché P et al. “Myoblast transplantation for heart failure.” Lancet 357, 279-280; Jan 27, 2001

Menasché P et al. [“Autologous skeletal myoblast transplantation for cardiac insufficiency. First clinical case.”] [article in French] Arch Mal Coeur Vaiss 94(3), 180-182; March 2001

PARKINSON’S DISEASE

Lévesque M and Neuman T, “Autologous transplantation of adult human neural stem cells and differentiated dopaminergic neurons for Parkinson disease: 1-year postoperative clinical and functional metabolic result”, American Association of Neurological Surgeons annual meeting, Abstract #702; 8 April 2002

Gill SS et al.; “Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease”; Nature Medicine 9, 589-595; May 2003 (published online 31 March 2003)

See also July 14, 2004 Senate testimony by Dr. Michel Lévesque:
commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3670

and Mr. Dennis Turner:
commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3676

SPINAL CORD INJURY

See July 14, 2004 Senate testimony by Dr. Jean Peduzzi-Nelson:
commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3671

and a more extensive testimony at:
www.stemcellresearch.org/testimony/peduzzi-nelson.htm

and Ms. Laura Dominguez:
commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3673

and Ms. Susan Fajt:
commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3674

For appended review paper on adult stem cells, see
bioethics.gov/reports/stemcell/appendix_k.html

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{
Adult/73
|
Embryonic/0
}