The Pediatric Hematopoietic Stem Cell Transplantation (HSCT) Program of the Stanford School of Medicine is housed in a discrete 12 bed unit in the Lucille Packard Childrens Hospital. The Program has performed more than 850 transplants for the treatment of children and young adults with cancer and non-malignant diseases. The Program performs conventional transplants using allogeneic HSC from a variety of sources including bone marrow, mobilized peripheral blood and umbilical cord blood. Autologous HSCT is used to treat some patients with cancer. In addition to the conventional HSCT, the Program is engaged a series of Phase1/Proof of Concept clinical trials to evaluate antibody-based conditioning instead of chemotherapy, T regulatory type 1 (Tr1) T lymphocytes to prevent graft versus host disease and the gene transfer/gene editing of autologous HSC for the treatment of genetic diseases including immune deficiencies, hemoglobinopathies and in born errors of metabolism.
Dr. Agarwal-Hashmi is the Clinical Director of Pediatric Stem Cell Transplantation Program and leads the development of the innovative clinical research trials. Dr. Agarwal-Hashmi received her MD from Indore University in 1983 and completed her fellowship in pediatric hematology/oncology at Cincinnati Children's Hospital Medical Center in 1995. She joined the faculty of the Stanford University School of Medicine in 2001.
Allogeneic HSCT is associated with several complications and risk factors, including graft versus host disease (GVHD). Since alpha-beta T lymphocytes are the primary mediators of GVHD, depleting them from the HSCT graft should reduce the risk of GVHD. The Program aims to understand how gamma-delta T lymphocytes support immune reconstitution after alpha-beta T-cell depleted HSCT and their impact on the outcome of children treated for both malignant and non-malignant diseases. Gamma-delta T lymphocytes combine the features of conventional adaptive immunity with rapid, innate-like responses. In addition, gamma-delta T lymphocytes recognize tumor cells irrespective of the classical major histocompatibility complex presentation. For this reason, they are the ideal cellular mechanism for immunotherapy.
Dr. Bertaina received her MD degree from the University of Pavia in 2000, obtained her PhD degree in Immunology and Biotechnology from Tor Vergata University in 2013, and completed her fellowship in HSCT at the Bambino Gesù Children’s Hospital in 2005, and she joined the faculty of the Stanford University School of Medicine in 2017.
The mission of the Binns Program for Cord Blood Research (BPCBR) is simple: to advance research into a wide array of blood and immune disorders, from leukemia to sickle cell disease,by providing Stanford researchers with umbilical cord blood, an invaluable yet often over-looked resource.
For more information on the Binns Program for Cord Blood Research, click here.
The new Stanford Center for Definitive and Curative Medicine will work to turn discoveries into stem cell and gene therapies to aid the millions of people who have genetic diseases.
July 24, 2017
At least 280 million people worldwide are living with a rare genetic disease. For many of these millions, the underlying cause of disease is known and well-defined, and yet eludes definitive treatment. At times, surgical interventions, public health measures, biological and small-molecule therapies can transform the health of these populations; often, however, the currently available treatment modalities result in mere palliative, rather than curative, medicine.
Stem cell and gene therapy hold enormous promise to cure conditions with well-defined genetic causes by engineering cells to treat disease or altering a patient’s personal DNA to “fix” an abnormality. To bring these new stem cell and gene therapies to their patients, Stanford Medicine has announced the opening of the Stanford Center for Definitive and Curative Medicine, a joint initiative of the Stanford University School of Medicine, Stanford Health Care and Stanford Children’s Health.
The center provides the organizational and physical infrastructure to support investigator-initiated clinical translational studies on stem cell and gene therapy from initial discovery through completion of clinical proof-of-concept studies. Stanford Medicine is in a unique position to develop the CDCM because of its outstanding expertise in disease pathophysiology, cell and stem cell biology, and an optimal and collaborative environment between the medical school and the hospitals.
“The Center for Definitive and Curative Medicine is going to be a major force in the precision health revolution,” said Lloyd Minor, MD, dean of the School of Medicine. “Our hope is that stem cell and gene-based therapeutics will enable Stanford Medicine to not just manage illness but cure it decisively and keep people healthy over a lifetime.”
Stanford Medicine’s clinical enterprise provides an exemplary clinical environment in which to deploy cures. The center will support the development of life-changing and curative treatments for patients who come to Stanford to receive the highest level of care.
“We are entering a new era in medicine, one in which we will put healthy genes into stem cells and transplant them into patients. And with the Stanford Center for Definitive and Curative Medicine, we will be able to bring these therapies to patients more quickly than ever before,” said Christopher Dawes, president and CEO of Stanford Children’s Health.
“The work of the center is not being done anywhere else in the country — only at Stanford,” added David Entwistle, president and CEO of Stanford Health Care. “We have a pipeline of clinical translational therapies that the center is now driving forward, enabling us to translate basic science discoveries into state-of-the-art therapies for diseases which up until now have been considered incurable.”
Housed within the Department of Pediatrics, the new center will be directed by renowned clinician and scientist Maria Grazia Roncarolo, MD, the George D. Smith Professor in Stem Cell and Regenerative Medicine, and professor of pediatrics and of medicine.
“It is a privilege to lead the center and to leverage my previous experience to build Stanford’s preeminence in stem cell and gene therapies,” said Roncarolo, who is also chief of pediatric stem cell transplantation and regenerative medicine, co-director of the Bass Center for Childhood Cancer and Blood Diseases and co-director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. “Stanford Medicine’s unique environment brings together scientific discovery, translational medicine and clinical treatment. We will accelerate Stanford’s fundamental discoveries toward novel stem cell and gene therapies to transform the field and to bring cures to hundreds of diseases affecting millions of children worldwide.”
The center consists of several innovative pieces designed to allow the rapid development of early scientific discoveries into the clinic that in the past have languished. This includes an interdisciplinary team of basic and clinical scientists to shepherd nascent therapies developed at Stanford. The team will be headed by associate directors Matthew Porteus, PhD, associate professor of pediatrics, and Anthony Oro, MD, the Eugene and Gloria Bauer Professor and professor of dermatology.
To help with clinical development, the center boasts a dedicated stem cell clinical trial office with Sandeep Soni, MD, clinical associate professor of pediatrics, as medical director. In addition, the center has dedicated clinical trial hospital beds in the Bass Center for Childhood Cancer and Blood Diseases located on the top floor of the soon-to-open Lucile Packard Children’s Hospital. From work performed by scientists over the past decade, the center already has a backlog of nearly two dozen early stage therapies whose development the center will accelerate.
“The center will provide novel therapies that can prevent irreversible damage in children, and allow them to live normal, healthy lives,” said Mary Leonard, MD, professor and chair of pediatrics and physician-in-chief at Stanford Children’s Health. “The stem cell and gene therapy efforts within the center are aligned with the strategic vision of the Department of Pediatrics and Stanford’s precision health vision, where we go beyond simply providing treatment for children to instead cure them definitively for their entire lives.”
Laboratory for Cell and Gene Medicine
One of the unique features of the center is its close association with the recently opened $35 million Stanford Laboratory for Cell and Gene Medicine, a 23,000-square-foot manufacturing facility located on California Avenue in Palo Alto. One of the first of its kind in the world, the laboratory has the ability to produce newly developed cell and gene therapy therapies according to the Good Manufacturing Practice standards as required for patient treatment.
Headed by executive director David DiGiusto, PhD, the lab can produce diverse cellular products for patient use, such as genetically corrected bone marrow cells for sickle cell anemia, genetically-engineered skin grafts for children with the genetic disease epidermolysis bullosa or genetically-engineered lymphocytes to fight rejection and leukemia.
“We are fortunate that Stanford researchers have created such a strong portfolio of innovative candidate therapeutics to develop,” said DiGusto. “The capabilities of the laboratory will bridge the gap between research and clinical investigation so that the curative potential of these exciting cell and gene therapies can be realized.”
For more information about the center, or for information about trials associated with the center, please visit the CDCM website, or contact Jennifer Howard at firstname.lastname@example.org.
Genome editing involves the targeted and engineered insertion, deletion, modification or replacement of DNA in the genome of a living organism. In 2011, Nature Methods selected genome editing as the 2011 Method of the Year. The Program is focused on developing genome editing as the safest and most robust approach to cure genetic diseases, particularly sickle cell disease, thalassemia, primary immunodeficiencies including severe combined immunodeficiency and hemophilia and ultimately other organ systems as well. Genome editing offers the precise modification of the target gene of interest by homologous recombination while leaving the rest of genome unperturbed. Engineered nucleases make a specific DNA double-strand break in the gene of interest. By simultaneously providing a piece of “donor” DNA, the cell’s endogenous homologous recombination machinery repairs the induced double-strand break using the donor DNA as a template. In this way, precise sequence changes can be introduced into the gene. The Program has made important discoveries in advancing the field of genome editing including the first use of genome editing using engineered nucleases in human cells and optimizing the use of the CRISPR/Cas9 system in primary human stem cells. The Program is planning an IND submission for the treatment of patients with sickle cell disease by the transplantation of their autologous HSC, which have been genetically modified to produce normal hemoglobin.
Matthew Porteus received his MD and PhD degrees from Stanford University in 1994 and completed a fellowship in pediatric hematology/oncology at Boston Children’s Hospital/Dana Farber Cancer Institute in 1999. He joined the faculty of the Stanford University School of Medicine in 2010.
The hemoglobinopathies are genetic diseases of hemoglobin metabolism. With approximately 7% of the worldwide population being carriers, hemoglobinopathies are the most common monogenic diseases and are one of the world’s major health problems. The Program specializes in the treatment of patients with hemoglobinopathies, specifically β -thalassemia and Sickle Cell Disease (SCD). β-thalassemia syndromes are due to insufficient (β+) or absent (β0) production of β-globin chains. In patients with SCD, at least the defective hemoglobin S. replaces one of the β-globin subunits of the hemoglobin molecule. The molecular basis for both β-thalassemia and Sickle Cell Disease are β-globin gene mutations. The only curative therapy for the hemoglobinopathies is allogeneic HSCT; however, appropriate donors can be identified for only 30% of patients. The Program in conjunction with alpha beta T cell depletion Program has developed a haploidentical HSCT clinical trial. In addition, the Program is collaborating in a gene editing approach in which SCD patients will have their autologous HSC corrected and transplanted following myeloablative conditioning.
Dr. Soni received his MD from the Lady Hardinge Medical College in 1991 and completed a fellowship in hematology/oncology at MD Anderson Cancer Center in 2003. He joined the faculty of the Stanford University School of Medicine in 2016.
Immunodeficiency diseases are characterized by abnormalities in specific components of the immune system that can lead to an increased susceptibility to infection. In some patients, these abnormalities can also result in immune dysregulation, resulting in an immune response that is not properly regulated. The Program is investigating the molecular basis of both immunodeficiency and immune dysregulation syndromes. By exploring the genetic and immunological basis of diseases with autoimmunity or immune dysregulation in children, the Program is developing in depth mechanistic understanding of pediatric autoimmune diseases. The Program has a particular interest in how mutations of key immune tolerance genes affect regulatory T cell (Treg) and effector T cell (Teff) functions. Mutation of one gene, FOXP3, which causes the IPEX syndrome, results in the prototypic pathology of a clinical Treg defect. The Program is currently testing the feasibility and safety of two different gene therapy approaches to treat IPEX patients: one based on lentivirus mediated conversion of Teff cells into Treg cells, and the other based on gene editing of the autologous HSC. A long-term goal is to facilitate gene correction for patients with IPEX syndrome and other genetic diseases of immune dysregulation.
Dr. Bacchetta received her MD degree from the University of Turin in 1987 and completed her fellowship in pediatric immunology at the University of Turin in 1991. She joined the faculty of Stanford University School of Medicine in 2014.
Management of the late effects after HSCT is important for the growing number of long-term HSCT survivors. Many studies have shown that HSCT survivors can suffer from significant late effects that adversely affect morbidity, mortality, working status and quality of life. The Program supports a Survivorship Program, which empowers survivors to take charge of their renewed health and teaches them how to educate their family members and healthcare team regarding their needs.
Dr. Shah received her MD degree from the University of North Carolina in 1990 and completed her fellowship in pediatric hematology/oncology at Children’s Hospital Los Angeles in 1996. She joined the faculty of the faculty of the Stanford University School of Medicine in 2015.
Understanding how HSC interact with their microenvironment and the principles controlling HSC engraftment is central to a successful HSCT. The Program has done pioneering work highlighting that host HSC limit donor HSC engraftment and has developed novel antibody-based conditioning regimens to overcome this limitation, the most advanced of which is being presently tested in clinical trials at Stanford in immunodeficiency patients undergoing HSCT. The Program’s current research is aimed at modulating how HSC interact with their microenvironment to ultimately improve HSCT. The focus is to study the cell surface receptors on HSC and bone marrow stromal cells to learn how to manipulate so that their cell fate can be altered.
Dr. Czechowicz received her MD and PhD degrees from Stanford University School of Medicine in 2011 and completed her fellowship in pediatric hematology/oncology at the Boston Children’s Hospital/Dana Farber Cancer Institute in 2017. She returned to the faculty of the Stanford University School of Medicine in 2017.
Lysosomal storage diseases are inherited metabolic diseases, which are characterized by the abnormal build-up of toxic materials in the body's cells because of genetic mutations leading to enzyme deficiencies. Current research is directed at developing safer, more effective therapies for lysosomal storage disorders with a special focus on those diseases with neurological involvement. For mucopolysaccharidosis type I lysosomal storage disease, present treatments include enzyme replacement therapy and allogeneic HSCT. Both methods are limited in efficacy and at best can slow disease progression. A safer, more effective approach would be to genetically engineer the patient’s own HSC to secrete high levels of enzyme following the transplantation of the genetically modified autologous HSC. The Program in conjunction with the Gene Editing Program has developed an efficient genome editing strategy to target α-L-iduronidase into the C-C chemokine receptor type 5, a “safe harbor locus”, in human CD34+ HSC.
Dr. Gomez-Ospina received her MD and PhD degrees from Stanford University School of Medicine in 2010 and fellowship in medical genetics in 2015.
Patients with primary immune deficiencies have defects in their immune system that places them at an increased risk of infection. The identification of their primary genetic defect has provided insights into the functioning of the normal human immune system. The Program’s research efforts are directed at identifying new genetic defects that result in either an increased rate of infection and/or immune dysregulation. The Program clinically is investigating approaches to improve allogeneic HSCT using an antibody-conditioning regimen and the transplantation of autologous HSC, which have been genetically modified.
Dr. Weinberg received his MD degree from the Stanford University School of Medicine in 1978 and completed his fellowship in pediatric hematology/oncology at the Childrens Hospital Los Angeles in 1985. He joined the faculty of Stanford University School of Medicine in 2004.
The Chromosome 22q11 Deletion Syndrome (22q11DS or 22q11 Syndrome) is the most common inherited chromosomal deletion syndrome, affecting approximately 1/4000 births. The 22q11 Thymus Project is a multi-institutional, multidisciplinary collaboration, which has the overarching goal of understanding the molecular and cellular pathogenesis of thymic abnormalities in 22q11 Syndrome to develop cell-based therapies to regenerate the thymus and restore thymic function in affected patients. Additionally, the 22q11 Syndrome is an experiment of nature that permits a deeper understanding of normal human thymic organogenesis and thymopoiesis.
Dr. Weinberg received his MD degree from Stanford University School of Medicine in 1978 and completed his fellowship in pediatric hematology/oncology at the Childrens Hospital Los Angeles in 1985. He joined the faculty of Stanford University School of Medicine in 2004.
Katja Weinacht received her MD and PhD from Technische Universitaet Muenchen School of Medicine in 2002 and 2004 and completed a fellowship in pediatric hematology/oncology at Boston Children’s Hospital/Dana-Farber Cancer Institute in 2012. She joined the faculty at Stanford University School of Medicine in 2017.
Because the Chromosome 22q11 deletion affects multiple systems, we will have a range of speakers addressing the genetics, cardiac, immunological and neuropsychological manifestations of the syndrome. The presentations will range from molecular and cell biology to studies of developmental biology, clinical manifestations, and yet to be tested therapies.
For more information on the 22q11 Deletion Syndrome Symposium, click here.
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