Stem Cell Therapies For Pediatric Diseases and Injuries - 3rd Annual Symposium at CHOC Children’s

CHOC Children’s Annual Symposium Highlights Urgent Need and Near-Term Potential for Stem Cell Therapies in Fatal Childhood Diseases

— Presenters challenge attendees to accelerate pace of translational progress and move more stem cell-based treatments into the clinic during 2009 —

More than 150 clinicians and researchers, including representatives from leading U.S. medical institutions, convened last week at Children’s Hospital Orange County (CHOC Children’s) to participate in a day-long symposium focusing on the urgent, unmet need and greatest near-term opportunities to advance stem cell therapies for life-threatening pediatric diseases into the clinic.

“Great strides have been made recently in understanding the remarkable ‘homing’ capacity of stem cells — their natural attraction to sites of disease or injury — and methods for exploiting this phenomenon to deliver missing enzymes or cancer killing drugs directly to target tissue,” said Philip Schwartz, PhD, the symposium co-chair and organizer, a senior research scientist, and the managing director of the Human Neural Stem Cell Resource at CHOC Children’s Research Institute. “We are finally at the cusp of translating these developments into real medical benefit, particularly for inherited neurodegenerative disorders and brain cancer.”
 
Hosted by the CHOC Children’s Research Institute, with support from the National Institutes of Health (NIH) and the California Institute of Regenerative Medicine (CIRM), the symposium was the culmination of a 10-day human stem cell culture training course attended by researchers from around the globe. This marked the sixth year that CHOC Children’s has sponsored the training program, the first such West Coast course sponsored by the NIH, and the third year for the symposium.  Dr. Schwartz and his team at CHOC Children’s have been at the forefront of perfecting techniques for deriving stem cells, including human neural stem cells (hNSC), from non-embryonic sources and have trained scientists from more than 25 countries in these methods.

“The training course and symposium allow us to bring bright young scientists and experienced clinicians together to share progress in translating stem cell research into therapies for currently untreatable, often fatal childhood diseases and to renew our common commitment to accelerating the pace of this work,” said Dr. Schwartz. “CHOC Children’s is an ideal setting for these two programs because of our track record of groundbreaking work in stem cell medicine, as well as the fact that we provide medical care for a large and diverse population of young patients impacted by these diseases.  For these children and their families, as well as the clinicians who see them every day, the jump from lab to clinic can’t come soon enough.”

Beyond its investigational stem cell research program, CHOC Children’s maintains a Blood and Bone Marrow Transplant lab and a Cord Blood Bank, both dedicated to serving the needs of infants, adolescents and young adults through bone marrow, peripheral blood and cord blood transplant treatment. The CHOC Cord Blood Bank is one of the few select cord blood banks in the United States that is affiliated with the National Marrow Donor Program (NMDP), making CHOC Children’s cord blood available to help patients worldwide. The hospital’s cancer research program continually seeks to improve the methods of blood and marrow transplant treatment available to patients.

Symposium Highlights: Translating Advances in Stem Cell Research into Clinical Progress for Fatally Ill Children

The slate of expert speakers at the 3rd Annual Symposium at CHOC Children’s included representatives from CHOC Children’s, City of Hope, Fred Hutchinson Cancer Research Center, Harbor-UCLA Medical Center, Stanford University, and the US Food and Drug Administration.  

According to Schwartz and other symposium presenters, two areas most likely to benefit from stem cell therapies in the near-term are inherited metabolic disorders – primarily lysosomal storage disorders (LSDs) - and invasive brain tumors. Not only are both of these areas the subjects of basic science and translational research in CHOC Children’s Research Institute, but CHOC Children’s is a leading, national treatment center for both: the hospital is currently caring for more than 40 children diagnosed with LSDs and treating more than 130 children battling malignant brain cancer.

LSDs represent a particularly compelling target for novel therapies. A group of approximately 40 inherited disorders that include Gaucher’s Disease, Tay-Sachs, Fabry disease, Krabbe’s Disease, Batten Disease, and Hurler Syndrome, LSDs occur when a particular enzyme or enzymes in the lysosomes of cells is missing, making it impossible for the cells to process defined cellular substrates, resulting in a build up of proteins, lipids and cholesterol as toxic waste within the cells. While there are intravenous enzyme replacement therapies (ERTs) available to treat the symptoms of some LSDs, there is no cure, and many lack any effective treatment at all.  Many of these diseases are lethal within the first several years of a child’s life.

LSDs can cause degeneration and malformation of many body systems, including the skeleton and muscles, the heart and lungs, and the brain and spinal cord. The majority of LSD patients develop central nervous system disease, including irreversible brain damage that results in speech and motor skill degradation, blindness, cognitive decline, seizures, and eventual death.

Several presenters at the CHOC Children’s symposium discussed the potential of stem cell therapies to transcend the limitations and extend the benefits of ERT to prevent central nervous system damage in patients with LSDs.

“We know that enzyme-deficient cells can take up enzymes produced by adjacent normal cells or introduced by injection,” said Raymond Wang, MD, director, Lysosomal Storage Diseases Clinic, Division of Metabolic Disorders, CHOC Children’s. “However, standard enzyme replacement therapies do not impact brain cells because the enzymes can’t cross the blood-brain barrier. But if we inject stem cells that produce the missing enzyme directly into the brain, we have the potential to arrest the disease process.  The key is being able to do this as early as possible, before irreversible damage is done.”

As proof of the principle described by Dr. Wang, Gregory M. Enns, MB, ChB, director of the Biochemical Genetics Program and the Division of Medical Genetics at Stanford University, provided an update on his research investigating a novel stem cell approach for the treatment of LSDs. Specifically, Dr. Enns discussed the utilization of neural stem cells (NSCs) delivered directly into the brain, including an overview of the first patients treated for the LSD neuronal ceroid lipofuscinosis (Batten disease) with this new therapy.

In addition to research investigating novel approaches for the treatment of LSDs, symposium presenters reviewed several other areas of active translational stem cell work, including:

Increasing the Number of Patients that can Benefit from Stem Cell Therapy
Lauri Burroughs, MD, acting assistant professor of pediatrics, Fred Hutchinson Cancer Research Center, discussed ongoing progress in non-myeloablative hematopoietic (blood forming) stem cell transplantation, including new protocols for matched and half-matched donor grafts. These less toxic approaches are more appropriate for pediatric patients and may expand the number of children who can benefit from stem cell transplantation.  Dr. Burroughs also described techniques for managing the balance between host immunity and graft-versus-host disease to ensure successful engraftment of stem cells in both cancer and non-malignant inherited disorders.

Specific Stem Cell Targeting of Invasive Brain Cancers
Karen S. Aboody, MD, assistant professor of Hematology, Hematopoietic Cell Transplantation & Neurosciences at the City of Hope, provided an update from ongoing research investigating the potential for NSCs to deliver chemotherapy to invasive and metastatic tumors. Dr. Aboody’s extensive research over the last 15 years has confirmed that NSCs display an inherent affinity for tumor cells, making them ideal “messengers” for selective targeting of therapy to tumors, particularly those that are traditionally difficult to reach with systemic therapy and/or surgery.

Dr. Aboody and her team are using a multi-potent, clonal NSC line modified to express a therapeutic transgene that allows the cells to create the enzyme cytosine deaminase. With this modification, the cells are able to convert the relatively benign pro-drug 5-fluorocystine (5-FC) to the active chemotherapeutic agent 5-fluorouracil (F-FU) at the site of the tumor.  Her team is now preparing for a phase 1 study to assess the feasibility, safety and intracerebral distribution of locally administered cytosine deaminase-expressing NSCs in combination with oral 5-FC in patients with recurrent high grade glioma.