CHOC Children's

CHOC Pressroom

March 14, 2007

A researcher from Children’s Hospital of Orange County (CHOC), Phillip Schwartz, Ph.D., is among an international collaborative group of scientists who have shown, for the first time, that human neural stem cells, of either adult or embryonic origin, can treat degenerative diseases safely and effectively, and do so by invoking multiple mechanisms. Such cells can be grown in a manner compatible with clinical use (i.e., without animal feeder layers) and even without the need for immunosuppression. These were a few of a number of conclusions arrived at by the team led by Evan Y. Snyder, M.D., Ph.D., of the Burnham Institute for Medical Research (“Burnham”). The study, to be published in Nature Medicine, was made available by advanced publication at the journal’s website on March 11, 2007.

To determine whether stem cell biology might play a role in benefiting degenerative diseases, the investigators first chose to approach, as proof-of-concept, a mouse model of a representative lethal neurodegenerative disease. Next, they used mouse neural stem cells, a type of “adult” stem cell, to establish the parameters of what might or might not be achievable in this disease. Then, having demonstrated success with mouse cells, they extended those insights to stem cells of human origin, neural stem cells derived from cadavers or from human embryonic stem cells, and, in fact, had the opportunity, for the first time, to compare those two types of stem cells head-to-head in the same model. The results, described in more detail below, prove to be the first successful use of neural stem cells derived from human embryonic stem cells in treating a degenerative disease, significantly preserving function and extending life.

The mouse model chosen falls in a class of genetic diseases (called lysosomal storage diseases, described in more detail below) that afflicts 1 in 5000 patients, typically children, but which is often used to model an array of adult neurodegenerative diseases such as Parkinson’s, ALS, and Alzheimer’s – particularly those with a genetic component. The mouse used in these studies has a mutation in a gene that makes the housekeeping enzyme hexosaminidase (Hex) and, therefore, has Sandhoff’s Disease, a uniformly lethal genetic disease related to Tay-Sachs Disease. When stem cells were implanted -- at simply one time point -- into brains of newborn Sandhoff mice, the onset of symptoms was delayed, well-being and motor function was preserved, and lifespan was extended by >70%. (Although not tested, it is assumed that repeated treatment would have a continued effect).

The researchers discovered that their implanted neural stem cells, which migrated and integrated extensively throughout the brain, did much more than just replace brain tissue destroyed by the disease. Some of the transplanted cells did replace damaged nerve cells and transmitted nerve impulses, offering the first evidence that stem cell-derived nerve cells may integrate electrically and functionally into a diseased brain, but the transplanted cells also boosted the brain’s supply of the enzyme Hex, which reduced the lipid accumulations in the treated animals. The experimental treatment also dampened the inflammation that typically occurs in the brains of most degenerative diseases, including Sandhoff’s, and likely contributes to disease progression.

To demonstrate that a better understanding of the fundamental mechanisms of stem cell action may permit the development of rational combined synergistic therapies, the investigators then gave the mice a simple oral drug that permitted the amount of enzyme provided by the engrafted stem cells to work even more efficiently by presenting them with a smaller burden of material to metabolize. The lifespan of the mice doubled. Neither treatment could work as effectively on its own and, together, the effect of the two treatments was more than simply additive. This was a demonstration that stem efficacy could be dramatically enhanced even without the need for genetic engineering. (The drug, a glycosphingolipid biosynthesis inhibitor, is in a class of compounds called “substrate reduction therapy” drugs.) This part of the study not only represented the first “multidisciplinary” approach with stem cells against a degenerative disease, but also highlighted the fact that, in the future, the most successful therapies – including those employing stem cells -- will likely invoke the use of multiple strategies in concert.

The researchers then sought to extend their insights to the use of human stem cells – either stem cells turned into neural progenitors from human embryonic stem cells – or isolated directly from the nervous system (colloquially called “adult” stem cells to distinguish them from embryonic stem cells even though they are taken from prematurely born infants). Both types of human stem cells were actually somewhat more effective than the mouse neural stem cells. And, they were equally as good as each other – in the first head-to-head comparison ever done between embryonic and “adult” stem cells, although the embryonic stem cells were somewhat easier to “scale up” into large quantities. Both types of human stem cells invoked the same range of multiple, collaborative mechanisms. Neither type of human stem cell created tumors, deformation, a worsening of symptoms, nor gave rise to inappropriate cells types. Neither cell type was rejected by the immune system. In fact, no immunosuppression was needed at all. Finally, the human embryonic stem cells were grown without mouse feeder layers and in a “defined” culture medium that is compatible with clinical use in patients and demonstrating for the first time that such preparations are consistent with a therapeutic impact.

Sandhoff results from a genetic mutation that reduces the body’s supply of an enzyme, called hexosaminidase (Hex), used by brain cells to metabolize excess fatty material called lipids. Onset is typically at six months in human infants. The accumulation of lipids in brain tissue destroys brain cells and results in inexorable deterioration of the brain and spinal cord. Children suffering with Sandhoff rarely see their sixth birthday. Sandhoff mice are similarly affected. Tay-Sachs, a related disease, is predominant to Ashkenazi Jewish populations, while Sandhoff’s, an even more severe form of Tay-Sachs, is not limited to any ethnic group. Both diseases are marked with deficient Hex enzyme functioning and are among a known group of about 40 diseases rooted in the inability to metabolize lipids or other materials. While Sandhoff’s and Tay-Sachs are relatively rare, one person in 5,000 is affected by a disease that falls into a category of lysosomal storage diseases. These diseases are part of a much more common group of diseases called “neurogenetic diseases”. It is believed that, ultimately, all degenerative diseases may be found to have a genetic basis, including Parkinson’s, Alzheimer’s, ALS, forms of cerebral palsy, autism, etc. In other words, these findings contribute fundamental basic knowledge about stem cell biology that will help inform medical scientists in their quest for understanding a host of other neurological diseases.

Currently, there is no treatment for Tay-Sachs or Sandhoff's. The researchers believe that their study may serve as a springboard for a clinical trial for Tay-Sachs. Given that the human stem cells used in this study – both of adult and embryonic origin – were safe and effective in so many mice, are suitable for clinical use, and have been demonstrated to be safe even in monkeys, the authors feel prepared to petition the FDA, at least for the use of the human neural stem cells of adult origin.

Support for this study includes grants from the National Institute of General Medicine, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health Development of the National Institutes of Health; the Glycobiology Institute, University of Oxford; and the Wellcome Trust. Private philanthropy played a significant role in supporting these studies, with funding from the Children’s Hospital of Orange County Foundation for Children,; National Tay-Sachs and Allied Diseases Foundation; the Late-Onset Tay-Sachs Foundation; Children’s Neurobiological Solutions; the A-T Children’s Project; the Barbara Anderson Foundation for Brain Repair; Project ALS; March of Dimes; and Hunter’s Hope.


1. First successful use of cells derived from human embryonic stem cells (hESCs) in a degenerative disease, significantly preserving function and prolonging life in this animal model, and laying the groundwork for a potential clinical trial.

2. First demonstration that stem cells employ multiple mechanisms – not just cell replacement -- to benefit disease.

3. First use of hESCs grown in a manner suitable for clinical use (i.e., without contaminating mouse cells).

4. First head-to-head comparison of human embryonic and “adult” stem cells in the same disease model using the same metrics in the hands of the same investigators.

5. First evidence that stem cells, including hESCs may also have anti-inflammatory actions.

6. First demonstration that immunosuppression may not be necessary for successful transplantation in some diseases, making applications to a broad range of patients easier.

7. First evidence that stem cell-derived nerve cells may integrate electrically and functionally into a diseased brain.


Named one of the best children’s hospitals by U.S. News & World Report (2014-2015) and a 2013 Leapfrog Top Hospital for the highest quality of care, Children’s Hospital of Orange County (CHOC Children's) is exclusively committed to the health and well-being of children through clinical expertise, advocacy, outreach, education and research that brings advanced treatment to pediatric patients. Affiliated with the University of California, Irvine, CHOC’s regional health care network includes two state-of-the-art hospitals in Orange and Mission Viejo, many primary and specialty care clinics, a pediatric residency program, and four clinical centers of excellence - the CHOC Children’s Heart, Neuroscience, Orthopaedic and Hyundai Cancer Institutes..

CHOC earned the Gold Level CAPE Award from the California Council of Excellence, the only children’s hospital in California to ever earn this distinction, and was awarded Magnet designation, the highest honor bestowed to hospitals for nursing excellence.  Recognized for extraordinary commitment to high-quality critical care standards, CHOC’s Pediatric Intensive Care Unit (PICU) is the first in the United States to earn the Beacon Award for Pediatric Critical Care Excellence.


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