Neurology :: Stem cells may benefit people with neurodegenerative disease

Human embryonic stem cells (hESCs) hold great promise forbenefiting degenerative diseases, and do so by invoking multiplemechanisms. Such cells can be grown in a manner compatible with clinicaluse (i.e., without animal feeder layers) and even without the need forimmunosuppression.

These were a few of a number of conclusions arrivedat by an international collaboration led by Evan Y. Snyder, M.D., Ph.D.,and spearheaded by a member of his lab, Jean-Pyo Lee, Ph.D., of theBurnham Institute for Medical Research (“Burnham”). The study, to bepublished in Nature Medicine, will be made available by advancedpublication at the journal’s website on March 11, 2007.

To determine whether stem cell biology might play a role inbenefiting degenerative diseases, the investigators first chose toapproach, as proof-of-concept, a mouse model of a representative lethalneurodegenerative disease. Next, they used mouse neural stem cells(NSCs), a type of “adult” stem cell, to establish the parameters of whatmight or might not be achievable in this disease. Then, havingdemonstrated success with mouse cells, they extended those insights tostem cells of human origin, both human neural stem cells and humanembryonic stem cells, and, in fact, had the opportunity, for the firsttime, to compare those two types of controversial stem cellshead-to-head in the same model. The results, described in more detailbelow, in fact prove to be the first successful use of human embryonicstem cells in treating a degenerative disease, significantly preservingfunction and extending life.

The mouse model chosen falls in a class of genetic diseasesthat afflicts 1 in 5000 patients, typically children (called lysosomalstorage diseases, described in more detail below), but which is oftenused to model an array of adult neurodegenerative diseases such asParkinson’s, ALS, Alzheimer’s – particularly those with a geneticcomponent. The mouse used here has mutation in a gene that makes thehousekeeping enzyme hexosaminidase (“hex”) deficient and, therefore, hasSandhoff’s Disease, a lethal genetic disease related to Tay-SachsDisease. 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 extendedby >70%.

The researchers discovered that their implanted neural stem cells, whichmigrated and integrated extensively throughout the brain, did much morethan replace brain tissue destroyed by the disease. Some of thetransplanted cells replaced damaged nerve cells and transmitted nerveimpulses, offering the first evidence that stem cell-derived nerve cellsmay integrate electrically and functionally into a diseased brain. Thetransplanted cells also boosted the brain’s supply of the enzyme Hex,which reduced the lipid accumulations in the treated animals. Theexperimental treatment also dampened the inflammation that typicallyoccurs in the brains of most degenerative diseases, includingSandhoff’s, and likely contributes to disease progression.

“Our studies suggest that functional neuronal replacement canbe complemented and, under some conditions, eclipsed by a range of otherstem cell actions that nevertheless exert a number of criticalstabilizing forces,” said Dr. Snyder, director of Stem Cells andRegeneration at Burnham. “In fact, our study offers the first evidencethat stem cells employ multiple mechanisms — not just cell replacement- which collaborate to benefit disease. These findings also raise thepossibility – somewhat counter-intuitively — that stem cells mayinherently exert an anti-inflammatory influence in degenerativediseases,” said Snyder.

To demonstrate that a better understanding of the fundamental mechanismsof stem cell action may permit the development of rational combinedsynergistic therapies, the investigators then gave the mice a simpleoral drug that permitted the amount of enzyme provided by the engraftedstem cells to work even more efficiently by presenting them with asmaller burden of material to metabolize. The lifespan of the micedoubled. (Neither treatment could work as effectively on its own. Infact, the effect was more than simply additive). This was ademonstration that stem cell efficacy could be enhanced even without theneed for genetic engineering. (The drug, a glycosphingolipidbiosynthesis inhibitor, is in a class of compounds called “substratereduction therapy” drugs.) This part of the study not only representedthe first “multidisciplinary” use of stem cells against a degenerativedisease, but also highlighted the fact that, in the future, the mostsuccessful therapies – including those employing stem cells — willlikely invoke the use of multiple strategies in concert. Indeed, thestem cell may be the “glue” that ultimately holds these therapiestogether in an effective manner by virtue of its fundamental biology.

The researchers then sought to extend their insights to the use of humanstem cells – either stem cells turned into neural progenitors from humanembryonic stem cells – or isolated directly from the nervous system(called “adult” stem cells to distinguish them from embryonic stem cellseven though they are taken from developing brain tissue). Both types ofhuman stem cells were actually somewhat more effective than the mouseneural stem cells. And, they were equally as good as each other – in thefirst 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 invokedthe same range of multiple, collaborative mechanisms. Neither type ofhuman stem cell created tumors, deformation, a worsening of symptoms, orgave rise to inappropriate cells types. Neither cell type was rejectedby the immune system. In fact, no immunosuppression was needed at all.Finally, the human embryonic stem cells were grown without mouse feederlayers and in a “defined” culture medium that is compatible withclinical use and demonstrating for the first time that such preparationsare consistent with a therapeutic impact.

Sandhoff results from a genetic mutation that reduces the body’s supplyof an enzyme, called hexosaminidase (“hex”), used by brain cells tometabolize excess fatty material called lipids. Onset is typically atsix months in human infants. The accumulation of lipids in brain tissuedestroys the brain cells instrumental in controlling and coordinatingbody movement and results in inexorable deterioration of the brain andspinal cord. Children suffering with Sandhoff rarely see their sixthbirthday. Sandhoff mice are similarly affected. Tay-Sachs is predominantto Ashkenazi Jewish populations, while Sandhoff, a severe form ofTay-Sachs, is not limited to any ethnic group. Both diseases are markedwith deficient Hex enzyme functioning and are among a known group ofabout 50 diseases rooted in the inability to metabolize lipids or othermaterials. While Sandhoff and Tay-Sachs are relatively rare, one personin 5,000 is affected by a disease that falls into a category oflysosomal storage diseases.

Currently there is no treatment for Sandhoff or Tay-Sachs. Given thatthe human stem cells used in this study-both human neural and embryonicstem cells-were safe and effective in so many mice, the researchersbelieve that their study may serve as a springboard for development intoa clinical trial.

These diseases are part of a much more common group of diseases called”neurogenetic diseases”. These findings contribute fundamental basicknowledge about stem cell biology that will help inform medicalscientists in their quest for understanding diseases such asParkinson’s, Alzheimer’s, ALS, and a host of other neurologicaldiseases.

“Dr. Snyder’s team has extended the promise of stem celltherapies to children with special-needs, including those with Sandhoffdisease.” said Fia Richmond, founder ofChildren’s Neurobiological Solutions Foundation and mother of abrain-injured child. “The CNS Foundation is proud to have contributedmajor funding for this research along with A-T Children’s Project onbehalf of the 14 million special-needs children in this country alone.”


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