Stem Cell Study Lays Groundwork For Clinical Bridge In Neurodegenerative Disease

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Stem Cell Study Lays Groundwork For Clinical Bridge In

Neurodegenerative Disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=65027

Human embryonic stem cells (hESCs) hold great promise for benefiting

degenerative diseases, 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 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 the Burnham Institute for Medical Research ( " Burnham " ).

The study, to be published in Nature Medicine, is available by

advanced publication at the journal's website.

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 (NSCs), 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, both human neural stem

cells and human embryonic stem cells, and, in fact, had the

opportunity, for the first time, to compare those two types of

controversial stem cells head-to-head in the same model. The

results, described in more detail below, in fact prove to be the

first successful use of 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 that

afflicts 1 in 5000 patients, typically children (called lysosomal

storage diseases, described in more detail below), but which is

often used to model an array of adult neurodegenerative diseases

such as Parkinson's, ALS, Alzheimer's - particularly those with a

genetic component. The mouse used here has mutation in a gene that

makes the housekeeping enzyme hexosaminidase ( " hex " ) deficient and,

therefore, has Sandhoff's Disease, a 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%.

The researchers discovered that their implanted neural stem cells,

which migrated and integrated extensively throughout the brain, did

much more than replace brain tissue destroyed by the disease. Some

of the transplanted cells replaced 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. 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.

" Our studies suggest that functional neuronal replacement can be

complemented and, under some conditions, eclipsed by a range of

other stem cell actions that nevertheless exert a number of critical

stabilizing forces, " said Dr. Snyder, director of Stem Cells and

Regeneration at Burnham. " In fact, our study offers the first

evidence that stem cells employ multiple mechanisms -- not just cell

replacement - which collaborate to benefit disease. These findings

also raise the possibility - somewhat counter-intuitively -- that

stem cells may inherently exert an anti-inflammatory influence in

degenerative diseases, " said Snyder.

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. In fact, the effect was more than simply

additive). This was a demonstration that stem cell efficacy could be

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 " use of 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. Indeed, the stem cell may be the " glue " that

ultimately holds these therapies together in an effective manner by

virtue of its fundamental biology.

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 (called " adult " stem cells to distinguish them from

embryonic stem cells even though they are taken from developing

brain tissue). 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, or 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 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 the brain cells instrumental in controlling

and coordinating body movement 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 is predominant to Ashkenazi Jewish

populations, while Sandhoff, a 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 50

diseases rooted in the inability to metabolize lipids or other

materials. While Sandhoff 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.

Currently there is no treatment for Sandhoff or Tay-Sachs. Given

that the human stem cells used in this study-both human neural and

embryonic stem cells-were safe and effective in so many mice, the

researchers believe that their study may serve as a springboard for

development into a clinical trial.

These diseases are part of a much more common group of diseases

called " neurogenetic diseases " . These findings contribute

fundamental basic knowledge about stem cell biology that will help

inform medical scientists in their quest for understanding diseases

such as Parkinson's, Alzheimer's, ALS, and a host of other

neurological diseases.

" Dr. Snyder's team has extended the promise of stem cell therapies

to children with special-needs, including those with Sandhoff

disease. " said Fia Richmond, founder of Children's Neurobiological

Solutions Foundation and mother of a brain-injured child. " The CNS

Foundation is proud to have contributed major funding for this

research along with A-T Children's Project on behalf of the 14

million special-needs children in this country alone. "