Down syndrome treatment

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Down Syndrome Treatment

Researchers at s Hopkins restored the normal growth of specific

nerve cells in the cerebellum of mouse models of Down syndrome that were

stunted by this genetic condition. The cerebellum is the rear, lower part of

the brain that controls signals from the muscles to coordinate balance and

motor learning (Proceedings of the National Academy of Sciences, January

2006).

The finding is important, investigators said, because the cells

rescued by this treatment represent potential targets for future therapy in

human babies with Down syndrome. Also, it suggests that similar success for

other Down syndrome-related disruptions of brain growth, such as occurs in

the hippocampus, could lead to additional treatments - perhaps prenatally -

that restore memory and the ability to orient oneself in space.

Down syndrome is caused by an extra chromosome 21, a condition called

trisomy - a third copy of a chromosome in addition to the normal two copies.

Children with Down syndrome have a variety of abnormalities, such as slowed

growth, abnormal facial features and mental retardation. The brain is always

small and has a greatly reduced number of neurons.

A report on the Hopkins work with trisomic mice, led by H.

Reeves, PhD, professor in the Department of Physiology and the

McKusick-s Institute for Genetic Medicine at Hopkins, appears in the

January 24 issue of the Proceedings of the National Academy of Sciences

(PNAS).

Dr. Reeves and his team used an animal model of Down syndrome called

the Ts65Dn trisomic mouse to show that pre-nerve cells called granule cell

precursors (GCP) fail to grow correctly in response to stimulation by a

natural growth-triggering protein. This protein, called Sonic hedgehog

(Shh), normally activates the so-called Hedgehog pathway of signals in these

cells. These signals stimulate mitosis (cell division) and multiplication of

the cells in the growing, newborn brain, according to the researchers.

The GCP originate near the surface of the cerebellum and migrate

deeper into the brain to form the internal granule layer (IGL), the

researchers note. Therefore, the team studied the growth of the cerebellum

in Ts65Dn trisomic mice at seven time points - beginning at birth - to

determine when GCP abnormalities first occurred. The IGL was similar in both

normal and Ts65Dn mice at birth, but was significantly reduced in the

trisomic mice by day six after birth.

Furthermore, the researchers found that the reduced number of GCP in

these mice compared to normal mice was not due to cell death; rather, there

were 21 percent fewer GCP undergoing cell division in Ts65Dn mice. This

suggested that stimulating these cells might restore normal numbers of GCP,

according to Dr. Reeves.

The Hopkins team then showed in test-tube experiments that GCP from

the brains of Ts65Dn mice had a significantly lower response to increasing

concentrations of a potent form of Shh called ShhNp. That is, increasing

concentrations of ShhNp triggered increasing rates of mitosis. Despite their

lower response, trisomic cells did show a dose response with increasing

ShhNp concentrations.

" The fact that trisomic GCP responded to stimulation of their Hedgehog

pathway even in a reduced way is significant, " stated Dr. Reeves, the senior

author of the paper. " It suggested that these cells could be stimulated to

reach normal levels of cell division by artificially increasing their

exposure to Hedgehog growth factor. "

Based on this initial discovery, the team injected into newborn Ts65Dn

mice a molecule that stimulates the Hedgehog pathway to trigger cell growth.

Treatment of the trisomic mice with this molecule, called SAG 1.1, restored

both the numbers of GCP and the number of GCP cells undergoing mitosis to

levels seen in normal mice by six days after birth.

" The normal mouse cerebellum attains about a third of its adult size

in the first week after birth, " said researcher Randall J. Roper, PhD. " This

is the time during which SAG 1.1 treatment of Ts65Dn restored GCP

populations and the rate of mitosis of those cells, " he added. " However,

further research is needed to determine if it's possible to reverse the

effects of trisomy in other parts of the DS mouse. " Dr. Roper is a

postdoctoral fellow in the laboratory of Dr. Reeves and a co-first author of

the PNAS paper.

The other authors of the Hopkins paper include Drs. L. Baxter,

Nidhi G. Saran, Donna K. Klinedinst, and Philip A. Beachy. Baxter is a

co-first author of this paper and currently is at the National Human Genome

Research Institute of the National Institutes of Health (Bethesda, MD).

The work was supported in part by the Public Health Service. P.A.B. is

a Medical Institute investigator.