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发帖数: 4845 | 1 Severe Congenital Disorder Successfully Treated in a Mouse Model for the
First Time
http://www.sciencedaily.com/releases/2011/12/111222103044.htm
ScienceDaily (Dec. 22, 2011) Using a mouse model, Heidelberg University Ho
spital researchers have for the first time successfully treated a severe con
genital disorder in which sugar metabolism is disturbed. The team headed by
Prof. Christian Korner, group leader at the Center for Child and Adolescent
Medicine, demonstrated that if female mice are given mannose with their drin
king water prior to mating and during pregnancy, their offspring will develo
p normally even if they carry the genetic mutation for the congenital disord
er. The team's outstanding work will contribute to better understanding of t
he molecular processes of this metabolic disease, along with the key stages
in embryonic development, and may offer a therapeutic approach for the first
time.
The Heidelberg-based researchers also collaborated with colleagues working w
ith Prof. Hermann-Josef Grore of the German Cancer Research Center (DKFZ)'s
Division of Cellular and Molecular Pathology in Heidelberg. Their results ha
ve now been published online in the journal Nature Medicine in advance of th
eir publication in the print edition.
Rare disease: Approx. 1,000 children affected
So far 1,000 children worldwide are affected by congenital disorders of glyc
osylation (CDG), which are classified as rare diseases. Affecting around 800
children, type CDG-Ia is most frequent. The number of unreported cases is h
igh, however. Children with CDG are severely physically and mentally disable
d, with approx. 20 percent dying before the age of two. To date, no therapy
has been available to treat the disorder.
CDG-Ia is caused by mutations in the genetic information for the enzyme Phos
phomannomutase 2 which is involved in important glycosylation processes: Man
nose-1-phosphate is not produced in sufficient quantities. As a result, glyc
osylation malfunctions, meaning that sugar chains that normally aid in form,
stability and function of the glycoproteins are not completely attached to
the body's proteins or in some cases, are not attached at all. The lack of o
ligosaccharide chains leads to impairment of neurological, growth and organ
development. The disorder only manifests if the baby inherits a mutated gene
from both the mother and the father. The parents, who each carry one mutate
d and one "healthy" copy of the gene, do not exhibit any symptoms.
Mice take up mannose in drinking water
The mouse model developed by Prof. Korner and his team is characterized by m
utations in the Phosphomannomutase 2 gene and demonstrates reduced enzyme ac
tivity, comparable to CDG-Ia in man. In their current study, the scientists
exploited the ability of mannose to cross the placental barrier. This means
that if the pregnant mouse takes up mannose, it also reaches the embryos in
the uterus.
"One week prior to mating, we began giving the female mice mannose with thei
r drinking water," explained biochemist Prof. Korner. The additional mannose
supply up to birth increased the mannose levels in the embryos' blood. "The
mice were born without defects and also after they were born, developed wit
hout any symptoms of the disorder, even if they no longer took up any mannos
e," Korner added. The successful studies performed by the Heidelberg Univers
ity Hospital researchers clearly show the key role played by the supply of p
roteins with sugar chains during embryonic development.
New therapeutic approach
"Clinical studies in the U.S. and Germany have already been performed in whi
ch children with CDG-Ia were given mannose after they were born, either oral
ly or by intravenous infusion. Unfortunately, these attempts have not been s
uccessful," explained Dr. Christian Thiel, head of the laboratory. "This mea
ns that the critical point at which it is possible to influence development
must be during development in the uterus." For women with a risk of CDG-Ia,
administering mannose during pregnancy may serve as a new therapeutic approa
ch. |
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