BALTIMORE, Md. (May 7, 1997) The development of genetically-engineered
supermouse could lead to new treatments for muscular dystrophy and related
diseases.
Using gene 'knock-out'; techniques, researchers at Johns Hopkins were
able to create healthy mice with two to three times normal muscle mass.
"The first thing that we noticed was that the knockout mice had unusually
large shoulders and hips," says Alexandra McPherron, a Hopkins Ph.D.
student and first author of a paper in this week's Nature.
"On closer analysis we found that all their muscles were two to three
times normal size."
To researchers "knocked out" a newly discovered gene called growth/differentiation
factor 8 (GDF 8). The GDF 8 protein limits skeletal muscle growth. Lacking
GDF 8, the mice's muscles grew dramatically.
The GDF 8 genes were altered in mouse embryonic stem cells, which appear
very early in a mouse's development before cell specialization occurs. When
these cells produce egg or sperm cells in a mouse, the genetic changes were
passed on to every cell of the mouse's descendants when they reproduced.
Nearly a year after their initial creation, the mutant mice show no other
signs of abnormality and can reproduce healthy offspring.
A human form of GDF 8 has been identified. The Hopkins team will now investigate
whether it performs the same function in humans. Early studies suggest the
gene is only active appears in skeletal muscle tissue. This might explain
which why removing it has had little effect beyond enlarging the mice's
muscles.
"Except for the muscles, the mice appear to be normal and healthy,"
says McPherron.
"We're excited that GDF 8 could give us new opportunities to treat
the many muscle-wasting diseases like muscular dystrophy or cachexia, the
muscle loss that accompanies some cancers and AIDS," said Se-Jin Lee,
M.D., Ph.D., an assistant professor of molecular biology and genetics.
"We've also found GDF 8 in cows and chickens, so we might be able to
interfere with it to create livestock with more meat and relatively less
fat," says Lee.
The Hopkins team found the gene by searching for new members of the transforming
growth factor-beta (TGF-beta) gene family. Other TGF-beta genes include
bone morphogenetic proteins, a group of genes that helps stimulate bone
growth, and glial-derived neurotrophic factor, a gene that sustains nerve
cells. Proteins from both of these groups are already in clinical trials
for treatment of various disorders.