Brittle Bones

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April 24, 2004

  Brittle Bones    

A crippling disease caused by a defective gene is the latest to be fought on

the genetic level. As this ScienCentral News video reports, the research

into stopping what is commonly called " brittle bone " disease may involve

modifying the patient's DNA.

Targeting Bone Disease

Osteogenesis imperfecta (OI), commonly called brittle bone disease, is a

genetic disorder characterized by bones that break easily, often from little

or no apparent cause. It's caused by a genetic defect that affects the

body's production of collagen.

While the number of people affected with OI in the United States is unknown,

the best estimate suggests between 20,000 and 50,000. There is currently no

cure for OI.

Braitmayer, 45, an award-winning Seattle architect who specializes in

accessibility, lives with this painful and challenging disease. " Maybe

that's just one of the amazing positive things about having OI, is that

you're gifted with a sort of positive, can-do kind of attitude. "

Braitmayer, who gets around in a wheelchair, describes her OI as " an

anomaly. " By the time she was 15, she'd had 25 fractures. " Some people with

OI lose count in the 250 range, so really, 25 is nothing, " she says.

Now Braitmayer is hopeful that a new gene therapy being pioneered at the

University of Washington in Seattle could convert very severe OI into a much

milder form.

" One of the things that's really been frustrating over many years is that

although we've really begun to focus on the molecular mechanics of OI, we've

had very little to offer children with these diseases, " says Byers, OI

specialist, professor of pathology at the University of Washington, and

Braitmayer's friend and physician. " OI really is a broad group of diseases.

The people who have only a mild disease usually do fairly well and respond

to exercise and having fractures treated appropriately so that there's no

deformity that develops. But the kids who dieŠhave had really nothing that's

been available to them and they've almost always died. It's the group that's

in the middle who have very significant deformity, who end up almost always

in a wheelchair, for whom mechanical therapies have not been very helpful. "

Byers teamed up with , professor of medicine at the University

of Washington, who is working to make the emerging field of gene therapy

more accurate, and Chamberlain, a member of 's lab. " We'd like

to take the cells from these patients, from inside their bones, and modify

the genes in these cells so that they no longer have the disease, and

hopefully eventually give those cells back to the patient so that they can

be cured of their disease, " says .

This is a slide of the modified human OI cells that were implanted in

mice.The pink-stained areas are forming bone.In gene therapy, scientists use

a harmless virus to deliver corrective pieces of DNA into cells. But right

now, these pieces can land anywhere in the cell's DNA. Besides limiting its

effectiveness, that can also cause unwanted side effects. 's lab

developed a technique they call " gene targeting " that hits only the part of

the DNA they want to modify.

" If your DNA is a book, and your mutation is a typographical error in that

book, it's sort of like trying to fix that error by throwing in a sentence

from the book and having it land in a random location on any page, " says

. " You can imagine that it's very hard to figure out if you've fixed

anything that way. Whereas in our case, we're actually trying to go in to

where the mutation is in the chromosome and manipulate that gene in its

normal location. It's a process we call gene targeting, and although it's a

lot more difficult than just adding genes to random locations, you can

easily imagine how it might be much more accurate. "

In this case, the target is the faulty bone-forming gene. " Because there's

two copies of this gene in each cell, one of them is mutant, one of them is

not and we hope that if we knock out that mutant gene that the cells will

still have their normal collagen gene intact and that that will lead to

normal collagen synthesis, " says .

and Byers used the gene targeting technique on cells from OI

patients and implanted them into mice, and the cells were able to form bone.

The technique must be tested in animals that also get OI, such as dogs,

before it can be tried in people.

" Certainly our first efforts would be in trying to take care of the kids who

have the most severe forms of OI, from which they do die, " says Byers.

" The best outcome would probably be any opportunity to increase the

activity, the strength, reduce the fractures and pain, and allow a lot of

kids to grow stronger, taller, more active and be healthier, not only for

their childhoods but for their adulthood as well, " says Braitmayer.

says ultimately this technique could be used, not to just turn off

the faulty collagen gene, but to actually correct it. The technique is also

promising for use against many other genetic diseases.

This research was published in the February 20, 2004 issue of Science, and

was funded by the National Institutes of Health, the Children's Brittle Bone

Foundation, and the F. Odland Research Fund.

 

 

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