Stem cells reverse sickle cell anemia in mice

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Stem cells reverse sickle cell anemia in mice

Rodents treated with reprogrammed adult cells show vast improvement

after three months. The therapy is several years away from being

applied to humans.

http://www.latimes.com/news/science/la-sci-

stemcells7dec07,1,6743546.story

By Kaplan, Los Angeles Times Staff Writer

Taking the next step in a series of breakthrough stem cell

experiments, scientists have cured sickle cell anemia in mice by

rewinding their skin cells to an embryonic state and manipulating

them to create healthy, genetically matched replacement tissue.

After the repaired cells were transfused into the animals, they soon

began producing healthy blood cells free of the crippling

deformities that deprive organs of oxygen, scientists from the

Whitehead Institute for Biomedical Research in Cambridge, Mass., and

the University of Alabama at Birmingham reported Thursday.

" It really works beautifully, " said Kathrin Plath, a researcher at

the Broad Center of Regenerative Medicine and Stem Cell Research at

UCLA, who wasn't involved in the study.

The experiments, published online by the journal Science, confirmed

the therapeutic potential of a new class of reprogrammed stem cells,

which can be custom-made for patients without creating and then

destroying embryos.

" This is a platform for any one of dozens of human genetic blood

diseases, not just sickle cell anemia, " said Dr. Q. Daley, a

stem cell scientist at Harvard Medical School who wasn't involved in

the research.

The strategy should work to treat hemophilia, thalassemia and severe

combined immunodeficiency disease, the so-called bubble boy disease,

Daley said. He and others said it would also apply to disorders

linked to mutations in a single gene, such as muscular dystrophy and

cystic fibrosis.

Scientists ultimately hope to use a similar approach to create

cardiac cells to treat heart attack patients or nerve cells that

could cure spinal cord injuries. Finding an abundant source of stem

cells that could be used as a personalized biological repair kit is

the ultimate goal of regenerative medicine.

The technique is still at least a few years away from being used to

treat people, scientists said. Before it could even be tried,

several rounds of animal experiments would need to be done.

Researchers will also need to overcome some key technical hurdles,

including finding a way to reprogram adult cells without using genes

and viruses that could cause cancer.

But as a proof of principle, the study is sure to lure more

researchers into studying the new class of induced pluripotent stem

cells, or iPS cells.

" There's going to be this tsunami, " said J. , director

of the Center for Stem Cell Biology at the University of Texas

Health Science Center in Houston. " One would have to predict that

the pace of observations made using iPS cells is going to rise

exponentially. "

The study is the latest in a string of significant experiments

published in the last five months involving a new approach of

reprogramming adult cells so that they are capable of growing into

any type of tissue in the body. They have captivated researchers,

ethicists and politicians looking for an alternative to embryonic

stem cells, which can be difficult to work with and are fraught with

ethical problems.

Japanese researchers pioneered the new method, which involves

turning on four genes that are dormant in adult cells but active in

days-old embryos. Once those genes are activated, the cells

essentially forget that they have become skin cells, and they then

behave like embryonic stem cells. Because they are derived from a

patient's own cells, there is no risk of tissue rejection.

In June, three research teams showed that the technique worked

reliably in mice. Last month, two groups demonstrated that it also

worked with human cells. But it remained to be seen whether the

cells could serve as the raw material to grow replacement parts for

patients.

The researchers started with sickle cell anemia because it has a

simple origin -- at a key point on the hemoglobin beta gene,

patients have what amounts to a misspelling in the chemical letters

of DNA, commonly known as A, C, T and G. Instead of having at least

one A, they have a pair of Ts. As a result, the gene makes the wrong

amino acid, resulting in red blood cells that are curved instead of

round.

Those sickle-shaped cells clog up as they travel through the body,

blocking blood flow to the small vessels that feed the brain,

kidneys and other organs. Tissues die because sickle cells can't

deliver enough oxygen to keep them healthy.

Some patients can be treated with a bone-marrow transplant, which

allows the body to make normal red blood cells. But only about 5% of

sickle cell patients are able to find a donor, said Dr. M.

Townes, chairman of the department of biochemistry and molecular

genetics at the University of Alabama and one of the study's senior

authors.

Townes figured that embryonic stem cells might help the 95% of

patients who couldn't find donors. But the process would be

complicated.

First, scientists would have to clone embryos using the patient's

own DNA. Then they would switch one of the errant Ts to an A. Stem

cells would then have to be harvested from the modified embryo and

used to make healthy bone marrow for a transplant.

But before scientists were able to do that, the first paper on

reprogrammed iPS cells appeared.

Townes teamed up with Rudolf Jaenisch, a stem cell researcher at

Whitehead and MIT, to see if iPS cells would work in place of

embryonic stem cells.

They took cells from the tail of a 12-week-old mouse with sickle

cell anemia and used viruses to turn on four dormant genes that are

active in days-old embryos. One of those genes, c-Myc, has a

tendency to cause tumors, so after the cells had completed their

transition back to an embryonic state, the researchers deleted it.

Then they corrected the genetic flaw that causes sickle cell anemia

by engineering a string of DNA that had an A in place of a T but was

otherwise identical to the original. It was swapped into place with

the help of an electric shock.

The researchers grew the iPS cells into bone marrow stem cells by

exposing them to special growth factors and culture conditions. When

the cells were ready, they were transplanted into three sick mice

that were genetic twins of the donor mouse.

Twelve weeks later, the mice were producing the normal version of

hemoglobin beta protein, and virtually all of their red blood cells

were round. Their body weight and respiratory capacity improved.

Their urine, previously watery due to the disease, had normal levels

of electrolytes.

None of the mice developed tumors, a sign that the threat from c-Myc

had been eliminated.

Plath said it was encouraging that the skin cells could be

reprogrammed, genetically altered and able to yield their

therapeutic benefits in a relatively short period of time.

" If this is ever applied to the human system, you need this to work

fairly fast, " she said. " You can't waste three years waiting for the

cells. "

Jaenisch is now using the same approach to treat other diseases,

though he declined to say which ones.