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Sickle Cell Mutation Corrected in Mice; Research May Have Implications for Humans Suffering From the Disease

Posted on: Tuesday, 10 January 2006, 15:00 CST

By KAWANZA NEWSON

Scientists have used embryonic stem cells to correct the mutation that causes sickle cell disease in mice, a preliminary finding that may lead to treatment options for people with the painful and debilitating disease.

Although it is unknown if the technique will ultimately work in humans, the research suggests the technique could allow people born with this genetic defect to live with few or no complications from their illness.

"These are fascinating scientific studies, and you hope it gets translated in the next few years to something that can be used to treat our sickest patients," said J. Paul Scott, director of the Sickle Cell Comprehensive Program at Children's Hospital of Wisconsin.

"But first they have to show and prove it cures the mouse model of sickle cell disease and that it's safe in the long term," he said.

Sickle cell disease is an inherited blood disorder that affects primarily African-Americans. It's a result of the body's production of abnormal adult hemoglobin, called hemoglobin S, instead of normal hemoglobin A.

As a result, the normally soft and round red blood cells that carry oxygen through the body become hard and pointed, making it difficult for them to travel through smaller vessels. These sickle- shaped cells block the flow of blood and can cause anemia, lung damage and pain in the arms, legs, chest and abdomen. It also damages many organs, including the spleen, kidneys and liver.

Manipulated cells' DNA

For the study, Y.W. Kan and his colleagues at the University of California, San Francisco used mouse embryonic stem cells harvested from blastocysts, or several-day-old embryos, that had sickle cell disease. They then manipulated the DNA so the hemoglobin S segment was replaced by hemoglobin A, creating a gene with the sickle cell trait.

People with the sickle cell trait tend to be healthy and can serve as donors for transplantation to patients with sickle cell disease.

These corrected cells were then placed into a cell dish where they were able to form hematopoietic stem cells, which are the cells found in adult bone marrow that can be used to treat patients with diseases such as leukemia, lymphoma and sickle cell.

The majority of the cells grown in the dish produced hemoglobin A and hemoglobin S, though a small number expressed only hemoglobin S.

However, the group has not yet reinserted the corrected cells back into the diseased mice, so it's unknown if sickle cell disease symptoms will improve or if the animal's body would accept them.

Similar to humans, the only way to transfer the cells back into the mice is through a bone marrow or cord blood transplant, said study author Kan, who is a professor of hematology in the departments of laboratory medicine and medicine.

That means that the bone marrow of the mice must first be suppressed usually through radiation or chemotherapy so that the healthy marrow or blood stem cells have a greater chance of being accepted, he said.

"We are trying to find the right dose of drug to suppress them so as not to kill them," Kan said.

"These mice are really sicker than what we see in humans," he said. "They are very anemic and don't survive as well."

It is estimated that more than 2.5 million Americans have the sickle cell genetic trait and more than 70,000 people have the disease.

In 2005, there were 19 newly diagnosed sickle cell disease cases in Wisconsin, said Scott, who is also a professor of pediatrics at the Medical College of Wisconsin.

Scott sees about 400 children with sickle cell disease and an additional 140 adults at the center at Children's Hospital.

Of the children he treats, 33 require regular transfusion therapy and more than 50 adults and children take hydroxyurea, an anti- cancer drug that reduces pain episodes, he said.

Last year, the Blood Center of Wisconsin began a program to increase the number of African-American blood donors in Wisconsin.

Because the genetic composition of African-American blood is unique, it's best that African-Americans with diseases such as sickle cell, cancer, leukemia and kidney disease receive blood donated by African-Americans.

The Blood Center reported that the number of African-American donations increased by 25% from 2004 to 2005. That translates to 72% of the sickle cell patients getting matched blood in 2005, compared with 63% in 2004, said spokeswoman Crystal McNeal.

Angela Gill, 37, of Milwaukee is a sickle cell disease patient who receives blood regularly.

She had a stroke a major complication associated with sickle cell disease when she was 13 years old and began receiving blood transfusions every four weeks to prevent another stroke. She now gets a red blood cell exchange every eight weeks.

Gill also receives an eight-hour chelation therapy daily to eliminate the dangerous accumulations of iron in her body caused by her long-term transfusions. Too much iron can lead to heart problems, liver damage or problems with the pancreas.

Gill has never experienced any pain episodes, and she has to avoid being outside too long on hot days because higher ozone levels can worsen her symptoms. She also has a weakened immune system and has to avoid being around anyone who's ill.

She likely won't benefit from the current research but said that's OK.

"I consider myself blessed because I am a believer in God and I owe him everything," she said.

19

Number of newly diagnosed sickle cell cases in Wisconsin in 2005

70,000

Number of Americans who have the disease

2.5

million

Number of Americans with the sickle cell genetic trait

Copyright 2006, Journal Sentinel Inc. All rights reserved. (Note: This notice does not apply to those news items already copyrighted and received through wire services or other media.)

Source: Milwaukee Journal Sentinel

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