Monday, March 26, 2012

Advances in sickle cell treatment

Production of fetal hemoglobin as an adult is a form of treatment for people with sickle cell disease.  Scientists have identified a protein that represses the production of fetal hemoglobin in adults.  If this protein can be targeted and reduced it could serve as a powerful treatment for patients with sickle cell disease.

Scientists identified that the protein BCL11A prevents the production of fetal hemoglobin in adults.  If the amount of BCL11A in individuals with sickle cell disease can be decreased, fetal hemoglobin levels in these individuals can increase while the amount of red blood cell produced by the body is unaffected.  This fetal hemoglobin can then substitute for the diseased adult hemoglobin and alleviate symptoms associated with sickle cell disease.

Researchers and physicians have been studying sickle cell disease, specifically sickle cell anemia, since the early 1900s.  The disease occurs because of a single mutation in the gene that codes for the adult hemoglobin protein.  The mutation changes the shape of adult hemoglobin, which in turn changes the shape of the red blood cell that contains the misshapen hemoglobin.  Normal adult hemoglobin is a robust, flexible disc shape but when it contains the mutation for sickle cell the shape changes to a rigid, crescent or "sickle".  This sickle shape decreases hemoglobin's ability to transport oxygen/collect carbon dioxide and makes the red blood cell more 'sticky'.  The stickiness is a problem because allows diseased red blood cells to adhere to the walls of blood vessels as well as other normal and sickle red blood cells, which can cause blood clots.

Sickle red blood cell above normal red blood cells; credit to wellcome images of Flickr.

The early idea to combat sickle cell diseases remains quite common: circumvent the mutated hemoglobin by prompting the body to use a different, healthy form of hemoglobin.  Fetal hemoglobin was introduced as that healthy form.  Fetal hemoglobin is present in fetuses from the 7th month of development until 6 months after birth.  It has the same role as adult hemoglobin: oxygen transport/carbon dioxide removal.

Attempts to increase fetal hemoglobin in patients with sickle cell disease have been underway since the late 1900s and provide evidence that increased levels do help alleviate symptoms of the disease.  However, these past studies were rather unsophisticated because scientists simply did not know how fetal hemoglobin production worked.  The identification of the protein that prevents fetal hemoglobin production, BCL11A, provides an essential puzzle piece its mechanism of production.  As Stuart Orkin of Howard Hughes Medical Institute said, "For the last 20 years we've been shooting arrows in the dark in hopes of hitting the target.  Now we can see the target and it is a meaningful one."

After the identification of BCL11A, scientists have a target protein to focus on.  Gene therapy or drug development can lead to methods that stop transcription/translation of BCL11A in patients with sickle cell disease to allow for the production of fetal hemoglobin.  When healthy fetal hemoglobin is produced it can supplement for the diseased adult hemoglobin to allow for normal oxygen/carbon dioxide exchange and decrease the likelihood of blood clots.  This would not be a permanent solution as it does not cure the patient of sickle cell disease but it would be an effective treatment.  However, the normal role of BCL11A must be thoroughly explored before this treatment could be offered.

It's interesting to think that genes used for functions at a different time can be turned on as treatment for a current ailment.  Good news for us because we already have the gene ready to roll, just need to activate it. 

If you're wondering why sickle cell disease, a genetic disease, hasn't been weeded by evolution check out its interesting correlation with malaria in this video.

No comments:

Post a Comment