Potential breakthrough in sickle cell treatment

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Blood sample showing sickle cell anaemia, characterised by the crescent shaped cells. Credit image@ euthman flickr.com

Scientists at the haematology division at The Children’s Hospital of Philadelphia may have discovered a breakthrough in treating sickle cell anaemia. Speaking at the American Society of Haematology’s (ASH) annual meeting, the researchers put forward a new technique that hopes to reverse the effects of the condition.

Sickle cell anaemia is a genetically inherited blood condition where the recessive gene, typically hidden by its dominant equivalent in the parents, reappears in their offspring, in what is known as an autosomal recessive pattern of inheritance. Should a parent have the condition, the likeliness of their child developing it is 50%. Should both parents only have the recessive gene, the likelihood decreases to one in four.

The mutation responsible occurs on the gene responsible for coding the beta-globin chain in haemoglobin, the compound that makes blood cells red and carries oxygen to respiring tissue, replacing one protein by another.

This seemingly innocuous swap means that the normally round and flexible red blood cell becomes rigid and sickle shaped. As a result they can become obstructed in the tiny capillaries within tissue, and carry less oxygen around the body.

However, scientists have found a way of restoring fully functional red blood cells that could be used to treat the condition if they are able to transfer their laboratory cell culture findings to actual human tissue.

The technique is called “forced chromatin looping” according Dr. Jeremy Rupon, haematologist at the Children’s Hospital of Philadelphia, during a press conference on their novel findings. This procedure causes the production of foetal haemoglobin, a type of haemoglobin that is usually silenced soon after birth in preference of adult haemoglobin production.

As foetal haemoglobin is unaffected by sickle cell anaemia, the researchers hope to use this reversal of a biological switch to restart foetal haemoglobin production, with the hope of treating the condition in patients.

These findings are based on previous work by Dr. Gerd Blobel, who also worked on the current project, published back in the June 2012 edition of the journal Cell.

They discovered that the creation of a chromatin loop between the separated enhancer and promoter regions of the beta-globin gene leads to gene transcription, the process where DNA code is “read” and a copy is created to be sent to specialized areas in the cell to be produced and hence expressed.

And, thanks to Dr. Blobel and his team’s previous work, they knew how to cause the looping thanks to the molecule known as looping factor Ldb1 attached to a zinc finger protein, the latter allowing attachment at a specific site on the DNA strand.

Dr. Rupon and his team designed and genetically engineered a zinc finger protein to attach and force a loop at the site in the DNA strand responsible for producing foetal haemoglobin. The loop allows the reactivation of the gene, causing expression of the genetic code.

The cell cultures showed that this technique was effective in “reversing”, so to speak, the biological switch responsible for silencing foetal haemoglobin production.

In the mice model, the researchers found that this zinc finger/Lbd1 compound was extremely effective in promoting embryonic beta-globin production, with the forced looping resulting in an 800-fold increase in transcription. A similar result was found when they tested human adult red blood cells.

These results are highly promising, and Dr. Rupon hopes to advance this research to clinical trials, with the hope of curing sickle cell anaemia. In addition, this may be the first of many conditions to be treated in this manner, said Dr. Rupon, with a variety of haemoglobin conditions that could be solved by reverting to foetal red blood cells.

How will this research help modern medicine advance to finding even more treatments?


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