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Author Topic: Researchers Model Fetal-to-Adult Hemoglobin Switching  (Read 6495 times)
Andy Battaglia
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« on: February 17, 2011, 02:20:54 PM »

Via CAF.
http://www.sciencedaily.com/releases/2011/02/110216120542.htm

Quote
Researchers Model Fetal-to-Adult Hemoglobin Switching: Important Step Towards Cure for Blood Diseases

ScienceDaily (Feb. 16, 2011) — Researchers have engineered mice that model the switch from fetal to adult hemoglobin, an important step towards curing genetic blood diseases such as sickle cell anemia and beta-thalassemia. The research is published in the February 2011 issue of the journal Molecular and Cellular Biology.

They also produced for the first time a mouse that synthesizes a distinct fetal-stage hemoglobin, which was necessary for modeling human hemoglobin disorders. These diseases manifest as misshapen hemoglobin, causing anemia, which can be severe, as well as other symptoms, which can range from minor to life-threatening. The cure would lie in causing the body to revert to use of fetal hemoglobin.

"The motivation for our research is to understand the basic mechanisms of gene regulation in order to cure human disease," says Thomas Ryan of the University of Alabama Birmingham, who led the research. "If we can figure out how to turn the fetal hemoglobin back on, or keep it from switching off, that would cure these diseases."

The new model "mimics precisely the timing in humans, completing the switch after birth," says Ryan. "The previous models didn't do that." In earlier models, researchers inserted transgenes, large chunks of DNA containing the relevant genes, randomly into the mouse chromosome. In the new model, the investigators removed the adult mouse globin genes, and inserted the human fetal and adult genes in their places.

The successful engineering of a mouse with a fetal-stage hemoglobin means that humanized mouse models with mutant human genes will not die in utero.

While the basic principals behind the research are simple, the details are complex. For example, Ryan and Sean C. McConnell, a doctoral student who is the paper's first author, had to deal with the fact that hemoglobin switching occurs twice in H. sapiens, from embryonic to fetal globin chains in early fetal life, and then to adult globin chains at birth, while wild type mice have a single switch from embryonic to adult chains early in fetal life. "Instead of the single hemoglobin switch that occurs in wild type mice, our humanized knock-in mice now have two hemoglobin switches, just like humans, from embryonic to fetal in early fetal life, and then fetal to adult at birth," says Ryan.

Hemoglobin switching is believed to have evolved to enable efficient transfer of oxygen from the mother's hemoglobin to the higher oxygen affinity fetal hemoglobin in the placenta during fetal life.
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« Reply #1 on: February 17, 2011, 04:23:57 PM »

This is great Andy.  Although fetal hemoglobin has a higher oxygen affinity - causing it to release less to tissue - it is still better than transfusion dependance. 

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« Reply #2 on: February 18, 2011, 11:49:18 AM »


great news!
do you remember an article about the inactivation of the BCL11A gene to switch on Fetal hemoglobin production? they we're able to carry this out in mice.
 
is this something that may benefit all thals or just those who can produce some fetal haemoglobin already?
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« Reply #3 on: February 18, 2011, 11:58:48 AM »

If the fetal hemoglobin "switch" can be turned back on, it would have the potential to help all who suffer from thalassemia or sickle cell disease. All people are born with a capability to produce fetal Hb but this is turned off shortly after birth, so learning how to reactivate the gamma gene responsible for fetal Hb production, would be a big step forward.
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« Reply #4 on: February 18, 2011, 12:00:37 PM »

KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching.
Summary
We show that knockdown of KLF1 in human and mouse adult erythroid progenitors markedly reduces BCL11A levels and increases human gamma-globin/beta-globin expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. Controlled knockdown of KLF1 in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with beta-thalassemia or sickle cell disease.

New approach to sickle-cell disease shows promise in mice
Published: Monday, December 7, 2009 - 15:25 in Health & Medicine
A new genetic approach to treating sickle cell disease is showing promising results in mice, report researchers from Children's Hospital Boston. By inactivating a gene they previously discovered to be important in the laboratory, they were able to boost production of a healthy fetal form of hemoglobin in the mice, potentially compensating for the defective adult hemoglobin that causes red blood cells to "sickle" and obstruct blood flow. The study was presented by first author Jian Xu, PhD, on Sunday, December 6, at the American Society for Hematology meeting in New Orleans, at a 3 p.m. Plenary Scientific Session.

Currently, there are only a limited number of therapies available for patients with sickle cell disease, the most common inherited blood disorder in the U.S., says senior study author Stuart H. Orkin, MD, of Children's Division of Hematology/Oncology, also David G. Nathan Professor of Pediatrics at Harvard Medical School.

Shortly after birth, babies switch from producing the fetal form of hemoglobin, the protein inside red blood cells that carries oxygen, to producing the adult form – the type that is affected in sickle cell disease. It's long been known that people who retain the ability to produce fetal hemoglobin have much milder disease. In previous studies (http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel485.html), the Children's researchers, with collaborators, found that a gene called BCL11A is involved in switching off fetal hemoglobin production in adults. Working with genetically engineered mice, they then explored whether that switch could be turned back on to alleviate the disease.

In embryonic mice, inactivation of the BCL11A gene led to a robust expression of gamma-globin (the long protein chains making up the fetal form of hemoglobin) during late gestation: more than 90 percent of the globin produced was of this fetal type. In adult mice (8-10 weeks old), inactivation of the BCL11A gene in the blood system resulted in more than a 1,000-fold increase in gamma-globin production in bone marrow erythroblasts (the precursors to red blood cells) as compared with control mice. This increase was rapid and persisted during the course of the experiments (up until the mice were 25 weeks old).

This line of research began with comprehensive gene association studies, published in 2008 with collaborators at the Broad Institute of Harvard and MIT (http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel452.html). These studies, involving 1600 patients with sickle cell disease, identified five DNA sequence variants (altered strings of genetic code) that correlated with fetal hemoglobin levels. BCL11A, on chromosome 2, had the largest effect, and Orkin and Vijay Sankaran, an MD-PhD student working with Orkin, later demonstrated that this gene directly suppresses fetal hemoglobin production.

If these preliminary results in mice hold up in human studies, inactivating BCL11A may also help patients with thalassemia, another blood disorder involving abnormal hemoglobin, adds Orkin

In the April issue of the journal Proceedings of the National Academy of Sciences, researchers reported for the first time that the protein, MBD2, mediates silencing of the fetal gamma-globin gene through DNA methylation, a process that chemically modifies DNA. Researchers used a transgenic mouse model containing the human hemoglobin gene locus to show that MBD2 interprets the DNA methylation “signal” throughout the genome, which determined how the pattern of methylation effected the expression of specific genes.


Putting a finger on the switch. Summary
The transition from fetal to adult beta-like globin expression is a key step in the maturation of the red blood cell lineage. Two new studies show that the KLF1 zinc finger protein uses direct and indirect means to regulate the final switch from fetal to adult globin expression and that monoallelic loss of KLF1 expression leads to persistence of fetal hemoglobin.





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« Reply #5 on: February 20, 2011, 03:22:46 AM »

Asa,
i got in touch with a team member of the research  'KLF1 regulates BCL11A expression and [gamma]- to [beta]-globin gene switching'

  We are now searching for small molecules that will down-regulate KLF1 and BCL11A and therefore up-regulate fetal hemoglobin.  After we identify a specific small molecule and prove that it is safe and effective in our mouse models of sickle cell disease and b-thal, we will plan a clinical trial.

I would be happy to update you on our progress.  The best way to receive an update is for you to email me in about 6 months.  We are probably 2-3 years away from a clinical trial.


All the best/  Tim
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« Reply #6 on: April 23, 2011, 01:35:00 PM »

http://www.ithanet.eu/archives/1735

The Community Portal for Thalassaemia and other Haemoglobinopathies
News
EKLF/KLF1 Multicenter Study
February 10th, 2011 2 comments

The ITHANET network is hosting a collaborative project intended to map KLF1 mutations and HbF levels including the Gγ ratio. We would like to invite your participation in this project. Details of the study can be found here.
...

Hi. Im Joseph Borg, one of the leading co-ordinators for this collaborative project. In order to fully explain the details of this project., can you kindly contact me by sending me an email on joseph.borg@biotech.um.edu.mt

Thanks, and looking very forward to your reply.

best

Joseph
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