Ahmedabad doctorshave carried out a rare successful stem cell transplant on a four-year-old girl suffering from Thalassemia major, relieving her of life-long blood transfusions.
Isha Gohel from Saurastra, who was diagnosed of suffering from advanced stages of Thalassemia, had started receiving blood transfusions at the age of 18 months.
When she was brought to Apollo hospital in Ahmedabad, doctors after investigations found that she was a case of class 3 Thalassemia Major. Since she did not get good quality blood transfusion, her condition was very poor. She had developed marked enlargement of the spleen leading to further poor response to blood transfusions.
Terming Isha's case as challenging, Dr Chirag A Shah, haematologist, Apollo hospital here, said that they followed the style of treatment of Dr G Lucarelli from the Mediterranean Institute of Haematology - an international centre for transplantation in thalassemia and Sickle Cell Anaemia - in Italy who has successfully treated advanced cases of thalassemia.
Her spleen was removed and stems cells from Isha's two-year-old brother were transplanted. "We followed his (Lucarelli's) formulae for treatment of Isha and we were successful," he said.
"Stemcell transplant in advanced cases of thalassemia results in poor outcome. Such patients are not advised a transplant as they frequently have poor results and have high risk of complications," Shah said.
He said that Isha's case was difficult for them as her spleen had blown out of proportion and her liver too was damaged due to iron deposits.
Giving details of her treatment, he said, "We first surgically removed her spleen in January and the following month we started on a special protocol of medicines to reduce her risk of being Class 3. This continued for over one month until finally she underwent stem cell transplant procedure in April. The stem cells were from her younger brother."
Isha is now on the road to recovery and and will be transfusion free forever as her underlying Thalassemia major is now cured after stem cell transplant.
May 14, 2011
"Behavioral Strategies for Parents" Webinar Available Online
Dr. Lauren Mednick's presentation on "Behavioral Strategies for Parents of Children with Thalassemia," CAF's March 2 webinar, is now available for watching.
Lauren Mednick, PhD, is an assistant in Psychology at Children’s Hospital Boston and is on the faculty at Harvard Medical School. She received her B.S. in Psychology from the University of Illinois and both her Master of Philosophy and her PhD in Clinical Child Psychology, with an emphasis on behavioral medicine, from The George Washington University. Her subsequent clinical, teaching and research efforts have focused on helping children and families cope with medical stressors. The majority of her time is spent in direct clinical care, conducting outpatient therapy with children and adolescents diagnosed with acute and chronic medical conditions, including thalassemia. Dr. Mednick also has an interest in how a parent is coping impacts a child’s physical and emotional well-being and focuses much of her work on investigating stress and coping in parents of children diagnosed with various medical conditions. CAF is thrilled to be able to offer the experience and knowledge that Dr. Mednick has learned working with families with thalassemia, as well as with other chronic conditions.
Kolkata conducts unique Thalassemia treatment
A Kolkata hospital conducted the first successful mixed stem cell (cord blood and bone marrow) transplant surgery to give new life to a child suffering form the HbE-Beta Thalassemia disease.
Dr. Ashish Mukherjee conducted the surgery on Apr 3 to treat a five year old boy named Moinam at the Netaji Subhash Chandra Bose Cancer research Institute in Kolkata.
For conducting this treatment they took the stem cells from the cord blood of the second child (sister of Moinam) of Ashim Pal and Monisha Pal and then preserved it under specified conditions at CordLife, lrgest network of stem cell bank with full processing.
"When stem cells are needed to treat a life threatening disease, doctors ans can effectively predict transplant success by evaluating two factors-HLA compatibility and stem cell count," Prosanto Chowdhury, Medial Director, Cord Life India, said.
"Transplants like these confirm CordLife's technology and our assurance to parents who bank with us their baby's cord blood. HLA matching was undertaken which provided that the tissues of both the children matched and the treatment could proceed. This is the first case of mixed stem cell transplant in India," he said.
Thalassemia is an inherited blood disorder in which the body produces an abnormal form of haemoglobin, the metallo protein in red blood cells that carries oxygen.
However, in case of Thalassemia when an HLA identical sibling marrow donor is available, the chance of cure is currently as high as 90 percent.
Illustrating the complicated treatment, Dr. Ashish Mukherhjee, Director NCRI, said: "The first step was to destroy all the existing bone marrow cells for which the conditioning chemotheraphy was used. Then the donor's stem cells from two different sources were injected into the patient's body."
"Bone marrow stem cell, on the other hand leads to Graft Versus Host Disese which is triggered by the body's defence mechanism while the transfusion is being done. The two therapies can complement, not only increase the Stem Cell count but also reduce the chance of Graft versus Host disease and lead to a complete cure," Mukherjee said.
The stem cells that were transplanted in the young patient came from his sister's cord blood and bone marrow.
"It was Dr. Asish Mukherjee who gave our child a new life. He told us that our child will get cured and that was the assurance on which we were bagging upon," Ashim Kumar Pal, father of Moinam said.
Dr. Ashish Mukherjee conducted the surgery on Apr 3 to treat a five year old boy named Moinam at the Netaji Subhash Chandra Bose Cancer research Institute in Kolkata.
For conducting this treatment they took the stem cells from the cord blood of the second child (sister of Moinam) of Ashim Pal and Monisha Pal and then preserved it under specified conditions at CordLife, lrgest network of stem cell bank with full processing.
"When stem cells are needed to treat a life threatening disease, doctors ans can effectively predict transplant success by evaluating two factors-HLA compatibility and stem cell count," Prosanto Chowdhury, Medial Director, Cord Life India, said.
"Transplants like these confirm CordLife's technology and our assurance to parents who bank with us their baby's cord blood. HLA matching was undertaken which provided that the tissues of both the children matched and the treatment could proceed. This is the first case of mixed stem cell transplant in India," he said.
Thalassemia is an inherited blood disorder in which the body produces an abnormal form of haemoglobin, the metallo protein in red blood cells that carries oxygen.
However, in case of Thalassemia when an HLA identical sibling marrow donor is available, the chance of cure is currently as high as 90 percent.
Illustrating the complicated treatment, Dr. Ashish Mukherhjee, Director NCRI, said: "The first step was to destroy all the existing bone marrow cells for which the conditioning chemotheraphy was used. Then the donor's stem cells from two different sources were injected into the patient's body."
"Bone marrow stem cell, on the other hand leads to Graft Versus Host Disese which is triggered by the body's defence mechanism while the transfusion is being done. The two therapies can complement, not only increase the Stem Cell count but also reduce the chance of Graft versus Host disease and lead to a complete cure," Mukherjee said.
The stem cells that were transplanted in the young patient came from his sister's cord blood and bone marrow.
"It was Dr. Asish Mukherjee who gave our child a new life. He told us that our child will get cured and that was the assurance on which we were bagging upon," Ashim Kumar Pal, father of Moinam said.
No marriage for Thalassemia couples in Sri Lanka
The Health Ministry will introduce legal provisions to forbid marriages between two Thalassemia carriers to eradicate the disease from Sri Lanka, Health Minister Maithripala Sirisena said.
Minister Sirisena said the ministry has taken measures to make blood tests mandatory for every young couple before marriage.
“If the blood tests do not bring the desired results, the Health Ministry has no option but to bring legislations forbidding marriages between two Thalassemia carriers as Thalassemia is a hereditary disease. Our aim is to eradicate Thalassemia from Sri Lanka by 2015,” Minister Sirisena stressed.
The government spends around Rs. 1.6 billion to treat Thalassemia patients annually and Rs. 350 million out of it is spent only on drugs. If Thalassemia which is a preventable disease could be eradicated, the government can utilize these funds for a better cause, he said.
Some 250,000 marriages are performed annually in Sri Lanka and offspring of 1,600 parents are born with Thalassemia. Latest data shows that there are 1,600 Thalassemia patients in the country and 160 of them are children.
Minister Sirisena said the ministry has taken measures to make blood tests mandatory for every young couple before marriage.
“If the blood tests do not bring the desired results, the Health Ministry has no option but to bring legislations forbidding marriages between two Thalassemia carriers as Thalassemia is a hereditary disease. Our aim is to eradicate Thalassemia from Sri Lanka by 2015,” Minister Sirisena stressed.
The government spends around Rs. 1.6 billion to treat Thalassemia patients annually and Rs. 350 million out of it is spent only on drugs. If Thalassemia which is a preventable disease could be eradicated, the government can utilize these funds for a better cause, he said.
Some 250,000 marriages are performed annually in Sri Lanka and offspring of 1,600 parents are born with Thalassemia. Latest data shows that there are 1,600 Thalassemia patients in the country and 160 of them are children.
Apr 27, 2011
Thalassemia cured using cord blood stem cells
R. PRASAD
Eight-year-old Thamirabharuni and her one-year-old brother Pugazhendhi share a special kind of bond not commonly seen among siblings. Thanks to her brother, Thamirabharuni no longer suffers from thalassemia disease.
The stem cells transplanted in March helped her get rid of thalassemia. And hundred days after the procedure, one can safely say that her disease has been cured.
The stem cells that were transplanted came from two different sources — her brother’s cord blood, which was harvested during the time of his birth, and his bone marrow. Stem cells from the bone marrow had to be transplanted as there was insufficient number of stem cells in Pugazhendhi’s cord blood.
In the absence of cord blood stem cells, about 200 ml of bone marrow would have been required. It is difficult to get this quantity of bone marrow from a nine-month-old baby.
The cord blood was collected by and stored at Chennai based LifeCell International Pvt. Ltd., a private cord blood bank.
Risk of infection So is it all over? “One has to be still careful. There is a risk of infection till the end of the first year [after transplantation],” said Dr. Revathy Raj, Consultant Paediatric Haemato Oncologist, Apollo Speciality Hospital, Chennai. Dr. Raj had done the transplantation for Thamirabharuni and two other cord blood transplantations for thalassemia before this.
The fact that patients are on immuno suppressing drugs for one year makes them vulnerable to infections. The risk of rejection of the transplanted stem cells, and the graft versus host disease (GVHD) reduce with time.
Thalassemia arises when red blood corpuscles (RBC) production is defective. A person suffers from the disease only when he inherits a defective gene from both parents. He becomes a carrier when he inherits a defective gene from only one parent. The diseased person has to undergo blood transfusion once every month for the rest of his life.
Gold standard Though stem cells separated from bone marrow have been used for more than 30 years to treat thalassemia, and is a gold standard in treating the disease, cord blood stem cells are slowly becoming an attractive alternative.
Contrary to what is projected by some cord blood banks, doctors are very reluctant to use cord blood stem cells to treat thalassemia in the absence of a full tissue match.
Perfect match “We need a 6/6 [perfect match] for thalassemia. Even a 5/6 match is not sufficient,” asserted Dr. Raj. And doctors refrain from using stem cells from unrelated donors, even if there is a perfect match.
Apart from infections, there are two major challenges from transplantation — graft versus host disease (GVHD) and rejection of the donated stem cells. “There is a 30 per cent chance of having graft versus host disease even when it is from a fully matched related (sibling) donor.” This risk increases to 50 per cent when it is from an unrelated donor, even if there is 6/6 tissue match.
Rejection rate becomes an issue even when there is a perfect tissue match. According to her, in the case of thalassemia, the rejection rate can be up to 20 per cent even with related donors, and up to 40 per cent in the case of unrelated donors.
But why should rejection and GVHD be an issue at all when there is a perfect 6/6 tissue match, and why should it be so high when stem cells are from unrelated donors?
Minor HLAs not tested “There are several minor HLA antigens that are not tested. So if we use stem cells from people belonging to some other ethnic background, there are greater chances of [minor] HLA differences,” Dr. Raj stressed. “And this causes rejection and GVHD.”
In general, greater the tissue match and higher the stem cell count in cord blood, lesser are the chances of rejection and GVHD.
“So why undertake procedures that are risky when thalassemia can be treated through monthly transfusions,” she noted.
Private banking of cord blood for use by the family therefore becomes important when one of the siblings is suffering from a disease that can be cured using it.
Case for public banking Despite the risk of rejection and GVHD, a less than perfect sample can be used to treat children suffering from life threatening diseases such as leukaemia and aplastic anaemia. This is where public cord blood banking gains significance.
There is a strong case for promoting public banks as depending solely on bone marrow samples will not be wise.
Even if a perfectly matched bone marrow donor is found, chances are that the person may no longer be interested in donating.
Collecting cord blood samples is easy, the number of samples that can be banked is limited only by resources, and samples can be made available at very short notice.
| Cord blood and bone marrow stem cells with a perfect tissue match from her one-year-old brother were used for transplantation |
Eight-year-old Thamirabharuni and her one-year-old brother Pugazhendhi share a special kind of bond not commonly seen among siblings. Thanks to her brother, Thamirabharuni no longer suffers from thalassemia disease.
The stem cells transplanted in March helped her get rid of thalassemia. And hundred days after the procedure, one can safely say that her disease has been cured.
The stem cells that were transplanted came from two different sources — her brother’s cord blood, which was harvested during the time of his birth, and his bone marrow. Stem cells from the bone marrow had to be transplanted as there was insufficient number of stem cells in Pugazhendhi’s cord blood.
In the absence of cord blood stem cells, about 200 ml of bone marrow would have been required. It is difficult to get this quantity of bone marrow from a nine-month-old baby.
The cord blood was collected by and stored at Chennai based LifeCell International Pvt. Ltd., a private cord blood bank.
Risk of infection
The fact that patients are on immuno suppressing drugs for one year makes them vulnerable to infections. The risk of rejection of the transplanted stem cells, and the graft versus host disease (GVHD) reduce with time.
Thalassemia arises when red blood corpuscles (RBC) production is defective. A person suffers from the disease only when he inherits a defective gene from both parents. He becomes a carrier when he inherits a defective gene from only one parent. The diseased person has to undergo blood transfusion once every month for the rest of his life.
Gold standard
Contrary to what is projected by some cord blood banks, doctors are very reluctant to use cord blood stem cells to treat thalassemia in the absence of a full tissue match.
Perfect match
Apart from infections, there are two major challenges from transplantation — graft versus host disease (GVHD) and rejection of the donated stem cells. “There is a 30 per cent chance of having graft versus host disease even when it is from a fully matched related (sibling) donor.” This risk increases to 50 per cent when it is from an unrelated donor, even if there is 6/6 tissue match.
Rejection rate becomes an issue even when there is a perfect tissue match. According to her, in the case of thalassemia, the rejection rate can be up to 20 per cent even with related donors, and up to 40 per cent in the case of unrelated donors.
But why should rejection and GVHD be an issue at all when there is a perfect 6/6 tissue match, and why should it be so high when stem cells are from unrelated donors?
Minor HLAs not tested
In general, greater the tissue match and higher the stem cell count in cord blood, lesser are the chances of rejection and GVHD.
“So why undertake procedures that are risky when thalassemia can be treated through monthly transfusions,” she noted.
Private banking of cord blood for use by the family therefore becomes important when one of the siblings is suffering from a disease that can be cured using it.
Case for public banking
There is a strong case for promoting public banks as depending solely on bone marrow samples will not be wise.
Even if a perfectly matched bone marrow donor is found, chances are that the person may no longer be interested in donating.
Collecting cord blood samples is easy, the number of samples that can be banked is limited only by resources, and samples can be made available at very short notice.
Feb 15, 2011
Medical leap gives hope to blood disorder sufferers
Gene therapy for the blood disorder beta-thalassemia will be carried out in Thailand for the first time by the end of this year.
A team of doctors at Ramathibodi Hospital is studying the gene therapy technology alongside experts in Paris under a collaboration programme between the Mahidol University led by Prof Suthat Fucharoen and French-American researcher Philippe Leboulch of Harvard Medical School and the University of Paris.The Thai doctors expect to return to Thailand to conduct a trial around December, said Dr Suradej Hongeng, of Ramathibodi Hospital's department of pediatrics.
The collaboration came about after the world's first successful treatment of beta-thalassemia with gene therapy.
A 21-year-old Frenchman treated with the therapy in 2007 now no longer has the need for blood transfusions. He previously had required transfusions every month since birth.
The successful treatment was published in the journal Nature last September.
Beta-thalassemia is caused when a patient cannot produce enough of the beta-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. This can cause life-threatening anaemia, leading to severe damage of the body's major organs.
Gene therapy is generally the insertion, alteration or removal of genes within a patient's cells and biological tissues to treat disease.
"This success justifies the hopes placed in the use of gene therapy to treat blood diseases," said Dr Suradej, a haematology specialist.
"It is also the first time an effective technology has been developed to improve the quality of life for people with thalassemia."
An estimated 20 million Thais are carriers of thalassemia. It is one of the world's most common genetic disorders, putting an enormous financial strain on Thailand and countries located in the "Thalassemia Belt", which stretches from the Mediterranean through the Middle East and Central Asia to Southeast Asia.
About three in 800 children born in Thailand are affected by the severest form of the disorder, beta-thalassemia, requiring regular blood transfusions.
However, blood transfusions carry the risk of contracting HIV and hepatitis B and C from donors, or iron overloading.
The only known cure for the condition is through a bone marrow transplant.
However, this process is dangerous and it can be very difficult to find a matching bone marrow donor, Dr Suradej said.
He hoped the gene therapy for thalassemia treatment would eliminate the problems posed by bone marrow transplants, as well as lead doctors to adapt the technology to treat the symptoms of beta-thalassemia, such as as neurological problems and muscle disabilities.
Feb 10, 2011
France's first 'saviour sibling' stirs ethical debate about biotechnology
The country’s first "saviour sibling", a healthy boy whose discarded umbilical cord will help heal one of his two siblings from a genetic blood disease, has brought complicated ethical issues over biotechnology to the forefront in France.
France’s first so-called "saviour sibling" was born in a hospital in the Parisian suburb of Clamart in late January, doctors announced Tuesday. The baby, whose blood stem cells will help cure one of his siblings from a severe genetic blood disease, has also opened a new front in the bioethics debate in France.
Born to parents of Turkish origin and named Umut Talha (Turkish for "our hope"), the child was conceived under circumstances that would have been unthinkable only a generation ago.
Umut Talha’s parents approached the hospital in Clamart a little more than a year ago with a serious problem: their two young children were both afflicted with an inherited blood disorder, Beta thalassemia, which requires monthly blood transfusions. The parents knew the hospital was one of only three in France that was developing a treatment for their children's illness.
An embryo was screened and genetically selected from an original group of 12 embryos. It was picked to ensure it did not carry the gene for Beta thalassemia, but also based on its compatibility with the sick siblings. Besides selecting an offspring that would be spared from the disorder, the parents hoped the future baby would also become a donor of the right kind of treatment cells.
In the end the boy was born disorder-free, and his cells were confirmed to be compatible with his older sister, now aged two. Doctors feel confident that Umut’s sister will be cured with the cells from his discarded umbilical cord, and her monthly blood transfusions will be discontinued.
The family have since returned to their home in southern France, but they plan to return to Clamart to undergo the same procedure to cure their other child, Umut’s four-year-old brother.
Hopes and hurdles
French newspapers spread “medicine baby” across headlines on Tuesday. But speaking at a press conference René Frydman, a fertility pioneer and father of the first French test-tube baby, who also oversaw Umut’s case, said he preferred the term “double-hope baby”.
“Medicine baby is a media term invented by people who are against this kind of procedure,” Frydman told reporters. In English-speaking countries, the terms “donor baby” and “saviour sibling” have been widely used in the media.
For Frydman, Umut represents a double hope for his parents: the hope of having a new, healthy baby, and the hope of curing one of their sick children. But other scientists, religious groups and parents beg to differ.
The issue of saviour babies has raised complex ethical debates, and renewed fears of a move towards “designer babies”, or babies whose traits – such as intelligence, eye-colour and height – have been predetermined.
The timing of Umut's birth could be significant. The very law that allows for cases like Umut’s is being revised starting today. Observers say that the existing legislation guiding biotechnology in France may be tightened and restrict research in certain fields, including stem cells.
The country’s standing bioethics law allows for cases like Umut’s. In fact, the government has earmarked 800,000 euros per year for Clamart to practice and develop the procedure.
But Frydman and his colleagues say a lot more needs to be done, complaining of endless hurdles to launch further research and access funds. They regret that France has started a decade after the United States and that the government is still reluctant to give them its full backing.
France’s first so-called "saviour sibling" was born in a hospital in the Parisian suburb of Clamart in late January, doctors announced Tuesday. The baby, whose blood stem cells will help cure one of his siblings from a severe genetic blood disease, has also opened a new front in the bioethics debate in France.
Born to parents of Turkish origin and named Umut Talha (Turkish for "our hope"), the child was conceived under circumstances that would have been unthinkable only a generation ago.
Umut Talha’s parents approached the hospital in Clamart a little more than a year ago with a serious problem: their two young children were both afflicted with an inherited blood disorder, Beta thalassemia, which requires monthly blood transfusions. The parents knew the hospital was one of only three in France that was developing a treatment for their children's illness.
An embryo was screened and genetically selected from an original group of 12 embryos. It was picked to ensure it did not carry the gene for Beta thalassemia, but also based on its compatibility with the sick siblings. Besides selecting an offspring that would be spared from the disorder, the parents hoped the future baby would also become a donor of the right kind of treatment cells.
In the end the boy was born disorder-free, and his cells were confirmed to be compatible with his older sister, now aged two. Doctors feel confident that Umut’s sister will be cured with the cells from his discarded umbilical cord, and her monthly blood transfusions will be discontinued.
The family have since returned to their home in southern France, but they plan to return to Clamart to undergo the same procedure to cure their other child, Umut’s four-year-old brother.
Hopes and hurdles
French newspapers spread “medicine baby” across headlines on Tuesday. But speaking at a press conference René Frydman, a fertility pioneer and father of the first French test-tube baby, who also oversaw Umut’s case, said he preferred the term “double-hope baby”.
“Medicine baby is a media term invented by people who are against this kind of procedure,” Frydman told reporters. In English-speaking countries, the terms “donor baby” and “saviour sibling” have been widely used in the media.
For Frydman, Umut represents a double hope for his parents: the hope of having a new, healthy baby, and the hope of curing one of their sick children. But other scientists, religious groups and parents beg to differ.
The issue of saviour babies has raised complex ethical debates, and renewed fears of a move towards “designer babies”, or babies whose traits – such as intelligence, eye-colour and height – have been predetermined.
The timing of Umut's birth could be significant. The very law that allows for cases like Umut’s is being revised starting today. Observers say that the existing legislation guiding biotechnology in France may be tightened and restrict research in certain fields, including stem cells.
The country’s standing bioethics law allows for cases like Umut’s. In fact, the government has earmarked 800,000 euros per year for Clamart to practice and develop the procedure.
But Frydman and his colleagues say a lot more needs to be done, complaining of endless hurdles to launch further research and access funds. They regret that France has started a decade after the United States and that the government is still reluctant to give them its full backing.
Researchers report gene therapy strategy that improves Beta Thalassemia in mice model
Researchers at Nationwide Children's Hospital report a gene therapy strategy that improves the condition of a mouse model of an inherited blood disorder, Beta Thalassemia. The gene correction involves using unfertilized eggs from afflicted mice to produce a batch of embryonic stem cell lines. Some of these stem cell lines do not inherit the disease gene and can thus be used for transplantation-based treatments of the same mice. Findings could hold promise for a new treatment strategy for autosomal dominant diseases like certain forms of Beta Thalassemia, tuberous sclerosis or Huntington's disease.
Embryonic stem cells have the potential to produce unlimited quantities of any cell type and are therefore being explored as a new therapeutic option for many diseases. Unfertilized eggs can be cultured to form embryonic stem cells, so-called parthenogenetic embryonic stem cells.
"Parthenogenetic embryonic stem cells can differentiate into multiple tissue types as do stem cells from fertilized embryos," said K. John McLaughlin, PhD, principal investigator in the Center for Molecular and Human Genetics at The Research Institute at Nationwide Children's Hospital. Previously, the group demonstrated that blood cells derived from parthenogenetic cells could provide healthy, long-term blood replacement in mice.
"Advantages of parthenogenetic stem cells are not only that fertilization is not needed, but also that the recipient's immune system may potentially not view them as foreign, minimizing rejection problems. Furthermore, since parthenogenetic embryonic stem cells are derived from reproductive cells which contain only a single set of the genetic information instead of the double set present in body cells, they may not contain certain abnormal genes present in the other copy," said Dr. McLaughlin also one of the study authors.
Embryonic stem cells have the potential to produce unlimited quantities of any cell type and are therefore being explored as a new therapeutic option for many diseases. Unfertilized eggs can be cultured to form embryonic stem cells, so-called parthenogenetic embryonic stem cells.
"Parthenogenetic embryonic stem cells can differentiate into multiple tissue types as do stem cells from fertilized embryos," said K. John McLaughlin, PhD, principal investigator in the Center for Molecular and Human Genetics at The Research Institute at Nationwide Children's Hospital. Previously, the group demonstrated that blood cells derived from parthenogenetic cells could provide healthy, long-term blood replacement in mice.
"Advantages of parthenogenetic stem cells are not only that fertilization is not needed, but also that the recipient's immune system may potentially not view them as foreign, minimizing rejection problems. Furthermore, since parthenogenetic embryonic stem cells are derived from reproductive cells which contain only a single set of the genetic information instead of the double set present in body cells, they may not contain certain abnormal genes present in the other copy," said Dr. McLaughlin also one of the study authors.
A single copy of an abnormal gene inherited from one parent can cause so-called autosomal dominant diseases such as tuberous sclerosis or Huntington's disease. The affected person has one defective and one normal copy of the gene, but the abnormal gene overrides the normal gene, causing disease. In normal sexual reproduction, each parent provides one gene copy to offspring via their reproductive cells. Therefore, the reproductive cells of a patient with an autosomal dominant disease could either pass along a defective copy or a normal copy.
"As the donor patient has one defective gene copy and one normal, and only one copy is used for normal reproduction, we can select egg-cell-derived embryonic stem cells with two normal copies," said Dr. McLaughlin. "These single-parent/patient-derived embryonic stem cells can theoretically be used for correction of a diverse number of diseases that occur when one copy of the gene is abnormal," said Dr. McLaughlin.
To test this theory, Dr. McLaughlin and colleagues from the University of Pennsylvania, University of North Carolina and University of Minnesota, examined whether parthenogenetic embryonic stem cells could be used for tissue repair in a mouse model of thalassemia intermedia. Thalassemia intermedia is an inherited blood disorder in which the body lacks sufficient normal hemoglobin, leading to excessive destruction of red blood cells and anemia. They used a mouse model in which one defective gene copy causes anemia.
Using approaches developed from a previous study done by this group, Nationwide Children's Research Fellow Sigrid Eckardt, PhD, derived embryonic stem cells from the unfertilized eggs of female mice with the disease, and identified those stem cell lines that contained only the "healthy" hemoglobin genes. These "genetically clean" embryonic stem cell lines were converted into cells that were transplanted into afflicted mice that were carriers of the disease causing gene. Blood samples drawn five weeks after transplantation revealed that the delivered cells were present in the recipients' blood. Their red blood cells were also corrected to a size similar to normal mice and red blood cell count, hematocrit and hemoglobin levels became normal.
"Overall, we observed long-term improvement of thalassemia in this model," said Dr. Eckardt. "Our findings suggest that using reproductive cells to generate embryonic stem cells that are 'disease-free' may be a solution for genetic diseases involving large, complex or poorly identified deletions in the genome or that are not treatable by current gene therapy approaches." Dr. McLaughlin says that this approach also contrasts with typical gene therapy approaches in that it requires no engineering of the genome, which is currently difficult to achieve in human embryonic and embryonic-like (IPS) stem cells.
Source: Nationwide Children's Hospital
"As the donor patient has one defective gene copy and one normal, and only one copy is used for normal reproduction, we can select egg-cell-derived embryonic stem cells with two normal copies," said Dr. McLaughlin. "These single-parent/patient-derived embryonic stem cells can theoretically be used for correction of a diverse number of diseases that occur when one copy of the gene is abnormal," said Dr. McLaughlin.
To test this theory, Dr. McLaughlin and colleagues from the University of Pennsylvania, University of North Carolina and University of Minnesota, examined whether parthenogenetic embryonic stem cells could be used for tissue repair in a mouse model of thalassemia intermedia. Thalassemia intermedia is an inherited blood disorder in which the body lacks sufficient normal hemoglobin, leading to excessive destruction of red blood cells and anemia. They used a mouse model in which one defective gene copy causes anemia.
Using approaches developed from a previous study done by this group, Nationwide Children's Research Fellow Sigrid Eckardt, PhD, derived embryonic stem cells from the unfertilized eggs of female mice with the disease, and identified those stem cell lines that contained only the "healthy" hemoglobin genes. These "genetically clean" embryonic stem cell lines were converted into cells that were transplanted into afflicted mice that were carriers of the disease causing gene. Blood samples drawn five weeks after transplantation revealed that the delivered cells were present in the recipients' blood. Their red blood cells were also corrected to a size similar to normal mice and red blood cell count, hematocrit and hemoglobin levels became normal.
"Overall, we observed long-term improvement of thalassemia in this model," said Dr. Eckardt. "Our findings suggest that using reproductive cells to generate embryonic stem cells that are 'disease-free' may be a solution for genetic diseases involving large, complex or poorly identified deletions in the genome or that are not treatable by current gene therapy approaches." Dr. McLaughlin says that this approach also contrasts with typical gene therapy approaches in that it requires no engineering of the genome, which is currently difficult to achieve in human embryonic and embryonic-like (IPS) stem cells.
Source: Nationwide Children's Hospital
Sep 21, 2010
Gene Rx May Fight Severe Blood Disorder
But far more research is needed to know whether treatment is safe and effective, researcher cautions
By Steven Reinberg - HealthDay Reporter
Patients suffering from a severe, inherited blood disorder may one day benefit from a new gene therapy and no longer need regular blood transfusions, new research suggests.
However, far more study is needed to determine whether the therapy is safe and effective. So far only one patient has received the experimental treatment, and the researchers have followed him for only three years.
The blood disorder -- beta-thalassemia -- occurs when a crucial blood protein known as beta globin is missing from the red blood cells that carry oxygen. Without beta globin, many of the red blood cells die off, causing severe anemia and eventually death if the person goes untreated.
Beta-thalassemia mostly affects people of Mediterranean, Middle Eastern, Southeast Asian and Chinese descent. Some 100,000 children are born with the disease each year around the world, according to the March of Dimes, and untreated, those with the most severe form usually die in childhood.
In those treated, the excess iron building up from the blood transfusions must be removed with chelating drugs, which can cause unpleasant side effects ranging from joint pain and vomiting to vision and hearing problems.
And even though lifesaving treatments have greatly improved prospects for long-term survival, those with the disorder are at risk of heart failure and other life-threatening complications -- some related to the treatments themselves -- as they age.
Among those struggling with this illness -- and often losing -- was a teenager who volunteered for the gene therapy. Like many others, he needed a matched donor for a stem cell transplant, but none was available, the study noted.
"The patient was 18 years old when we first treated him and [had been] transfused monthly for most of his life," said lead researcher Dr. Philippe Leboulch, a professor of medicine and cell biology at the University of Paris in France.
Transfusions continued until a year after the treatment, Leboulch said. "One year after the treatment he became transfusion-independent," he said. "That has been the case for over two years now."
For the study, Leboulch's team worked on a modified virus and removed all the viral genes. They then replaced those genes with a so-called globin gene. In addition, they added factors so the gene would act only on red blood cells, where the iron-rich protein known as hemoglobin normally carries oxygen throughout the body.
This new "gene" was then injected into the patient, where it went on to repair the damaged globin gene and started producing normal hemoglobin, Leboulch said.
"This is one more example of a gene therapy that starts to show a clinical benefit for patients," he said.
However, Leboulch is cautious. "This is the first patient in the trial. Of course we need to do more patients and see what happens," he said.
Leboulch noted another problem with gene therapy: the inability to control all the effects a new gene will have in the body. The globin gene, for example, appears to link to another gene that is involved in cell growth, causing a mild expansion of blood stem cells in the patient's body. This could account for some therapeutic benefits, but might also be a precursor to cancer, the researchers noted.
"So far there is no sign of any abnormality," Leboulch said.
Dr. Francoise Bernaudin, a clinical hematologist who has followed the patient since early childhood, said it was "wonderful to see that this young man is for now free of transfusions and injections for iron chelation.
"He is happy to have a normal life back, and for the first time has a full-time job as a cook in a main restaurant in Paris," said Bernaudin in a news release on behalf of bluebird bio, developer of the LentiGlobin gene therapy treatment that the researchers are using. The trials are sponsored by the Cambridge, Mass.-based bluebird bio.
The report is published in the Sept. 16 issue of Nature.
Based on their initial success with gene therapy, Leboulch's group plans to treat another two patients. If they also respond well, they will enroll "a larger cohort" of patients, he said.
In addition, the researchers plan to treat patients who have sickle cell disease with the gene therapy as well, Leboulch said. The same technique can be used for both diseases, he said.
Leboulch concedes that the treatment is very expensive. But he hopes that if it becomes widely used, the price will drop, eventually costing less than a lifetime of monthly transfusions and chelating drugs.
Dr. Mustafa Tekin, an associate professor at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, said that "gene therapy has been long awaited for thalassemia."
"This is the first example of a successful gene therapy for beta-thalassemia," he said. "This brings great hope for patients for the final cure for the disorder."
However, there are possibilities of adverse effects, Tekin said. He joined the researchers in cautioning that treatment to date has been limited to just one patient.
Tekin said that the gene that absorbed the therapeutic gene is associated with certain cancers, such as leukemia. While the patient does not have signs of the cancer, it is important "to follow this patient for the long-term for signs of leukemia," he said.
More trials and patients are needed to really assess the effects and side effects of the treatment, Tekin said. Whether it will treat other forms of thalassemia isn't known, he added.
"One patient is important and a significant achievement, but you still need to see more patients to make sure that it works for many patients and also that it works safely," he said.
However, far more study is needed to determine whether the therapy is safe and effective. So far only one patient has received the experimental treatment, and the researchers have followed him for only three years.
The blood disorder -- beta-thalassemia -- occurs when a crucial blood protein known as beta globin is missing from the red blood cells that carry oxygen. Without beta globin, many of the red blood cells die off, causing severe anemia and eventually death if the person goes untreated.
Beta-thalassemia mostly affects people of Mediterranean, Middle Eastern, Southeast Asian and Chinese descent. Some 100,000 children are born with the disease each year around the world, according to the March of Dimes, and untreated, those with the most severe form usually die in childhood.
In those treated, the excess iron building up from the blood transfusions must be removed with chelating drugs, which can cause unpleasant side effects ranging from joint pain and vomiting to vision and hearing problems.
And even though lifesaving treatments have greatly improved prospects for long-term survival, those with the disorder are at risk of heart failure and other life-threatening complications -- some related to the treatments themselves -- as they age.
Among those struggling with this illness -- and often losing -- was a teenager who volunteered for the gene therapy. Like many others, he needed a matched donor for a stem cell transplant, but none was available, the study noted.
"The patient was 18 years old when we first treated him and [had been] transfused monthly for most of his life," said lead researcher Dr. Philippe Leboulch, a professor of medicine and cell biology at the University of Paris in France.
Transfusions continued until a year after the treatment, Leboulch said. "One year after the treatment he became transfusion-independent," he said. "That has been the case for over two years now."
For the study, Leboulch's team worked on a modified virus and removed all the viral genes. They then replaced those genes with a so-called globin gene. In addition, they added factors so the gene would act only on red blood cells, where the iron-rich protein known as hemoglobin normally carries oxygen throughout the body.
This new "gene" was then injected into the patient, where it went on to repair the damaged globin gene and started producing normal hemoglobin, Leboulch said.
"This is one more example of a gene therapy that starts to show a clinical benefit for patients," he said.
However, Leboulch is cautious. "This is the first patient in the trial. Of course we need to do more patients and see what happens," he said.
Leboulch noted another problem with gene therapy: the inability to control all the effects a new gene will have in the body. The globin gene, for example, appears to link to another gene that is involved in cell growth, causing a mild expansion of blood stem cells in the patient's body. This could account for some therapeutic benefits, but might also be a precursor to cancer, the researchers noted.
"So far there is no sign of any abnormality," Leboulch said.
Dr. Francoise Bernaudin, a clinical hematologist who has followed the patient since early childhood, said it was "wonderful to see that this young man is for now free of transfusions and injections for iron chelation.
"He is happy to have a normal life back, and for the first time has a full-time job as a cook in a main restaurant in Paris," said Bernaudin in a news release on behalf of bluebird bio, developer of the LentiGlobin gene therapy treatment that the researchers are using. The trials are sponsored by the Cambridge, Mass.-based bluebird bio.
The report is published in the Sept. 16 issue of Nature.
Based on their initial success with gene therapy, Leboulch's group plans to treat another two patients. If they also respond well, they will enroll "a larger cohort" of patients, he said.
In addition, the researchers plan to treat patients who have sickle cell disease with the gene therapy as well, Leboulch said. The same technique can be used for both diseases, he said.
Leboulch concedes that the treatment is very expensive. But he hopes that if it becomes widely used, the price will drop, eventually costing less than a lifetime of monthly transfusions and chelating drugs.
Dr. Mustafa Tekin, an associate professor at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, said that "gene therapy has been long awaited for thalassemia."
"This is the first example of a successful gene therapy for beta-thalassemia," he said. "This brings great hope for patients for the final cure for the disorder."
However, there are possibilities of adverse effects, Tekin said. He joined the researchers in cautioning that treatment to date has been limited to just one patient.
Tekin said that the gene that absorbed the therapeutic gene is associated with certain cancers, such as leukemia. While the patient does not have signs of the cancer, it is important "to follow this patient for the long-term for signs of leukemia," he said.
More trials and patients are needed to really assess the effects and side effects of the treatment, Tekin said. Whether it will treat other forms of thalassemia isn't known, he added.
"One patient is important and a significant achievement, but you still need to see more patients to make sure that it works for many patients and also that it works safely," he said.
Anemia Drugs Could Pose Threat to Some Kidney Patients
Study finds 'poor responders' to meds like Aranesp at higher risk for heart trouble, death
By Serena GordonHealthDay Reporter
When people with chronic kidney disease
and type 2 diabetes take certain anemia drugs, the level of hemoglobin cells in their blood should go up.
But a new study finds that if those levels don't increase by much, these "poor responders" experience a significantly increased risk of heart problems and death.
Reporting in the Sept. 16 issue of the New England Journal of Medicine
, a team of international researchers says that those who had the worst response to erythropoiesis-stimulating agents (ESAs) -- drugs that include Aranesp, Epogen and Procrit -- had a 31 percent rise in the risk of cardiovascular complications and a 41 percent increased risk of death.
"For people who have chronic kidney disease, I think this is further evidence that we have to be extremely cautious when we use ESAs. There is a potential for harm. The patients who respond poorly are the ones who get the most drug, and we may be putting them at increased risk," said the study's lead author, Dr. Scott Solomon, director of noninvasive cardiology at Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School in Boston.
"What we can't determine from this study is if these patients had worse outcomes because they were sicker to begin with, or because they got more of the drug, or some combination of the two," added Solomon.
When someone has kidney disease, the kidneys may not produce enough of the hormone erythropoietin to prevent anemia, a deficiency in red blood cells. Symptoms of anemia include fatigue and pale skin, and it can even contribute to heart disease, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.
ESAs were developed to replace the missing erythropoietin in kidney patients and stimulate red blood cell production. But these drugs can cause serious, even life-threatening complications in some patients. Because of this, the U.S. Food and Drug Administration requires manufacturers to include a warning about the risks.
The current study is a secondary analysis of a randomized, double-blind, placebo-controlled study done in 24 countries from 2004 to 2009. All of the study volunteers -- 1,872 in all -- had type 2 diabetes and chronic kidney disease.
The study volunteers were randomly assigned to receive either 0.75 micrograms of darbepoietin alfa (Aranesp) per kilogram of body weight or a placebo. In people who didn't respond well to the initial dose of the drug, the dose was repeated after two weeks. After that, hemoglobin levels were monitored and doses adjusted based on an individual's hemoglobin levels, reported the study.
In the initial analysis of these study volunteers, the researchers found no reduction in the risk of death or of cardiovascular or kidney problems in those taking the drug compared to those on placebo. But they did see a significant increase in the risk of stroke. Solomon said there was only a slight, "unimpressive" increase in quality of life for those taking the ESA.
At the same time, other studies have been finding an increased risk of heart problems in people taking ESAs. Solomon's team wanted to know why some people might be at greater risk than others.
In a sub-analysis of the initial study, they divided the group into four smaller groups based on their response to darbepoietin alfa, which is how they found the increased risk of death and cardiovascular events in people who responded poorly to the drug.
Solomon said he thinks this effect would likely be seen in other ESAs, not just darbepoietin alfa. Amgen, the maker of Aranesp, provided funding for the study.
"This study helps clarify some of the confusion from previous studies. When you isolate who are the people who got into trouble, it was people who wouldn't respond to ESAs. I think it helps clarify how to use ESAs. If I see that you don't respond, there may be something else going on with you, and I need to give you some special attention because you're at greater risk of having a bad outcome," said Dr. Robert Provenzano, chair of the department of nephrology at St. John Providence Health System in Detroit.
But, if you respond normally to ESAs, he said, the drugs may improve your quality of life when the medication is adjusted to keep your hemoglobin levels between 10 and 12.5 mg/dL.
Solomon said he wasn't sure if the modest benefit seen in patients was worth the potential increase in stroke risk. Provenzano countered that such a decision needs to be individualized based on the effects of the anemia, along with other aspects of the patient's life.
If you take this medication, Provenzano suggested asking your doctor where you fall on the continuum of response and whether you're in a high-risk group.
and type 2 diabetes take certain anemia drugs, the level of hemoglobin cells in their blood should go up.But a new study finds that if those levels don't increase by much, these "poor responders" experience a significantly increased risk of heart problems and death.
Reporting in the Sept. 16 issue of the New England Journal of Medicine
, a team of international researchers says that those who had the worst response to erythropoiesis-stimulating agents (ESAs) -- drugs that include Aranesp, Epogen and Procrit -- had a 31 percent rise in the risk of cardiovascular complications and a 41 percent increased risk of death."For people who have chronic kidney disease, I think this is further evidence that we have to be extremely cautious when we use ESAs. There is a potential for harm. The patients who respond poorly are the ones who get the most drug, and we may be putting them at increased risk," said the study's lead author, Dr. Scott Solomon, director of noninvasive cardiology at Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School in Boston.
"What we can't determine from this study is if these patients had worse outcomes because they were sicker to begin with, or because they got more of the drug, or some combination of the two," added Solomon.
When someone has kidney disease, the kidneys may not produce enough of the hormone erythropoietin to prevent anemia, a deficiency in red blood cells. Symptoms of anemia include fatigue and pale skin, and it can even contribute to heart disease, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.
ESAs were developed to replace the missing erythropoietin in kidney patients and stimulate red blood cell production. But these drugs can cause serious, even life-threatening complications in some patients. Because of this, the U.S. Food and Drug Administration requires manufacturers to include a warning about the risks.
The current study is a secondary analysis of a randomized, double-blind, placebo-controlled study done in 24 countries from 2004 to 2009. All of the study volunteers -- 1,872 in all -- had type 2 diabetes and chronic kidney disease.
The study volunteers were randomly assigned to receive either 0.75 micrograms of darbepoietin alfa (Aranesp) per kilogram of body weight or a placebo. In people who didn't respond well to the initial dose of the drug, the dose was repeated after two weeks. After that, hemoglobin levels were monitored and doses adjusted based on an individual's hemoglobin levels, reported the study.
In the initial analysis of these study volunteers, the researchers found no reduction in the risk of death or of cardiovascular or kidney problems in those taking the drug compared to those on placebo. But they did see a significant increase in the risk of stroke. Solomon said there was only a slight, "unimpressive" increase in quality of life for those taking the ESA.
At the same time, other studies have been finding an increased risk of heart problems in people taking ESAs. Solomon's team wanted to know why some people might be at greater risk than others.
In a sub-analysis of the initial study, they divided the group into four smaller groups based on their response to darbepoietin alfa, which is how they found the increased risk of death and cardiovascular events in people who responded poorly to the drug.
Solomon said he thinks this effect would likely be seen in other ESAs, not just darbepoietin alfa. Amgen, the maker of Aranesp, provided funding for the study.
"This study helps clarify some of the confusion from previous studies. When you isolate who are the people who got into trouble, it was people who wouldn't respond to ESAs. I think it helps clarify how to use ESAs. If I see that you don't respond, there may be something else going on with you, and I need to give you some special attention because you're at greater risk of having a bad outcome," said Dr. Robert Provenzano, chair of the department of nephrology at St. John Providence Health System in Detroit.
But, if you respond normally to ESAs, he said, the drugs may improve your quality of life when the medication is adjusted to keep your hemoglobin levels between 10 and 12.5 mg/dL.
Solomon said he wasn't sure if the modest benefit seen in patients was worth the potential increase in stroke risk. Provenzano countered that such a decision needs to be individualized based on the effects of the anemia, along with other aspects of the patient's life.
If you take this medication, Provenzano suggested asking your doctor where you fall on the continuum of response and whether you're in a high-risk group.
Sep 17, 2010
Gene-therapy hope for β-thalassaemia patients
A defective haemoglobin gene has been successfully replaced with a healthy copy.
Patients with β-thalassaemia carry faulty copies of the genes needed to produce the β-globin chain of haemoglobin, sometimes lacking the genes altogether. This leads to a shortage of red blood cells, the body's oxygen carriers.
Sufferers must have regular blood transfusions throughout their lives, an inconvenient and debilitating regime that ultimately shortens life expectancy. The only known cure is stem-cell transplantation, but few patients are able to find a suitable donor.
Because of the gruelling nature of this treatment, the development of gene therapies for β-thalassaemia is seen by many as an exciting prospect. The subject of the latest trial was an 18-year-old man with βE/β0-thalassaemia — in this form of the disease, one copy of the β–globin gene produces unstable β-globin and the other copy is non-functional.
Around half of the patients with this form of β-thalassaemia are dependent on transfusions, and the patient concerned had received blood transfusions since the age of three.
Philippe Leboulch of Harvard Medical School, part of the team that carried out the study, described the treatment as "life-changing". "Before this treatment, the patient had to be transfused every month. Now he has a full-time job as a cook," he says.
Unrepeatable?
However, Michael Antoniou of King's College London, suggests that this case was "an extremely fortuitous event", and that the positive outcome seen is unlikely to be repeatable in other patients.The procedure was carried out as follows. In 2007, an international team led by Marina Cavazzana-Calvo of University Paris-Descartes extracted haematopoietic stem cells (HSCs) from the patient's bone marrow. These cells give rise to all blood cell types, including the haemoglobin-containing red cells. The researchers cultured these cells, and mixed them with vectors based on the lentiviruses — a retrovirus subgroup with a long incubation period — into which a functional copy of the β-globin gene had been introduced. These vectors were shown in preclinical trials to be safer than those derived from the retroviruses — which are also replicated in a host cell — that have been used in previous gene-therapy procedures.
Chemotherapy was used to eliminate as many of the patient's faulty HSCs as possible, to prevent dilution of the genetically corrected cells, which were then transplanted. Levels of healthy red blood cells and normal β-globin in the subject's body gradually rose until, around a year after the treatment, he no longer required transfusions. After 33 months he remains mildly anaemic, but the fact that he remains transfusion-free has been hailed as a success.
However, that achievement is tempered by a cautionary note. The researchers have detected overexpression of a protein called HMGA2, which has been linked to cancers, in a high proportion of the genetically modified cells.
Overexpression occurred because the lentivirus vector can randomly integrate into chromosomes. By chance, one transplanted haematopoietic cell clone contains a vector insertion in the HMGA2 gene. A year after the transplant, the researchers noticed that the proportion of genetically modified cells that originated from this particular cell clone was rising until it reached a plateau at around 50%.
The reasons for the over-representation of that particular clone remain unclear, but that could be down to the fact that the patient's haematopoietic system was reconstituted from just a few modified HSCs. Luigi Naldini, a gene-therapy researcher at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, says that successfully grafting a larger initial population of modified HSCs could potentially prevent the problem from developing.
Looking at the haematopoietic system in its entirety, the researchers found that increased levels of HMGA2 were present in only about 5% of the patient's circulating cells, but overexpression of HMGA2 has led to enlargement of the patient's red blood cells. The researchers say that this enlargement caused by the overexpression of HMGA2 could be partly responsible for the therapeutic benefits, but it could also be a signal of future malignancies.
Antoniou suggests that the HMGA2 effect is "key" to the therapeutic effect, and that without the unintended insertion, combined with the patient's ability to produce some β-globin naturally, transfusions would probably still be required.
But Leboulch says that β-globin production from the modified cells was just as high before the cells containing the insertion reached the 50% mark, so that most of the therapeutic effect must be due to the implanted modified cells, rather than the expansion of the blood cells caused by the HMGA2 insertion. And Naldini says that the fact that β-globin expression by the implanted cells is being seen at all represents a major step forward.
Sep 16, 2010
Johns Hopkins Children's Center urges new screening program to improve sickle cell trait
The Johns Hopkins Children's Center top pediatrician is urging a "rethink" of a new sickle cell screening program, calling it an enlightened but somewhat rushed step toward improving the health of young people who carry the sickle cell mutation.
Beginning this fall, all Division I college athletes will undergo mandatory screening for the sickle cell trait. The program, rolled out by the National Collegiate Athletic Association (NCAA), is an attempt to prevent rare but often-lethal complications triggered by intense exercise in those who carry the genetic mutation yet don't have the disease.
Nationwide, newborns are screened for sickle cell disease, but carriers, or people with one mutant and one normal sickle cell gene, do not have symptoms of the disease and may be unaware that they are carriers.
While the program's goal is laudable, its implementation has been hasty and its consequences poorly thought out, warns Johns Hopkins Children's Center Director George Dover, M.D., in a Sept. 9 commentary for The New England Journal of Medicine.
The program is expected to affect nearly 170,000 college athletes and identify anywhere between 400 to 500 new cases each year. Carriers of the sickle cell trait are asymptomatic but are at higher risk for infarction of the spleen caused by lack of oxygen supply to the organ and exercise-induced rhabdomyolysis, a condition marked by the rapid breakdown of injured muscle followed by the release of proteins in the bloodstream that harm the kidneys and can lead to kidney failure. Research has shown that the risk of sudden death during exercise is between 10 and 30 percent higher among those who have the sickle cell trait than those without it. The program stems from the 2006 death of a 19-year-old freshman who died after football practice from exercise-induced rhabdomyolysis.
Dover and co-authors Vence Bonhaj, J.D., and Lawrence Brody, Ph.D., of the National Human Genome Research Institute, call the program "an enlightened first step by the NCAA toward improving the health of student athletes," but one rife with pitfalls and raising many questions. Such questions include: "Will any positive test results be followed by a second test to eliminate false positives?" and "Who is responsible for counseling students who test positive in order to explain the difference between actual disease and carrier status and the risks associated with each?"
Dover and his co-authors say that the following stipulations should be included in the program:
• Verifying test result accuracy by follow-up testing to eliminate false positives • Post-test counseling • Measures to prevent discrimination based on positive test results • Making athletic practice safer to reduce or eliminate the risk for death among carriers by instituting proper hydration and avoiding workouts during high humidity and peak heat
Students will be allowed to opt out of screening if they show proof of previous testing or sign a waiver releasing their college of any legal liability. These suggest that the program was designed primarily as a legal defense measure, but its medical, social and psychological consequences remain unaddressed, the authors say.
As the most extensive sickle cell screening program in the past 30 years, this initiative will likely pave the way for other mass screening programs among college athletes, including ones aimed at identifying the carriers of cardiac anomalies, the most common cause of sudden death in athletes.
"The precedent-setting nature of this screening program dictates that we proceed with caution because any subsequent genetic screening programs may be modeled after this prototype," says Dover, a pediatric hematologist and expert on sickle cell disease.
Some 100 million people worldwide and 2 million people in the United States are believed to be carriers of the sickle cell mutation (sickle cell trait) but do not have sickle cell anemia. Named for the unusually sickle-shaped red blood cells caused by an inherited abnormality, sickle cell anemia affects nearly 100,000 Americans, most of them African-American. In sickle cell anemia, the red blood cells become rigid, which reduces their oxygen delivery to vital organs and causes them to get stuck in the blood vessels, leading to severe pain and so-called "sickling crises," which require hospitalization.
Source : Johns Hopkins Children's Center
Beginning this fall, all Division I college athletes will undergo mandatory screening for the sickle cell trait. The program, rolled out by the National Collegiate Athletic Association (NCAA), is an attempt to prevent rare but often-lethal complications triggered by intense exercise in those who carry the genetic mutation yet don't have the disease.
Nationwide, newborns are screened for sickle cell disease, but carriers, or people with one mutant and one normal sickle cell gene, do not have symptoms of the disease and may be unaware that they are carriers.
While the program's goal is laudable, its implementation has been hasty and its consequences poorly thought out, warns Johns Hopkins Children's Center Director George Dover, M.D., in a Sept. 9 commentary for The New England Journal of Medicine.
The program is expected to affect nearly 170,000 college athletes and identify anywhere between 400 to 500 new cases each year. Carriers of the sickle cell trait are asymptomatic but are at higher risk for infarction of the spleen caused by lack of oxygen supply to the organ and exercise-induced rhabdomyolysis, a condition marked by the rapid breakdown of injured muscle followed by the release of proteins in the bloodstream that harm the kidneys and can lead to kidney failure. Research has shown that the risk of sudden death during exercise is between 10 and 30 percent higher among those who have the sickle cell trait than those without it. The program stems from the 2006 death of a 19-year-old freshman who died after football practice from exercise-induced rhabdomyolysis.
Dover and co-authors Vence Bonhaj, J.D., and Lawrence Brody, Ph.D., of the National Human Genome Research Institute, call the program "an enlightened first step by the NCAA toward improving the health of student athletes," but one rife with pitfalls and raising many questions. Such questions include: "Will any positive test results be followed by a second test to eliminate false positives?" and "Who is responsible for counseling students who test positive in order to explain the difference between actual disease and carrier status and the risks associated with each?"
Dover and his co-authors say that the following stipulations should be included in the program:
• Verifying test result accuracy by follow-up testing to eliminate false positives • Post-test counseling • Measures to prevent discrimination based on positive test results • Making athletic practice safer to reduce or eliminate the risk for death among carriers by instituting proper hydration and avoiding workouts during high humidity and peak heat
Students will be allowed to opt out of screening if they show proof of previous testing or sign a waiver releasing their college of any legal liability. These suggest that the program was designed primarily as a legal defense measure, but its medical, social and psychological consequences remain unaddressed, the authors say.
As the most extensive sickle cell screening program in the past 30 years, this initiative will likely pave the way for other mass screening programs among college athletes, including ones aimed at identifying the carriers of cardiac anomalies, the most common cause of sudden death in athletes.
"The precedent-setting nature of this screening program dictates that we proceed with caution because any subsequent genetic screening programs may be modeled after this prototype," says Dover, a pediatric hematologist and expert on sickle cell disease.
Some 100 million people worldwide and 2 million people in the United States are believed to be carriers of the sickle cell mutation (sickle cell trait) but do not have sickle cell anemia. Named for the unusually sickle-shaped red blood cells caused by an inherited abnormality, sickle cell anemia affects nearly 100,000 Americans, most of them African-American. In sickle cell anemia, the red blood cells become rigid, which reduces their oxygen delivery to vital organs and causes them to get stuck in the blood vessels, leading to severe pain and so-called "sickling crises," which require hospitalization.
Source : Johns Hopkins Children's Center
Promising results in mice could prevent fatal iron buildup in humans
A new study shows that a protein found in blood alleviates anemia, a condition in which the body's tissues don't get enough oxygen from the blood. In this animal study, injections of the protein, known as transferrin, also protected against potentially fatal iron overload in mice with thalassemia, a type of inherited anemia that affects millions of people worldwide.
Implications of the study, published in the January 24 online edition of Nature Medicine, could extend well beyond thalassemia to include other types of anemia including sickle cell anemia and myelodysplastic syndromes (bone marrow disorders that often precede leukemia) if proven in humans. The research was conducted by scientists at Albert Einstein College of Medicine of Yeshiva University.
"People who have thalassemia or other types of anemia need frequent blood transfusions over many years to correct the problem," says Mary E. Fabry, Ph.D., professor of medicine at Einstein and a study author. "But the human body has no way to get rid of the massive amount of iron in the transfused blood, and the resulting iron overload - especially its accumulation in the heart and liver - is often fatal. Our study suggests that treatment with transferrin could prevent this."
It's projected that over the next 20 years, more than 900,000 children with thalassemia will be born each year. Ninety-five percent of thalassemia births are in Asian, Indian, and Middle Eastern regions. However, the U.S. is seeing more cases due to a growing influx of immigrants.
In thalassemia, gene mutations lead to underproduction of the globin protein chains that form hemoglobin, the iron-containing, oxygen-carrying molecule in red blood cells. (Normal hemoglobin consists of four globin protein chains - two alpha chains and two beta chains.) Fewer globin chains mean a shortage of red blood cells, a shorter lifespan for red cells that are produced, and anemia.
Thalassemia is classified as alpha or beta thalassemia, depending on which of the globin protein chains are affected. In a 2009 study involving beta thalassemic mice at Einstein, Dr. Fabry and her colleagues made a paradoxical observation: Despite the rodents' anemia and iron overload, injecting them with more iron improved their anemia by increasing both hemoglobin and the number of red cells.
This finding indicated that "overload" iron wasn't accessible for use in making red cells. And it suggested to Yelena Z. Ginzburg, M.D., a postdoctoral research fellow in Dr. Fabry's lab at the time and a senior author of the present study, that transferrin might be able to tap into that stored iron.
Transferrin is a crucially important protein responsible for transporting iron in the bloodstream and delivering it to cells that need it - particularly the cells that develop into red blood cells. "Yelena [now a researcher at the New York Blood Center in New York City] hypothesized that too little transferrin in the circulation may account for the reduced red cell production and anemia observed in beta thalassemia," says Dr. Fabry. "So she decided to see if injections of transferring - obtainable as a byproduct of blood collection - could help in treating thalassemia."
In the present study, the researchers gave the beta thalassemia mice daily injections of human transferrin for 60 days. The results were impressive.
"The injected transferrin killed three birds with one stone," says Dr. Fabry. "It not only helped in depleting the iron overload that can be so toxic, but it recycled that iron into new red blood cells that ameliorated the anemia. Plus, those red cells survived for a longer time because they had fewer defects."
The Einstein researchers are cautiously optimistic that transferrin could have similar benefits for people.
"Before doing clinical trials, we need to work out a lot of details such as the proper dose of transferrin and the frequency of treatment," says Eric E. Bouhassira, Ph.D., another author of the study who is professor cell biology and of medicine and the Ingeborg and Ira Leon Rennert Professor of Stem Cell Biology and Regenerative Medicine at Einstein. "But transferrin's striking effectiveness in reducing iron overload makes me hopeful that people with anemia could really benefit from it."
The paper, "Transferrin therapy ameliorates disease in beta-thalassemic mice," appears in the January 24 online edition of Nature Medicine.
Source: Albert Einstein College of Medicine
Implications of the study, published in the January 24 online edition of Nature Medicine, could extend well beyond thalassemia to include other types of anemia including sickle cell anemia and myelodysplastic syndromes (bone marrow disorders that often precede leukemia) if proven in humans. The research was conducted by scientists at Albert Einstein College of Medicine of Yeshiva University.
"People who have thalassemia or other types of anemia need frequent blood transfusions over many years to correct the problem," says Mary E. Fabry, Ph.D., professor of medicine at Einstein and a study author. "But the human body has no way to get rid of the massive amount of iron in the transfused blood, and the resulting iron overload - especially its accumulation in the heart and liver - is often fatal. Our study suggests that treatment with transferrin could prevent this."
It's projected that over the next 20 years, more than 900,000 children with thalassemia will be born each year. Ninety-five percent of thalassemia births are in Asian, Indian, and Middle Eastern regions. However, the U.S. is seeing more cases due to a growing influx of immigrants.
In thalassemia, gene mutations lead to underproduction of the globin protein chains that form hemoglobin, the iron-containing, oxygen-carrying molecule in red blood cells. (Normal hemoglobin consists of four globin protein chains - two alpha chains and two beta chains.) Fewer globin chains mean a shortage of red blood cells, a shorter lifespan for red cells that are produced, and anemia.
Thalassemia is classified as alpha or beta thalassemia, depending on which of the globin protein chains are affected. In a 2009 study involving beta thalassemic mice at Einstein, Dr. Fabry and her colleagues made a paradoxical observation: Despite the rodents' anemia and iron overload, injecting them with more iron improved their anemia by increasing both hemoglobin and the number of red cells.
This finding indicated that "overload" iron wasn't accessible for use in making red cells. And it suggested to Yelena Z. Ginzburg, M.D., a postdoctoral research fellow in Dr. Fabry's lab at the time and a senior author of the present study, that transferrin might be able to tap into that stored iron.
Transferrin is a crucially important protein responsible for transporting iron in the bloodstream and delivering it to cells that need it - particularly the cells that develop into red blood cells. "Yelena [now a researcher at the New York Blood Center in New York City] hypothesized that too little transferrin in the circulation may account for the reduced red cell production and anemia observed in beta thalassemia," says Dr. Fabry. "So she decided to see if injections of transferring - obtainable as a byproduct of blood collection - could help in treating thalassemia."
In the present study, the researchers gave the beta thalassemia mice daily injections of human transferrin for 60 days. The results were impressive.
"The injected transferrin killed three birds with one stone," says Dr. Fabry. "It not only helped in depleting the iron overload that can be so toxic, but it recycled that iron into new red blood cells that ameliorated the anemia. Plus, those red cells survived for a longer time because they had fewer defects."
The Einstein researchers are cautiously optimistic that transferrin could have similar benefits for people.
"Before doing clinical trials, we need to work out a lot of details such as the proper dose of transferrin and the frequency of treatment," says Eric E. Bouhassira, Ph.D., another author of the study who is professor cell biology and of medicine and the Ingeborg and Ira Leon Rennert Professor of Stem Cell Biology and Regenerative Medicine at Einstein. "But transferrin's striking effectiveness in reducing iron overload makes me hopeful that people with anemia could really benefit from it."
The paper, "Transferrin therapy ameliorates disease in beta-thalassemic mice," appears in the January 24 online edition of Nature Medicine.
Source: Albert Einstein College of Medicine
Subscribe to:
Posts (Atom)