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.
 

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.

Gene-therapy hope for β-thalassaemia patients

A defective haemoglobin gene has been successfully replaced with a healthy copy.

Joseph Milton

Gene therapy for a form of β-thalassaemia, a genetic disorder whose sufferers require frequent blood transfusions because they cannot properly produce red blood cells, seems to have been successful in a patient who, three years after treatment, no longer requires transfusions¹. Doubts remain, however, over whether a set of lucky circumstances is behind the success.
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 β^E/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.

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

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

H1N1 flu increases complication in children with sickle cell anemia: Study

Children with sickle cell disease are especially hard-hit by the H1N1 flu strain, causing more life-threatening complications than the seasonal flu, according to a study from Johns Hopkins Children's Center.

The study's findings, published online July 23 in an early edition of the journal Blood, should be heeded as a warning call by parents and pediatricians that children with sickle cell anemia are more likely to need emergency treatment and to be hospitalized if they contract the H1N1 flu.

While H1N1 flu in the general population turned out to be much less severe than feared at the start of the 2009 pandemic, children with sickle cell disease remain at greater risk for complications from it, as well as other strains of the flu. A 2009 Hopkins Children's study found that children with sickle cell disease are hospitalized with seasonal flu nearly 80 times more often than other children.

Lead investigator John Strouse, M.D., Ph.D., a hematologist at Hopkins Children's says the study underscores the importance of timely immunization against both the H1N1 and the seasonal flu strains, which this year will be given in a single vaccine.
The Hopkins team analyzed the records of 123 children with sickle cell disease treated for any kind of flu at Hopkins Children's between September 1993 and December 10, 2009. Of them, 29 were infected with the H1N1 virus, a new strain that emerged for the first time in April of 2009.

While both the seasonal flu and the H1N1 virus caused most of the typical flu symptoms — fever, cough and a runny nose — in most of the children, sickle cell patients infected with H1N1 were nearly three times more likely to develop acute chest syndrome, a leading cause of death among such patients, marked by inflammation of the lungs, reduced ability to absorb oxygen and shortness of breath.

H1N1-infected children also were more than five times more likely to end up in the intensive-care unit than those with the regular flu, and they were overall more likely to need a ventilator for breathing.
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. The cells' abnormal structure 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.

The CDC estimates that up to one-fifth of Americans get the flu each year, resulting in 200,000 hospitalizations and 36,000 deaths.
Source : Johns Hopkins Children's Center

New Medicare Rules May Curb Use of Anemia Drugs for Dialysis

By ANDREW POLLACK

Yet more restrictions in the use of anemia drugs are on the way.
Medicare issued final rules Monday that are expected to sharply curtail the use of anemia drugs, particularly Amgen’s Epogen, in the treatment of patients undergoing kidney dialysis.
However, after getting lots of protest, Medicare decided to exempt certain oral drugs from the new system until 2014, which could be good news for Genzyme.
Under the new system, the Centers for Medicare and Medicaid Services will pay a set fee for each dialysis treatment. That so-called bundled payment is supposed to cover both the dialysis service, in which wastes are removed from the body, and the drugs and laboratory tests that accompany it. The new system starts phasing in on Jan. 1.
The new system somewhat resembles concepts in the new health care law, but the dialysis system reform was initiated earlier by Congress, under different legislation.
Until now, Medicare has paid a set fee for the service but certain drugs, like Epogen, are reimbursed separately.
Critics say that gave hospitals and dialysis clinics financial incentives to use a lot of Epogen, which dominates the dialysis market because of Amgen’s patent position. Amgen sells about $2.5 billion of Epogen a year, virtually all for use in dialysis in the United States, and the drug is one of the biggest pharmaceutical expenses for Medicare.

Concern about this system grew stronger when some clinical trials revealed that overuse of Epogen might harm patients, increasing their risk of heart attacks and strokes.
“When drugs remain outside the payment bundle, financial issues can influence both facility and patient behavior, as the over-utilization of EPO to the detriment of patient care in the past has demonstrated,’’ Medicare said in its ruling Monday.
Of course, the new system could have the opposite effect. Epogen will go from being a potential profit source for dialysis clinics to an expense that detracts from profit. So now there will be an incentive to under-use the drug, perhaps subjecting dialysis patients to more anemia and fatigue.
But clinics will have to meet certain standards for quality of care, which Medicare hopes will deter under-use. Medicare said it expects less costly alternatives might be used.
One approach would be to give Epogen by separate injections under the skin. Less of the drug is needed that way than when it is given through the intravenous line now used to deliver dialysis.
When they had a financial incentive to use more Epogen, dialysis clinics resisted giving such separate injections, saying they added to the pain and discomfort for patients. Now, however, many clinics are expected to switch.
Analysts have been expecting the final rules since Medicare first proposed the changes last year, and they have by and large already factored in a reduction in sales of Epogen of as much as 40 percent.
In a note to clients Monday afternoon, however, Jim Birchenough, an analyst at Barclays Capital, said such estimates might be too high and that the transition to giving patients separate injections will occur gradually.
The big suspense in the final rules would be whether Medicare would stick with its original proposal to include certain oral drugs, like Amgen’s Sensipar and Genzyme’s Renvela, in the bundle. These drugs are used to control calcium and phosphorus levels in the patient’s blood.
Opponents of inclusion of the oral drugs argued Medicare had no right to do so, because the drugs typically are not given at the dialysis clinic. Like most other pills, patients get a prescription and Medicare pays for the drugs under its prescription coverage, known as Part D, not under its dialysis program.
The opponents also said that because the drugs were expensive, inclusion in the bundle would curtail their use, to the detriment of patients.
In the final rules issued Monday, Medicare defended its position to include the drugs, but postponed the starting date by three years, until Jan. 1, 2014, to allow time for the study of “operational and safety issues.’’

Anemia and Thrombocytopenia in Pregnancy

Author: Diana Curran, MD, FACOG, Assistant Professor, Residency Program Director, Department of Obstetrics and Gynecology, University of Michigan Health Systems

Thrombocytopenia

Thrombocytopenia in pregnancy is common and is diagnosed in approximately 7% of pregnancies. It is typically defined as a platelet count of less than 150,000/µL. The most common cause of thrombocytopenia during pregnancy is gestational thrombocytopenia, which is a mild thrombocytopenia with platelet levels remaining greater than 70,000/µL.

Patients who are affected usually are asymptomatic and have no history of thrombocytopenia prior to pregnancy. Their platelet levels should return to normal within several weeks following delivery. An extremely low risk of fetal or neonatal thrombocytopenia is associated with gestational thrombocytopenia. Gestational thrombocytopenia may result from increased platelet consumption and can be associated with antiplatelet antibodies. Gestational thrombocytopenia can be hard to distinguish from immune thrombocytopenia purpura (ITP) presenting during pregnancy.


Immune thrombocytopenia purpura
Acute ITP is a disorder occurring in childhood with little implication for women who are pregnant because it resolves spontaneously. Chronic ITP may occur in the second or third decade of life, affecting females 3 times as frequently as males. This condition is characterized by immunologically mediated platelet destruction. Antiplatelet antibodies (immunoglobulin G) attack platelet membrane glycoproteins and destroy platelets at a rate that cannot be compensated by the bone marrow. ITP is usually associated with persistent thrombocytopenia (<100,000/µL), normal or increased megakaryocytes on bone marrow aspirate, exclusion of other disorders associated with thrombocytopenia, and the absence of splenomegaly. Patients may report a history of easy bruising and petechiae or epistaxis and gingival bleeding preceding the pregnancy.
Although worsening of the disease is not typical during pregnancy, when it occurs, the mother is at risk for bleeding complications at the time of delivery. Therapies aimed at improving the maternal platelet count in anticipation of delivery include intravenous immunoglobulin (IVIg) and steroids. The patient may require platelet transfusion during delivery if the platelet count drops below 20,000/µL. Splenectomy is reserved for severe cases only.
Some controversy exists regarding the threat of intracranial hemorrhage (ICH) in neonates born to mothers with ITP. Although as many as 12-15% of infants born to mothers with ITP may develop platelet counts less than 50,000/µL, the risk of ICH is estimated at less than 1% in 2 recent prospective studies.

Neonatal alloimmune thrombocytopenia
In contrast to ITP, neonatal alloimmune thrombocytopenia may pose a serious risk to the newborn. It may occur in 1 in 1000 live births and often is unanticipated when it occurs in first pregnancies. The presentation may be in the setting of an unremarkable pregnancy and delivery. Clinical manifestations in the neonate include generalized petechiae, ecchymoses, hemorrhage into viscera, increased bleeding at the time of circumcision or venipuncture, or, most gravely, ICH. ICH may occur in utero in as many as 25% of cases. Like Rhesus (Rh) disease, neonatal alloimmune thrombocytopenia results from maternal alloimmunization against fetal platelet antigens. The most severely affected antigen is human platelet antigen-1a, which has been described in approximately 50% of cases in white persons. A high risk of recurrence of neonatal alloimmune thrombocytopenia exists, and it tends to worsen with subsequent gestations in a manner similar to Rh disease.
For patients who have a history of the disease and are experiencing their first pregnancy, referral to a maternal-fetal medicine specialist skilled in cordocentesis may be warranted because the fetus may need to have platelet counts or a transfusion while in utero. IVIg has been shown to improve fetal thrombocytopenia. Cesarean delivery is the preferred route of delivery for infants with platelet counts less than 50,000/µL to reduce the risk of ICH secondary to trauma incurred during labor.

Anemia

With normal pregnancy, blood volume increases, which results in a concomitant hemodilution. Although red blood cell mass increases during pregnancy, plasma volume increases more, resulting in a relative anemia. This results in a physiologically lowered hemoglobin (Hb) level, hematocrit (Hct) value, and red blood cell (RBC) count, but it has no effect on the mean corpuscular volume (MCV). Many centers define anemia in a patient who is pregnant as an Hb value less than 10.5 g/dL, as opposed to the reference range of 14 g/dL in a patient who is not pregnant. Treatment with 1 mg folic acid and daily iron is helpful when deficiencies are noted.
Iron deficiency anemia
Iron deficiency anemia accounts for 75-95% of the cases of anemia in pregnant women. A woman who is pregnant often has insufficient iron stores to meet the demands of pregnancy. Encourage pregnant women to supplement their diet with 60 mg/d of elemental iron. An MCV less than 80 mg/dL and hypochromia of the RBCs should prompt further studies, including total iron-binding capacity, ferritin levels, and Hb electrophoresis if iron deficiency is excluded.

Clinical symptoms of iron deficiency anemia include fatigue, headache, restless legs syndrome, and pica (in extreme situations). Treatment is additional supplementation with oral iron sulfate (320 mg, 1-3 times daily). Iron is preferable once daily because more frequent iron supplementation can cause constipation. The clinical consequences of iron deficiency anemia include preterm delivery, perinatal mortality, and postpartum depression. Fetal and neonatal consequences include low birth weight and poor mental and psychomotor performance.1
Folate and vitamin B-12 deficiency
Folate deficiency is much less common than iron deficiency; however, taking 0.4 mg/d to reduce the risk of neural tube defects is recommended to all women contemplating pregnancy. Patients with a history of neural tube defect should take 4 mg/d. An increased MCV can be suggestive of folate deficiency; in this case, determine serum levels of vitamin B-12 and folate. If the levels are low, the patient may require oral folate at a dose of 1 mg 3 times daily. Patients with vitamin B-12 deficiency need further workup to determine the level of intrinsic factor to exclude pernicious anemia. The Schilling test is not recommended during pregnancy because of the radionuclide used in testing. Treatment of vitamin B-12 deficiency includes 0.1 mg/d for 1 week, followed by 6 weeks of continued therapy to reach a total administration of 2 mg.
Infectious causes of anemia
Although rare, anemia can be caused by infections such as parvovirus B-19, CMV, HIV, hepatitis viruses, EBV, malaria, babesiosis, bartonellosis, and clostridium toxin. If the patient's history suggests exposure to any of these infectious agents, appropriate laboratory studies should be performed.

Diamond-Blackfan anemia

This is a rare (7 per 1 million) autosomal dominant disorder of pure red cell aplasia requiring life-long transfusion. Women who are contemplating or who are pregnant require the consultation and care of a hematologist in conjunction with a Maternal Fetal Medicine specialist. Concerns during pregnancy include maintaining adequate hemoglobin while decreasing the risk of fetal exposure to the iron chelating agent (Deferoxamine) used during transfusions.1

One Patient's Story: Living with and Learning from Thalassemia

August 12, 2010 - High school student Aaron Cheng shares a speech about thalassemia which he recently delivered to his classmates. We share this inspiring testimony with you below.
To My Classmates

Throughout the course of this year you all have learned little snippets about my interests: my passions for science, for music, and for learning in general; however, you do not yet know my whole story. You do not yet understand what has led to my extreme love of learning, my dedication to the sciences, and my goals for the future. And through this speech, I intend to tell you about my greatest passion of all.
My life began - well, when I was born, as lives tend to do. And for a while I lived normally, a chubby little tyke who rolled around on the floor, spending my days observing the world from eleven inches off the ground, philosophizing, getting acquainted with the floor on which I crawled; however, when I was only a few months old, a five-syllable word crudely entered my life and took control of it:
“Thalassemia.”
This seemingly Martian term isn’t as alien as it may appear. In fact, this term describes a blood disease that is carried by over sixty million people in the world. But thalassemia alone isn’t what made me genetically unique. No, doctors discovered soon after my birth that I had the worst form of thalassemia, the form that affects only a thousand people in the United States, the form that renders the victim helpless and completely dependent on blood from other people: beta-thalassemia major. My innocent, happy life came tumbling down around me with this medical discovery.
And my bright, hopeful days as an infant became the darkest days of my life. You see, thalassemia, in simple terms, is a genetic mutation that affects the blood cell and causes it to be unable to carry oxygen. While a red blood cell should be plump and red, my blood is shriveled and useless. The single change in the nucleotide sequence in my DNA that causes this monstrous disease leads to a multitude of problems. Ever since I was born, I’ve had to go to the Miller Children’s Hospital in Long Beach to receive a four- to eight-hour blood transfusion every month. And every day at home I took shots to counteract the iron deposits that have resulted from these transfusions.
Thalassemia is a daunting disease. The victim must receive blood from donors, but in doing so he receives an excess of iron through the transfusion. The very process that is saving his life is killing him. Though there are drugs that help patients excrete iron, the sad fact is that not all the iron exits the body. As a result, iron deposits form in the pituitary gland, the liver, the pancreas, and eventually, the heart. So while the victim of thalassemia usually does not die from lack of functioning blood cells, he eventually dies from heart complications caused by the iron.
My infancy was the most difficult part of my life. Doctors were unable to find suitable veins in my tiny arms, so they stabbed my feet with the needles. Needles often fell out during the course of the transfusion, so one trip to the hospital could mean up to five shots. At home I continued to take shots every day to counteract the deadly iron deposits. By the age of five I had taken more shots than most adults had taken in their lifetime.
I still remember my elementary school days. I was often ostracized because of the frequency of my doctor appointments, and I missed up to three days of school per week. And when I realized that the blood that was being pumped into my body was from other living people, I felt like a vampire. Not as shiny and awesome as Edward Cullen, but a vampire nonetheless. It was during my elementary school days that I resolved to repay all of my blood donors for their generosity, to pay back all of my doctors for all the work they had put into me.
Through middle school I immersed myself in the world of academia, motivated to help the medical community all I could. Whenever I felt exhausted of studying, it only took one more visit to the hospital, one more transfusion, to make me work at full speed once again. I was determined to make an impact on the medical community, to ensure that everybody with disease as devastating as thalassemia would be able to fulfill happy, productive lives.
Upon entering high school I joined every club associated with academics that I could, such as the Academic Decathlon, science club, and math club, with the hopes of being as prepared for my future as possible. And my internal drive to learn and to contribute to society continues even as I speak.
As I write this, I realize that within thalassemia is a hidden jewel: the treasure of dedication and passion. Thalassemia is no longer a monster to me; rather, it is part of me, and it breathes the fire of passion and inspiration throughout my body. What was once a weakness, a flaw, is now my prized gem. The darker my circumstances, the brighter its light will shine. It is because of thalassemia that the motivation to succeed runs through my veins. It is because of thalassemia that I have learned to endure pain. And it is because of thalassemia that I am able to lead a productive, albeit shortened, life today.
There is something I want you all to take away today from my experience, since I’m not just up here to say my life story. Always embrace obstacles, for obstacles are actually valuable lessons cleverly disguised. Without confronting obstacles you will never grow. Obstacles will never crush you as long as you have the resolve to overcome them.

Gene Therapy Breakthrough Heralds Treatment for Beta-Thalassemia

Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (ß-globin) in patients' blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients The disorder β-thalassemia, also known as Cooley's anemia, is caused when a patient cannot produce enough of the ß-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of ß-globin causes life threatening anemia, leading to severe damage of the body's major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations.

"Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients," said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. "Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder."

Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient's bone marrow. The team developed a tool to deliver the correct gene for ß-globin into these harvested cells, a viral vector they called GLOBE.

The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.
This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research

"This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish," said Williams. "Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward." As the Milan based team can now correct the defective production of beta-globin in patients' blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.

Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients" concluded Ferrari. "We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector."
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Experimental treatment for sickle cell disease enters Phase 3 clinical trials

An experimental treatment for sickle cell disease developed at the Los Angeles Biomedical Research Institute (LA BioMed) has entered Phase 3 clinical trials, David I. Meyer, PhD, LA BioMed president and CEO announced today.
Researchers throughout the U.S. have begun administering the sickle cell treatment developed by investigators led by Yutaka Niihara, MD, MPH, at LA BioMed and licensed to Emmaus Medical, Inc. The patented drug treatment involves the oral administration of L-glutamine, which is the most common amino acid in the body. This is one of a very few experimental treatments for sickle cell disease to reach the Phase 3 clinical trial stage.
Sickle cell disease is an inherited disorder that causes red blood cells to become oxidized, sticky and sickle shaped instead of smooth, pliable and round. Sickle cell disease leads to anemia, organ damage, chronic and acute pain and a host of other problems.

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"This is exciting news in the potential development of a novel new treatment for the millions of people who suffer from the painful effects of sickle cell disease," said Dr. Meyer. "We are proud of the dedication of Dr. Niihara and the team of researchers who first developed this treatment. They demonstrate the pioneering spirit that has kept LA BioMed at the forefront of translating discoveries into treatments that can transform lives."
Phase 3 clinical trials are large, randomized studies conducted at multiple sites to determine the safety and efficacy of a potential treatment. They are usually the last clinical trials conducted before the Food and Drug Administration gives its approval for a treatment to be made widely available to the patient population.
"As a physician I have seen firsthand the severe pain in patients with sickle cell disease, so I am very pleased we have reached this stage in our development of this potential treatment," said Dr. Niihara. "In the Phase 2 clinical trial, we observed an excellent safety profile and positive trends in decreasing the number of crises as well as reducing the frequency of hospitalizations in sickle cell disease patients. We look forward to the findings from the much larger group of research volunteers we will be seeking in the Phase 3 clinical trial."
In the Phase 3 clinical trial, researchers at 20 to 25 sites around the country will be seeking up to 225 research volunteers, age 5 years and older, with a diagnosis of sickle cell anemia or sickle beta O-thalassemia who have a history of at least two episodes of painful crisis during the past 12 months. The trial is a 53-week study requiring monthly visits to the research facility.

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Source: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed)

Beta-Thalassemia: Gene Therapy Breakthrough

Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (β-globin) in patients' blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients.

The disorder β-thalassemia, also known as Cooley's anemia, is caused when a patient cannot produce enough of the β-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of β-globin causes life threatening anemia, leading to severe damage of the body's major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations.

"Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients," said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. "Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder."

Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient's bone marrow. The team developed a tool to deliver the correct gene for ß-globin into these harvested cells, a viral vector they called GLOBE.

The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.

This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research

"This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish," said Williams. "Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward." As the Milan based team can now correct the defective production of beta-globin in patients' blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.

Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients" concluded Ferrari. "We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector."

Source:
Ben Norman
Wiley-Blackwell

Researchers discover genetic explanation for non-diabetic kidney disease in African-Americans

Variants in the APOL1 gene help explain high rates of renal disease in individuals of recent African ancestry; authors speculate that these variants originally evolved as a survival mechanism against parasitic disease in Africa
Kidney disease is a growing public health problem, with approximately half a million individuals in the United States requiring dialysis treatments to replace the function of their failed kidneys. The problem is particularly acute among African-Americans, whose rates of kidney disease are four times higher than those of European Americans.

As reported online this month by the journal Science, collaborating research groups found that patients with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) harbored variants in the APOL1 gene that changed the ApoL1 protein sequence. These variants are commonly found in individuals of recent African ancestry.

Furthermore, in a twist of evolutionary medicine, the disease-causing variants may have protected Africans against a lethal parasite, explaining why these genetic variants are so common in the population today.
Researchers at Wake Forest University Baptist Medical Center contributed to and participated in this scientific team, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Universite Libre de Bruxelles. Together, they discovered a genetic explanation - with evolutionary roots - for the higher incidence of non-diabetic kidney disease in African-Americans.

"We found that the APOL1 risk genes for renal disease occur in more than 30 percent of African-American chromosomes," explained co-senior author Martin Pollak, M.D., chief of nephrology at BIDMC and associate professor of medicine at Harvard Medical School. "In fact, the increased risk of kidney disease in individuals who inherited two copies of these variant forms of APOL1 is reported to be approximately 10-fold."
FSGS is a form of injury to the kidney's filtering system, which causes proteins to be lost into the urine and gradually reduces kidney function. ESKD, or end-stage kidney disease, is defined by kidney failure that has progressed to the point that the patient requires dialysis or kidney transplantation.

It has long been thought that high blood pressure is a common cause of end stage kidney disease in African-Americans," said study co-researcher Barry Freedman, M.D., John H. Felts III Professor and chief of the section on nephrology at WFUBMC. "However, the strong association between variants in the APOL1 gene and hypertension-attributed kidney disease suggested that this kidney disease truly resides in the spectrum of FSGS and is not due to hypertension as was initially believed."
More than 2,000 study participants from the southeastern United States were recruited to the study by WFUBMC.

Last year, Freedman led a team of WFUBMC researchers who found that genetic variation near the MYH9 gene on chromosome 22 was also associated with increased risk of hypertension-attributed kidney disease in African-Americans. However, because genome analyses had shown a strong signal of natural selection in the region containing both the MYH9 and APOL1 genes, the authors reasoned that the location of the disease-causing genetic variants was in a broader region. They also predicted that the frequency of these variants would be markedly different between European-Americans and Africans.

Using data from the 1000 Genomes Project DNA data bank, the authors identified candidate genetic variants and tested for their presence in DNA sample sets. They found that two APOL1 variants - dubbed G1 and G2 - were associated with an increased risk of both FSGS and hypertension-attributed ESKD in African-Americans.
"G1 and G2 both changed the coding sequence of APOL1," Pollak explained. "Further analyses revealed that these very same genetic variants [G1 and G2] conferred human immunity against the parasite responsible for sleeping sickness."

African sleeping sickness is caused by an African trypanosome parasite, which is transmitted by the tsetse fly. The disease, which produces severe nervous system disorders that can ultimately lead to brain damage, coma and death, is estimated to affect tens of thousands of people, but is not found outside of Africa.
The APOL1 protein circulates in the blood and helps defend against trypanosomes, a finding initially discovered by co-senior author Etienne Pays, Ph.D., of the Universite Libre de Bruxelles, in Belgium. In the current study, Pays' laboratory found that the plasma from patients harboring the G1 and G2 variants inactivated the trypanosomes that cause the deadliest forms of African Sleeping Sickness, as did the APOL1 protein with these same variants inserted.

"We were excited that our findings appeared to relate kidney disease in the United States with human evolution and parasite infection in Africa," Pollak said. "While there are many details that remain to be clarified in future studies, we do know that sickle-cell disease is a well-established precedent for this model, in which one copy of the mutation confers protection against a parasitic infection but two copies of the mutation can cause severe disease." Pollak explained that, when present in a single copy, certain hemoglobin mutations protect against malaria. But two copies cause sickle cell disease or thalassemia, severe red-blood cell diseases.
"It appears that we may have found a similar situation in APOL1," Pollack added. "Consequently, while these genetic variants protect against sleeping sickness, they also greatly increase a person's susceptibility to kidney disease. We hope that these new findings will not only lead us to a better understanding of the underlying mechanisms leading to kidney failure, but will also help us develop new ways to treat trypanosome infection and kidney disease."

Pregnancy: Should I bank my baby's umbilical cord blood?

Your options
• Have your baby's cord blood collected and sent to a private cord blood bank or a public cord blood bank.
• Do not bank or donate your baby's cord blood.

Key points to remember•
Doctors do not recommend that you bank cord blood on the slight chance that your baby will need stem cells someday. If your baby were to need stem cells, he or she would probably need stem cells from someone else rather than his or her own stem cells.1
• Although privately banked cord blood is not likely to help your baby, it may help a sibling who has an illness that could be treated with a stem cell transplant. These include leukemia, sickle cell disease, Hodgkin's lymphoma, and thalassemia. Doctors recommend that you bank your baby's cord blood only if a family member already has one of these illnesses.
• You might consider donating the cord blood to a public bank instead. You probably won't be able to use the blood, but it could be used for research or for another child.
• Private cord blood banking is expensive. You will pay a starting fee of about $1,000 to $2,000, plus a storage fee of around $100 a year for as long as the blood is stored.
• If you want to save the cord blood, you must arrange for it ahead of time. It is not a decision you can make at the last minute.
• Collecting the cord blood does not cause pain.

What is umbilical cord blood?
Cord blood is the blood left in the umbilical cord after birth. It contains stem cells. These cells have the amazing ability to grow into many different kinds of cells, like bone marrow cells, blood cells, or brain cells. This can make them valuable for treating some diseases.

Diseases that can be treated with stem cell transplants include leukemia, Hodgkin’s disease, and some types of anemia. When healthy stem cells are transplanted into a child who is ill, those cells can grow new bone marrow cells to replace the ones destroyed by the disease or its treatment. Stem cells from the child's own cord blood often cannot be used, because they may have led to the disease in the first place.

Much research is being done to see if stem cells can be used to treat more problems. For now, though, treatment is limited to diseases that affect blood cells.
Cord blood kept in a private bank is usually used to treat disease in a brother or sister. Cord blood stem cells are rarely used to treat adults, who normally need more stem cells than cord blood has.

What is cord blood banking?
The umbilical cord is usually thrown away after birth. But the blood inside the cord can be saved, or banked, for possible later use. The blood is drawn from the umbilical cord after the cord has been clamped and cut. Cord blood banks freeze the cord blood for storage.

You may save your baby's cord blood in a private bank or donate it to a public bank. Private banks charge a fee to store cord blood for your family's use. If you donate the cord blood to a public bank, the cord blood can be used by anyone who needs it.
During your pregnancy, you may get ads or brochures from private cord blood banks. Some of them suggest that parents should save the cord blood in case the baby should one day need a stem cell transplant. Be wary of banks that urge cord blood banking for this reason. It is not known how likely a child is to need a transplant of his or her own cells, but experts say the chances are very small.1

Private cord blood banks have collected hundreds of thousands of cord blood samples. But the blood has been used in only a small number of transplants.2 Most transplants of cord blood stem cells use cord blood donated by others to public banks.
One reason why donations to public cord banks are so valuable is that stem cells from cord blood do not need to be as perfectly matched for a transplant as do stem cells from adult bone marrow. Stem cells from cord blood are not as mature, so the transplant patient's body is much less likely to reject them.

What are the risks of cord blood banking?
Collecting a baby’s cord blood is quick and does not cause pain. But it does have a small risk. The umbilical cord must not be clamped and cut too soon. Clamping as soon as possible increases how much blood is collected. But if it is done too quickly, it could cause the baby to have less blood. This could lead to anemia.
It is very unlikely that anyone in your family will ever need your baby's cord blood. The only people likely to use privately banked blood are those who already have a child with an illness that could be treated with cord blood from a baby brother or sister.1
It costs money to store your baby’s cord blood. Private banks charge about $1,000 to $2,000 to start. Then you must pay yearly storage fees for as long as the blood is stored. The storage fees cost $115 to $125 a year. Health plans usually do not cover these costs. Only you can decide if the cost makes sense for you and your family.
Doctors worry that the advertising done by private cord blood banks may make some parents feel guilty if they do not want or cannot pay to store their baby’s cord blood. Pregnancy and childbirth are emotional times, so learn all you can ahead of time.

What other things should you consider?
The American Academy of Pediatrics says storing cord blood in a private bank without a medical reason is not wise. This group of doctors recommends that you consider it only if a family member has a disease that could be treated with a stem cell transplant.3
Some private blood banks will waive their fees for families who need the stem cells right away.
If you bank or donate your baby's cord blood, it will be tested for genetic and infectious diseases. What you learn from a genetic test can affect your life and that of your family in many ways.
• Learning that your child is likely to develop a serious disease can be scary or depressing. This information may also affect your relationships with other family members.
• If your child tests positive for a gene that will cause a disease, you may decide to use treatment, if available, to prevent the disease or to make it less severe. Although many treatments work well, others may be unproven or may even be dangerous.
• Some people worry that gene test results will make it hard to get insurance.

Private banking: If you decide to bank your baby's cord blood, make sure that the blood bank you use is approved by a reputable regulatory agency, such as the American Association of Blood Banks. Look for a bank that has tested and stored many cord blood samples and whose samples have been used successfully in transplants. Ask for a copy of the bank's policies and procedures.

Public banking: You may decide that you would like to donate your baby’s cord blood. Donating makes the stem cells available to others. It does not cost anything. Unfortunately, it is not yet an option in many communities. Call the hospital where you plan to give birth to find out if you can donate cord blood there.

Why might your doctor recommend banking your baby's cord blood?
Your doctor might recommend privately banking your baby's umbilical cord blood if:
• You have another child who has a disease that could be treated with a stem cell transplant.

Compare your options
Bank cord blood Bank cord blood
What is usually involved?
• Long before birth, you arrange to bank your baby's cord blood.
• The blood is drawn from the umbilical cord after the cord has been clamped and cut.
• A cord blood bank freezes the cord blood for storage.

What are the benefits?•
Cord blood in a private bank could be used for a sibling who has an illness that can be treated with cord blood from a baby brother or sister.
• Giving the blood to a public cord bank could help research or some other child who needs it.

What are the risks and side effects?
• If the cord is clamped and cut too soon, your baby may become anemic.
• Private cord banking costs a lot. Banks charge $1,100 to $1,750 to start storage, then fees of more than $100 a year.
• Cord blood is tested for diseases. You could find out about a gene that may one day give your child a disease. This news could affect health insurance and job options.
Don't bank cord blood Don't bank cord blood

What is usually involved?
• The umbilical cord is thrown away after birth.
What are the benefits?
• You save money by not putting blood in a private cord bank.
• You avoid the small risk that the cord could be clamped and cut too soon. With less blood, the baby may become anemic.
What are the risks and side effects?
• Your child could later get an illness that could have been treated with a stem cell transplant. But experts say the chance that a child will need a transplant of his or her own cells is very small.1

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Alpha thalassemia X-linked mental retardation syndrome

What is alpha thalassemia X-linked mental retardation syndrome?
Alpha thalassemia X-linked mental retardation syndrome is an inherited disorder that affects many parts of the body. This condition occurs almost exclusively in males.
Males with alpha thalassemia X-linked mental retardation syndrome have intellectual disability and delayed development. Their speech is significantly delayed, and most never speak or sign more than a few words. Most affected children have weak muscle tone (hypotonia), which delays motor skills such as sitting, standing, and walking. Some people with this disorder are never able to walk independently.
Almost everyone with alpha thalassemia X-linked mental retardation syndrome has distinctive facial features, including widely spaced eyes, a small nose with upturned nostrils, and low-set ears. The upper lip is shaped like an upside-down "V," and the lower lip tends to be prominent. These facial characteristics are most apparent in early childhood. Over time, the facial features become coarser, including a flatter face with a shortened nose.
Most affected individuals have mild signs of a blood disorder called alpha thalassemia. This disorder reduces the production of hemoglobin, which is the protein in red blood cells that carries oxygen to cells throughout the body. A reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues. Rarely, affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, and fatigue.
Additional features of alpha thalassemia X-linked mental retardation syndrome include an unusually small head size (microcephaly), short stature, and skeletal abnormalities. Many affected individuals have problems with the digestive system, such as a backflow of stomach acids into the esophagus (gastroesophageal reflux) and chronic constipation. Genital abnormalities are also common; affected males may have undescended testes and the opening of the urethra on the underside of the penis (hypospadias). In more severe cases, the external genitalia do not look clearly male or female (ambiguous genitalia).

How common is alpha thalassemia X-linked mental retardation syndrome?Alpha thalassemia X-linked mental retardation syndrome appears to be a rare condition, although its exact prevalence is unknown. More than 200 affected individuals have been reported.

What genes are related to alpha thalassemia X-linked mental retardation syndrome?
Alpha thalassemia X-linked mental retardation syndrome results from mutations in the ATRX gene. This gene provides instructions for making a protein that plays an essential role in normal development. Although the exact function of the ATRX protein is unknown, studies suggest that it helps regulate the activity (expression) of other genes. Among these genes are HBA1 and HBA2, which are necessary for normal hemoglobin production.
Mutations in the ATRX gene change the structure of the ATRX protein, which likely prevents it from effectively regulating gene expression. Reduced activity of the HBA1 and HBA2 genes causes alpha thalassemia. Abnormal expression of other genes, which have not been identified, probably causes developmental delay, distinctive facial features, and the other signs and symptoms of alpha thalassemia X-linked mental retardation syndrome.

How do people inherit alpha thalassemia X-linked mental retardation syndrome?
This condition is inherited in an X-linked recessive pattern. The ATRX gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), one working copy of the ATRX gene can usually compensate for the mutated copy. Therefore, females who carry a single mutated ATRX gene almost never have signs of alpha thalassemia X-linked mental retardation.
A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What other names do people use for alpha thalassemia X-linked mental retardation syndrome?• alpha-thalassemia/mental retardation syndrome, nondeletion type
• alpha thalassemia/mental retardation, X-linked
• alpha-thalassemia X-linked mental retardation syndrome
• ATRX syndrome
• ATR-X syndrome
• X-linked alpha-thalassemia/mental retardation syndrome
• XLMR-hypotonic face syndrome

Immunization in Children and Adults who have Thalassemia

General Recommendations
Children who have thalassemia trait should be treated and immunized in a manner identical to all other children. The United States Center for Disease Control (CDC) has recently published an immunization schedule for 1998. This schedule represents the latest recommendations of this United States Government body. Their recommendations cover Hepatitis B vaccination, to be completed in the first year of life. Diphtheria, tetanus, and pertussis vaccination initially completed in the first 18 months of life with booster vaccination between 4 and 6 years and an adult tetanus booster between 14 and 16 years. Haemophilus influenzae conjugate vaccination completed by 15 months. Polio vaccination completed by 4 to 6 years, the first two vaccine doses optionally being the Salk IPV killed vaccine followed by the Sabin live oral vaccine. Measles, mumps and rubella vaccination completed by the age of 4 to 6 years. Varicella vaccine is recommended before the age of 18 months.

Hepatitis A VaccineChildren who have thalassemia intermedia or thalassemia major receive the above vaccines. In addition transfused children who test negative for Hepatitis A should be immunized against this virus whether or not they have been infected with Hepatitis C. Infection with Hepatitis A after infection Hepatitis C can lead to fulminant disease. It is not know whether late infection with this virus can cause worse hepatitis in individuals co-infected with other hepatitis viruses or with severe hemosiderosis.

Pneumococcal Vaccination
All children are immunized against Streptococcus pneumoniae with the 23-valent pneumococcal polysaccharide vaccine prior to splenectomy and boosters given every five years if their pneumococcal immunoglobin titers are negative. The conjugate pneumococcal vaccine is now available and should be considered for infants who have the possibility of early splenectomy; children who have Hemoglobin H Constant Spring might fall into this category. Children who have sickle thalassemia syndromes such as Sickle Beta Zero Thalassemia and Sickle Beta Plus Thalassemia should also receive either the conjugate vaccine as infants or the polysaccharide vaccine if they are over two years old. All children should receive boosters if they have negative titers to Streptococcus pneumoniae.

Influenza Vaccine
All children who have thalassemia intermedia or major should receive the influenza vaccine beginning at the age of six months (split vaccine with a booster the first season). Children who have other risk factors should also receive this vaccine.
HIV Infected Children
Children who are immune suppressed with HIV viral infection should not receive live virus vaccines: Measles, Mumps, Rubella; Oral Polio Vaccine; Varicella Vaccine. Nor should their siblings receive these vaccines without medical management to prevent infection of the immunosuppressed child.

Recommendations for children infected with the human immunodeficiency virus (HIV):
• All routine inactivated vaccines (IPV, Hib, Hepatitis B, and DTaP) are recommended for all children.
• Children who are six months or older receive the influenza vaccine (split dose with booster during the first season).
• Children who are two years old or older receive pneumococcal vaccine.
• The MMR vaccine is recommended only for children infected with HIV who are not severely immune compromised.
• Live virus vaccines are contraindicated in all children who are infected with HIV with the above exception.

Children Receiving Intravenous Gamma Globulin
Children who are receiving intravenous gamma globulin (IVIG) have the possibility that live virus vaccines will be inactivated or that they will not develop immunity.
Children After Bone Marrow Transplantation
Centers performing bone marrow transplantation each have their own preferred schedule for reimmunization of their patients. These schedules should be followed. After immunocompentence is documented and all other immunizations are complete these children should receive the influenza vaccination annually.

Other VaccinesNew vaccines are being developed and will be available periodically. The Rotavirus Vaccine has recently been released and is not specifically indicated for children who have thalassemia.
The meningococcal vaccine is available, but is not generally recommended in most references. It would be indicated for splenectomized children and adults. This vaccine is not thought to be optimal and is not routinely administered at this center.

Gene therapy represents safe alternative to current cures for blood disorder β-thalassemia

Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (β-globin) in patients' blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients.
The disorder β-thalassemia, also known as Cooley's anemia, is caused when a patient cannot produce enough of the β-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of β-globin causes life threatening anemia, leading to severe damage of the body's major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations
"Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients," said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. "Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder."
Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient's bone marrow. The team developed a tool to deliver the correct gene for β-globin into these harvested cells, a viral vector they called GLOBE.
The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.
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This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research.
"This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish," said Williams. "Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward." As the Milan based team can now correct the defective production of beta-globin in patients' blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.
Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients" concluded Ferrari. "We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector."
Source EMBO Molecular Medicine

Indian children with AIDS from infected blood transfusions

by Nirmala Carvalho
Children with thalassemia need blood transfusions for treatment. In five years it has happened to thousands of children. Inadequate controls in Indian blood banks. For Pascoal Carvalho, immunologist and member of the Pontifical Council for Life, the solution exists and costs 16 euros: "We want the NAT, but the government must give subsidies to those who can’t afford it."
Jaipur (AsiaNews) - Three children who suffer from thalassemia in Jodhpur in Rajasthan this week contracted HIV after blood transfusions required to treat the disease. It is not the first time that such cases occur in India. According to statistics, over the past five years thousands of children have fallen ill with AIDS after blood transfusion from the state blood bank.
Marwar Thalassemic Society says that in the last six months eight children have contracted HIV and hepatitis C for 43 additional transfusions of infected blood. The three children are in care at the Ummed Hospital which treats children with thalassemia free of charge. Hospital managers said they had scrupulously followed the guidelines of the National AIDS Control Organization. Both hospitals blood banks are testing to verify that the donated blood is healthy, but often this is not enough.
"Tests of blood cells are not adequate," Pascoal Carvalho, immunologist and member of the Pontifical Council for life tells AsiaNews. "We need the Nucleic Acid Testing (NAT), but since it has a very high cost it is not always done".
Performing NAT on the blood cost 1000 rupees (16 Euros) and in most cases the cheaper Elisa test is carried out: "The Elisa test" continues the doctor, "often fails to identify the HIV virus, especially since detects it only after the virus has been circulating in the donor’s blood for three months".
India’s health system is well aware of the technologies needed to solve the problem, but does not invest: "The government must urgently upgrade its monitoring system in blood banks. The problem of infection is even more tragic because they are poor families who use government blood banks.
For Pascoal Carvalho, the only positive note is that better therapies are being introduced to treat thalassemia. But the doctor calls the government on its responsibilities: "The instruments for Nat cost 400 thousand rupees (6700 million) and 1000 rupees each test, but poor patients can not afford it. Only the government can require that Nat be used in all hospitals and blood banks and provide subsidies for those who must take the test. Only then will we avoid similar tragedies in India. "
Fr. Antonio Grugni, PIME missionary and doctor in Mumbai, told AsiaNews about the health situation in India: "The number of poor in India is enormous and they can only afford public health, where there are few doctors for a huge amount of patients. You can not say that the government does nothing: the cure for tuberculosis and leprosy are free, for example. It is not true that in India there is no money. There are but are often misused by individual states".

Bone Marrow Stem Cells Reverse Sickle Cell Disease

By Drew Halley
A revolutionary new procedure for stem cell transplant is reversing the effects of severe adult sickle cell disease. For years, adults suffering from sickle cell anemia have relied on consistent blood transfusions and drug treatments to combat the disorder. Bone marrow transplants can reverse sickle cell, but have so far been restricted to children in the early stages of the disease. That is, until now.
Sickle cell anemia is a congenital blood disorder that affects all races, but is most common to persons with African ancestry, affecting about 72,000 in the US and millions worldwide. Red blood cells normally take the shape of a doughnut without its hole; in the blood of sickle cell patients, the cells assume an abnormal sickle shape. Sickle cells block small blood vessels and inhibit blood flow, which causes debilitating pain, damages organs and increases the risk of stroke. Many of the risks of sickle cell can be mediated through early diagnosis, dietary supplements, and drug treatment. But even with modern treatment, life expectancy for sickle cell patients is 42 in males, 48 in females. Some severe cases are resistant to existent therapies and can cut life even shorter.
Because red blood cells are produced in bone marrow, some high-risk children qualify for marrow transplants from a suitable sibling donor. Like all organ transplants, the procedure carries the danger of immune rejection, and so requires immunosuppressant drugs in addition to radiation therapy to kill diseased marrow. Transplants have been traditionally restricted to children, whose organs are comparably stronger than adults who suffer from the disease. Transplants are rare – there have been about 200 in the past few decades – and are attempted only in children whose disorders are life-threatening.
But a new procedure developed by the National Institute of Health (NIH) and Johns Hopkins University has successfully transplanted marrow to adults, reversing the disorder in 9 out of 10 patients. The new treatment uses significantly less radiation (about one fourth) to kill the patient’s existent marrow, combined with the immunosuppressant drug Sirolimus to reduce the likelihood of transplant rejection. By allowing more of the patient’s own marrow to remain, recovery from the transplant is faster and healthier (patients could previously spend months in germ-free isolation while their immune systems recovered). Thirty months after the transplant, the nine patients with successful transplants are healthy and show no side effects.
Many adults with sickle cell anemia take the drug hydroxyurea to treat the disorder. Hydroxyurea works by stimulating the body to produce a form of hemoglobin normally only found during development in the womb. The production of this hemoglobin type helps to balance the proportion of healthy vs. sickle cells in the blood, and reduces the damage done to lungs, kidneys, and liver (not to mention the risk of stroke). But hydroxyurea doesn’t work for all adult patients, making the prospect of adult marrow transplant a much-needed form of alternative therapy.

Kelly Halloway, the first half-match donation recipient at the National Institute of Health
So far, most adult patients who have received marrow transplants have had “full match” donors – siblings with a fully compatible genetic makeup. The chances of a sibling being fully matched are only 25%. But new procedures are expanding the pool of potential donors to “half match” donors, which includes parents and improves the likelihood of a compatible sibling to 75%. That means more sources of transplant marrow, and a better shot at a successful reversal of the disease.

Future research will aim to expand marrow transplants beyond sickle cell patients. Several other congenital blood diseases could conceivably be treated with marrow transplants, including such debilitating disorders as beta-thalassemia.Researchers are currently exploring the emerging possibilities of adult marrow transplants, and will doubtless yield more amazing treatments in coming years