Cure for sickle cell in adults validated

Source:

University of Illinois at Chicago

Summary:

Physicians have cured 12 adult patients of sickle cell disease using a unique procedure for stem cell transplantation from healthy, tissue-matched siblings. The new technique eliminates the need for chemotherapy to prepare the patient to receive the transplanted cells and offers the prospect of cure for tens of thousands of adults suffering from sickle cell disease.

Ieshea Thomas was the first adult to be cured of sickle cell disease with the chemotherapy-free procedure at UI Health.

Credit: Image courtesy of University of Illinois at Chicago

Physicians at the University of Illinois Hospital & Health Sciences System have cured 12 adult patients of sickle cell disease using a unique procedure for stem cell transplantation from healthy, tissue-matched siblings.

The transplants were the first to be performed outside of the National Institutes of Health campus in Maryland, where the procedure was developed. Physicians there have treated 30 patients, with an 87 percent success rate. The results of the phase I/II clinical trial at UI Health, in which 92 percent of treated patients were cured, are published online in the journal Biology of Blood & Marrow Transplantation.
The new technique eliminates the need for chemotherapy to prepare the patient to receive the transplanted cells and offers the prospect of cure for tens of thousands of adults suffering from sickle cell disease.
About 90 percent of the approximately 450 patients who have received stem cell transplants for sickle cell disease have been children. Chemotherapy has been considered too risky for adult patients, who are often more weakened than children by the disease.
"Adults with sickle cell disease are now living on average until about age 50 with blood transfusions and drugs to help with pain crises, but their quality of life can be very low," says Dr. Damiano Rondelli, chief of hematology/oncology and director of the blood and marrow transplant program at UI Health, and corresponding author on the paper.
"Now, with this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just one month of the transplant," said Rondelli, who is also the Michael Reese Professor of Hematology in the UIC College of Medicine. "They are able to go back to school, go back to work, and can experience life without pain."
Sickle cell disease is inherited. It primarily affects people of African descent, including about one in every 500 African Americans born in the U.S. The defect causes the oxygen-carrying red blood cells to be crescent shaped, like a sickle. The misshapen cells deliver less oxygen to the body's tissues, causing severe pain and eventually stroke or organ damage.
Sickle Cell Natural Healing: A Mother's Journey
Doctors have known for some time that bone marrow transplantation from a healthy donor can cure sickle cell disease. But few adults were transplanted because high-dose chemotherapy was needed to kill off the patients' own blood-forming cells -- and their entire immune system, to prevent rejection of the transplanted cells, leaving patients open to infection.
In the new procedure, patients receive immunosuppressive drugs just before the transplant, along with a very low dose of total body irradiation -- a treatment much less harsh and with fewer potentially serious side effects than chemotherapy.
Next, donor cells from a healthy and tissue-matched sibling are transfused into the patient. Stem cells from the donor produce healthy new blood cells in the patient, eventually in sufficient quantity to eliminate symptoms. In many cases, sickle cells can no longer be detected. Patients must continue to take immunosuppressant drugs for at least a year.
In the reported trial, the researchers transplanted 13 patients, 17 to 40 years of age, with a stem cell preparation from the blood of a tissue-matched sibling. Healthy sibling donor-candidates and patients were tested for human leukocyte antigen, a set of markers found on cells in the body. Ten of these HLA markers must match between the donor and the recipient for the transplant to have the best chance of evading rejection.
In a further advance of the NIH procedure, physicians at UI Health successfully transplanted two patients with cells from siblings who matched for HLA but had a different blood type.
In all 13 patients, the transplanted cells successfully took up residence in the marrow and produced healthy red blood cells. One patient who failed to follow the post-transplant therapy regimen reverted to the original sickle cell condition.
None of the patients experienced graft-versus-host disease, a condition where immune cells originating from the donor attack the recipient's body.
One year after transplantation, the 12 successfully transplanted patients had normal hemoglobin concentrations in their blood and better cardiopulmonary function. They reported less pain and improved health and vitality.
Four of the patients were able to stop post-transplantation immunotherapy without transplant rejection or other complications.
"Adults with sickle cell disease can be cured without chemotherapy -- the main barrier that has stood in the way for them for so long," Rondelli said. "Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications."

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Story Source:
The above post is reprinted from materials provided by University of Illinois at Chicago. The original item was written by Sharon Parmet. Note: Content may be edited for style and length.

Daniella Macolino a 24 year old actress who pursues her dreams each day while living, and thriving, with thalassemia major

When I was four months old, my family and I were on vacation in Vermont when my mom noticed I was turning yellow after my older brother took me out in the snow. She overlooked it, thinking I may have just been tired from all the traveling and playing outside. But the next day I was looking worse with bags under my eyes, so my parents rushed me to the hospital. The doctor ran some tests and broke the news to my parents that I have thalassemia major, also known as Cooley’s Anemia. Not only would I need a blood transfusion right away, I would also need to continue receiving transfusions every two weeks for the rest of my life in order to survive.

My mother was born and raised in France, and she came to America not speaking any English. Neither of my parents had any knowledge that they carried the thalassemia trait and had never even heard of it before my diagnosis. Since then, my parents have become my biggest advocates and made sure I grew up with an amazing support system of friends and family. My siblings, Paul, Joseph, and Victoria, understand what I go through and don’t look at me any differently.
Living with thalassemia has been difficult, especially as a teenager. I wanted to be like my friends—go out and have sleepovers—but couldn’t because I had to be home to take my Desferal injection. This nightly routine requires me to sleep with a needle pumping medication into my body to remove the deadly iron buildup caused by receiving frequent blood transfusions. I hated it, and it was very inconvenient for me. It was frustrating waking up with bruises on my legs and arms from the needle being in all night.

Beyond that, it was hard trying to fit in while feeling so different because I had an illness and had to go to the hospital frequently. I only told a few of my closest friends that I had this disorder. Now that I am older and more confident, I am very open about sharing my experience with everyone. This illness isn’t going to define who I am, but it will make me stronger and I know that’s why people are inspired by my story!

Isabella's Journey: Her Battle with the Blood Disorder, Thalassemia Major.

 The Cooley’s Anemia Foundation has been so amazing to me and my family. I can contact the Foundation anytime I have questions or need anything and they are there for me. The amount of gratitude I have for them, I can’t even put into words! I have been able to meet the most amazing people by attending Foundation conferences and other events. We are a true community, supporting each other’s passions, goals, and dreams.
It is so important to get involved with and support the Foundation, especially if you or someone you know has thalassemia. I know I can speak on behalf of patients like me when I say that getting involved is worth it because we are raising public awareness of our disorder as well as funds for medical research. One day, there will be a cure and I believe it will come sooner than expected!

“Choose a job you love, and you will never have to work a day in your life.” -Confucius
I believe that no matter what, everyone should follow their dreams and
no obstacle should stand in the way of accomplishing that! Those who know me know that I am pursuing an acting career and I have been for a while now. I don’t know exactly what it is about being in front of the camera or on stage that makes me feel amazing… but I know that I could not live without acting.
I’ve had to sacrifice so many things in order to keep doing what I love, but I’m no stranger to challenges! This is what I want to do and I will never give up. All the hard work is paying off because each year, I find myself doing better and better in my acting career. From January to May of this year I played a leading role in an independent feature film called The Prey—look out for it in October! And in August, I will be in a short horror film which I am really excited about. Tonight, I appear in an episode of The Perfect Murder on the ID channel. It is so crazy to even think that I have made it this far! Even though I put myself down every now and then thinking that I should be doing more, I am still really proud of what I have accomplished so far.
My advice to other thalassemia patients is to not look at yourself any differently than anyone else. Live your life day by day. Do what you love and don’t listen to anyone who puts you down, because at the end of the day you are a strong individual capable of doing what you want!
Just always remember to be safe and take care of yourself. It is important to be compliant by doing your chelation EVERY DAY and staying on schedule with blood transfusions. If you’re tired or feeling ill, don’t put it to the side! Your health comes first no matter what.
Thalassemia is rare and I know many people have not heard about it, but it is just as dangerous as any other chronic illness. Every patient is different and there is a wide range of complications. Please help us raise awareness and if you have never gotten your blood tested, visit your doctor to see if you carry the trait.

Scientists find new way to use CRISPR gene editing to help fix sickle cell disease

An international team of scientists led by researchers at St. Jude Children's Research Hospital has found a way to use CRISPR gene editing to help fix sickle cell disease and beta-thalassemia in blood cells isolated from patients. The study, which appears online today in Nature Medicine, provides proof-of-principle for a new approach to treat common blood disorders by genome editing.
"Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin," said Mitchell J. Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology and one of the study's lead authors. "It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits."
Fetal and adult hemoglobin are two different molecular forms of the essential oxygen-carrying molecule in red blood cells. Hemoglobins are made up of different combinations of four molecular subunits. Sickle cell disease and beta-thalassemia are caused by mutations in a gene encoding an adult-expressed subunit termed "beta." Disease becomes apparent after birth as the levels of adult hemoglobin take hold and levels of fetal hemoglobin decline. These mutations can affect the survival of red blood cells and inhibit oxygen delivery to tissues, causing impaired function of different organs with devastating consequences for patients. Fetal hemoglobin lacks beta subunits and has gamma subunits instead. Thus, beta-thalassemia or sickle cell disease–associated mutations, which impair the production or function of the beta subunit, do not cause problems with fetal hemoglobin, which can transport oxygen effectively in adults.
Experts have known for some time that inhibiting or reversing "gamma-to-beta" switching of hemoglobin subunits can raise levels of fetal hemoglobin in adults and significantly ameliorate the debilitating symptoms of beta-thalassemia or sickle cell disease.

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"Our work has identified a potential DNA target for genome editing–mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia," added Weiss. "We have been able to snip that DNA target using CRISPR, remove a short segment in a "control section" of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells." When the scientists edited the DNA of blood-forming stem cells derived from patients with sickle cell disease, they were able to activate those genes and produce red blood cells that had enough fetal hemoglobin to be healthy.
Recently, scientists have used several gene editing approaches to manipulate blood-forming stem cells for the possible treatment of sickle cell disease and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching. All of these approaches remain untested in patients.
"Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system," said Weiss. Using genome editing to restore the hereditary persistence of fetal hemoglobin is an attractive possibility, because it can be achieved relatively easily using current technologies. The condition is known to be benign in people who inherit similar naturally occurring mutations.
At this stage, the scientists emphasize that it is still too early to begin clinical trials of the new gene editing approach. The researchers want to refine further the gene editing process and perform other experiments to minimize potentially harmful off-target mutations before in-human clinical trials are considered. Additionally, it will be important to compare different approaches head-to-head to determine which one is safest and most effective.

Source:

St. Jude Children's Research Hospital

 

Pediatric sickle cell study stopped early due to positive results

Hydroxyurea shown as viable option for some children with sickle cell anemia

Source:

Medical University of South Carolina

Summary:

For some children with sickle cell disease, the drug hydroxyurea is as effective as blood transfusions to reduce blood flow speeds in the brain, a national sickle cell disease study has found. Increased blood flows are a major risk factor for stroke in these children, report investigators. 

 

 

FULL STORY

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Pediatric/hematologist Dr. Sherron Jackson of the Medical University of South Carolina examines a patient with sickle cell disease.

Credit: Photograph by Sarah Pack, Medical University of South Carolina

Pediatric/hematologist Dr. Sherron Jackson of the Medical University of South Carolina examines a patient with sickle cell disease.

Credit: Photograph by Sarah Pack, Medical University of South Carolina

"It was a privilege to be a part of this well-designed and executed study. Russell Ware presented the results at the ASH meeting, and 18 years ago, almost to the day, I presented the STOP study results to the same meeting," said Robert J. Adams, M.D., study principal investigator, MUSC professor of neurosciences and director of the South Carolina Stroke Center of Economic Excellence. "That study showed how effective transcranial Doppler risk stratification, followed by regular red cell transfusions in those with high risk blood flow, can be in the prevention of stroke in these children. This became known as the STOP protocol and its wide adoption has been associated with a sharp drop in ischemic strokes in children with sickle cell disease. The drawback of indefinite transfusions however, was a limitation to wider use of the STOP protocol. This study shows that some children can be moved from transfusion to medication after at least a year. The combined understanding and evidence from these two studies brings us closer to achieving the National Institutes' goal of a 'stroke free generation' in sickle cell disease."

Standard treatment for children with sickle cell disease who are at high risk of stroke consists of regular blood transfusions. Children who receive regular blood transfusions are then at risk for iron overload. Chelation, or iron-reduction, therapy is needed for those receiving transfusions. The National Institutes of Health (NIH)-supported study sought to answer whether hydroxyurea would provide the same benefit as blood transfusions, given these additional treatment impacts. Hydroxyurea is the only drug approved by the Food and Drug Administration to treat sickle cell disease. The Transcranial Doppler with Transfusions Changing to Hydroxyurea (TWiTCH) study was stopped early due to positive preliminary results in November 2014.
Researchers from 26 clinical sites supported by the NIH's National Heart, Lung, and Blood Institute (NHLBI) recruited and studied 121 children ages 4 to 16 years old and divided them into two groups: one that received transfusions and one that was transitioned from transfusions to daily doses of hydroxyurea.
"No child should ever have to face the prospect of suffering through a stroke," said Gary H. Gibbons, M.D., director of the NHLBI. "Our institute is striving to achieve a stroke-free generation of children living with sickle cell disease. Studies like this are vital for moving us toward this worthwhile goal."
Study authors indicated that the findings suggest that hydroxyurea could be effective at reducing risk of stroke for other patient populations, though this was not a primary goal of the study.

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Story Source:
The above post is reprinted from materials provided by Medical University of South Carolina. Note: Materials may be edited for content and length.

How Vitamin A can Reduce Scarring in Blood Vessels

While scarring is a natural part of any healing process, scar formation within our blood vessels can be deadly. A team of US researchers has developed a new biodegradable material with built-in vitamin A which has been shown to reduce scarring in blood vessels.

"When injury occurs, cells proliferate and migrate into the blood vessel, creating scar-like tissue. It can create blockages that impair blood flow," said lead researcher Guillermo Ameer from the Northwestern University.

The soft elastic material can be used to treat injured vessels or be used to make medical devices such as stents and prosthetic vascular grafts. Early tests have shown that the material can reduce cell migration - a major contributor to the scarring process - by 57%.

"In his new work, vitamin A is integrated into the material, harnessing the beneficial properties of vitamin A and allowing for its broader application in medical devices," the authors noted in a paper published in the ACS Biomaterials Science and Engineering.

This new advanced material brings together two major advantages. Its antioxidant component can reduce the oxidative stress that leads to chronic inflammation.

Vitamin A, which is released as the material degrades, can prevent or reduce scarring.

It can potentially also be used outside the body such as for wound-healing bandages for diabetic patients.

Because the new material releases vitamin A as it degrades, the potential for toxic build up is much lower.

Ameer's team can also control how quickly the material degrades - and thus releases the vitamin A - depending on how the material is produced in the laboratory.

The team now plans to explore the material's potential for additional applications. Vitamin A is already widely known for its anti-aging properties and topical antioxidants can be used to combat cell damage or improve wound healing.

Source: IANS

Encapsulated Human Islet Cells can Normalize Blood Sugar Read more: Encapsulated Human Islet Cells can Normalize Blood Sugar

Scientists studying a mouse model of diabetes have implanted encapsulated insulin-producing cells derived from human stem cells and maintained long-term control of blood sugar -- without administering immunosuppressant drugs.

 The results of the multi-institutional effort are published in Nature Medicine. People with type 1 diabetes have an overactive immune system that destroys the insulin-producing islet cells in the pancreas. Lacking that hormone, the body fails to convert sugars to usable energy, and glucose rises to harmful levels in the blood without daily insulin injections.

Islet cells have been successfully transplanted to treat type 1 diabetes, but those patients must take immunosuppressant drugs to keep their immune system from destroying the transplanted cells. Previous research had shown that rodent islet cells could normalize blood sugar levels in animal models without immunosuppression if the cells were encased in hydrogel capsules.

The semi-porous capsules allow insulin to escape into the blood, while preventing the host's immune system from attacking the foreign cells. Larger capsules, about 1.5 millimeters across, even seemed able to avoid the buildup of scar tissue, which can choke off the cells' supply of oxygen and nutrients. The new study, a collaboration led by scientists at the Massachusetts Institute of Technology and Boston Children's Hospital, used islet cells derived from human stem cells and capsules made of chemically-tweaked gel that are even more resistant to the build-up of scar tissue.

Dr. Jose Oberholzer, chief of transplantation surgery and director of cell and pancreas transplantation at the University of Illinois Hospital & Health Sciences System, professor of bioengineering at the University of Illinois at Chicago, and an author on the paper, tested several varieties of chemically-modified alginate hydrogel spheres -- in various sizes -- to see if any excelled at resisting scar-tissue formation.

Oberholzer and his coworkersat the University of Illinois at Chicago first tested the spheres to ensure they would allow the islet cells to function inside a host. Using a special microfluidic device developed at UIC under a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, they delivered minute amounts of glucose into tiny wells containing encapsulated islet cells and measured the amount of insulin that seeped out.

They implanted spheres that showed promise into rodents and non-human primates to look for the development of scar tissue. They found (and reported in the journal Nature Biotechnology) that 1.5-millimeter spheres of triazole-thiomorphine dioxide (TMTD) alginate were best at allowing allowing insulin to escape while resisting immune response and the buildup of scar tissue. When implanted into a mouse model of diabetes, TMTD-alginate spheres containing human islet cells were able to maintain proper blood glucose control for 174 days -- decades, in terms relative to the human lifespan.

"When we stopped the experiment and took the spheres out, they were virtually free of scar tissue," Oberholzer said. "While this is a very promising step towards an eventual cure for diabetes, a lot more testing is needed to ensure that the islet cells don't de-differentiate back toward their stem-cell states or become cancerous," said Oberholzer. If the cells did become cancerous, he said, they could easily break through the spheres.

Oberholzer also cautioned that a cure for human diabetes would require scientists to develop techniques to grow large numbers of human islet cells from stem cells -- a worthy goal. "In the United States, there are 30 million cases of type 2 diabetes and about 2 million patients with type 1 diabetes who could potentially benefit from such a procedure," he said. "But we need to grow billions of islet cells."

Source: Eurekalert

Three Simple Suggestions for a Healthy Diet

In the article below, Ellen Fung, PhD, RD of UCSF Benioff Children’s Hospital Oakland and Farah Sultan, RD of McMaster University, share some nutritional information for people with thalassemia.

One of the most common questions we are asked as nutritionists is, “What should I be eating?” In many ways, the diet for individuals with thalassemia is no different than for anyone else: the key is balance. However, the needs for certain nutrients are much higher in thalassemia. Therefore, nutrient density is very important! This means every calorie must count. Rather than worrying about which specific foods are “good” for you or which foods are “bad,” it’s better to focus on choosing a variety of foods that are packed with vitamins, minerals, fiber and other nutrients. Making smart, balanced food choices every day can help you stay healthy.
Here are some strategies you can use:

• Eating Around the Rainbow: Healthy foods we eat come in a variety of colors: kale (green), carrots (orange), beets (red), red cabbage (purple). Fruit loops don’t count here! Each food derives its color from the rich concentration of antioxidants in its skin and flesh. The variety of colors comes from a diverse range of anthocyanins (plant pigments) and antioxidants (for example, carrots and sweet potatoes are orange because of the antioxidant, beta-carotene). By eating a variety of foods of different colors throughout the day (eating around the rainbow), you will be consuming more antioxidants, substances which are important for reducing the damage that can be caused by the free iron in your body.

• My Plate: Smaller Portions, More Vegetables and Fruit. If you are not familiar with the “My Plate” campaign from the USDA, you should take a look at it (see below and at www.choosemyplate.gov). This newest guideline for eating healthy is a simple set-up of a small plate which is divided into portions, roughly ¼ for protein, ¼ for grain/carbohydrates and ½ of the plate set aside for fruits & vegetables. If we ate all our meals this way, we would be consuming many more vitamins and minerals in our diet. Think about this the next time you sit down for lunch and dinner.

• Eat Food, not Supplements. The best way to get all of our nutrients is through our food. Most nutrients are best absorbed when they come from our food (e.g. calcium – milk, zinc – chicken) rather than in the form of supplements. Nutrients found within foods are created in such a way to avoid competition for absorption in your body whereas the form of nutrients in some supplements may result in poor absorption. Food also contains much needed fiber as well as other substances (phytochemicals, flavonoids) that are important for your health. When healthy foods are replaced by foods with poor nutrient density (e.g. empty calories) + dietary supplements, you miss out on all of the benefits of food. Not to mention the simple joys of consuming delicious, nutritious foods! However, we must be clear…Individuals with thalassemia may require certain supplements (e.g. vitamin D) in addition to their diet; but supplementation should NOT REPLACE a healthy diet.

Making healthy choices doesn’t have to be complicated — simply begin by making one change in your daily routine, such as making sure to have one colorful vegetable every day. You may just be surprised how simple it can be, and how great you can feel.
Ellen Fung, PhD RD
Associate Research Scientist
UCSF Benioff Children’s Hospital Oakland
Oakland, CA USA
Farah Sultan, RD
Master’s Degree Student, Nutritional Science
McMaster University
Toronto, ON Canada

Educating Public on Sickle Cell Disease Risk

In sub-Saharan Africa, members of the public who are carriers of the hereditary disease sickle cell disease must be educated aggressively through public health campaigns to raise awareness of the risks of parenting offspring with the disease if their partner is also a carrier.

This is according to research published in the International Journal of Medical Engineering and Informatics. There are many physical and emotional public health components of sickle cell disease, explains William Ebomoyi of the Department of Health Studies College of Health Sciences, Chicago State University, Illinois, USA. Moreover, there ethical and legal considerations surrounding the screening of newborns for this potentially lethal disease.

Sickle-cell disease (SCD), also known as sickle-cell anemia (SCA) or drepanocytosis is an inherited condition in which a child of parents both of whom are carriers of the associated hemoglobin gene who inherits both copies will produce abnormal red blood cells that are rigid and often sickle-shaped. The disorder causes both acute and chronic health problems, such as repeated infections, severe attacks of pain and potentially stroke and death. Carriers of just one copy of this particular hemoglobin gene tend to have greater resistance to the lethal parasitic disease malaria compared to people without a copy of the gene. However, around 2 percent of the population of sub-Saharan Africa is born with SCD. Moreover, incidence is rising across the globe as populations migrate.

In the age of genomics, however, Ebomoyi suggests that raising awareness of the risks of having children with SCD if both parents are carriers is important. "An aggressive health education of the public is required to maintain a shared responsibility for their courtship behaviour by alerting potential suitors of their heterozygous status," he suggests. He adds that, "Major sickle cell education programmes need to be integrated into the curriculum of elementary, secondary and tertiary academic institutions."

Successful outcome prompts early end to sickle cell anemia clinical trial

Conclusive data show that hydroxyurea therapy offers safe and effective disease management of sickle cell anemia (SCA) and reduces the risk of stroke, prompting early termination by the National Heart Lung and Blood Institute (NHLBI) of a key clinical trial studying the drug's efficacy.

NHLBI officials issued the announcement today, about one year before the study was originally scheduled to end. Going by the title TWiTCH (TCD With Transfusions Changing to Hydroxyurea), the Phase III randomized clinical trial at 25 medical centers in the U.S. and Canada compared standard therapy (monthly erythrocyte transfusions) with the alternative (daily hydroxyurea) for children with elevated transcranial Doppler (TCD) velocities and high risk of stroke.

"Early results indicate that TWiTCH is a success. Hydroxyurea works as well as blood transfusions to lower TCD velocities, which lowers the risk of the child having a stroke," said Russell E. Ware, MD, PhD, principal investigator of the study and director of Hematology at Cincinnati Children's Hospital Medical Center, which served as the study's Medical Coordinating Center.

"A group of outside experts has been reviewing the TWiTCH data every few months to ensure the safety of children in the clinical trial and to monitor the data," Ware explained. "This group met recently and after careful consideration of the interim data results, recommended that the study be stopped since hydroxyurea worked as well as transfusions to lower TCD velocities." The NHLBI and National Institutes of Health (NIH) agreed with the recommendation.

"No child should ever suffer a stroke, which is why it was so important for the NHLBI to support the TWiTCH trial," said Gary Gibbons, MD, director of the NHLBI. "This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease."

The study enrolled its first patient in September 2011 and included children between ages 4 and 16 years with sickle cell anemia and abnormally elevated TCD velocities, which increases their risk of developing a stroke. The current standard therapy for children with elevated TCD velocities is monthly blood transfusions. A total of 121 children were randomized: half received the standard therapy of transfusions while the other half received the alternate treatment with daily hydroxyurea, which has not yet been approved for children with sickle cell anemia.

The clinical data-collection portion of the study was originally scheduled for 24 months, but collection is now being stopped early, after only half of the children have completed the treatment phase.

"We did not know if hydroxyurea would reduce the risk of stroke as well as transfusions, so TWiTCH was an important research study," said Barry R. Davis, MD, PhD, principal investigator for the Data Coordinating Center at the University of Texas Health Science Center at Houston (UTHealth) School of Public Health. "The study has now shown that hydroxyurea has a similar benefit as transfusions, so the study is closing early since the main research question has been answered."

An important reason for testing hydroxyurea is that the current standard therapy of monthly blood transfusions to reduce stroke risk can lead to problems such as antibody formation and iron overload, which are increasingly recognized as a source of morbidity in young patients with SCA.
Over the past decade, the laboratory and clinical efficacy of hydroxyurea has been demonstrated in children and adults with SCA. Originally developed as a drug to treat cancer and infections, hydroxyurea boosts fetal hemoglobin production in SCA, which prevents the red blood cells from acquiring the sickled shape that fuels the many complications. Hydroxyurea has been previously shown to have clinical efficacy for a variety of sickle-related complications, but TWiTCH is the first Phase III trial that demonstrates its benefits for children with cerebrovascular disease and increased stroke risk.

Sickle Cell Anemia Treatment So Successful in Kids That Trial Is Halted

Hydroxyurea pills worked as well as transfusions in reducing stroke risk, researchers report

 (HealthDay News) -- A clinical trial of hydroxyurea therapy for children with sickle cell anemia has been halted a year early because the results show it is a safe and effective way to manage the disease and reduce the risk of stroke.
The announcement about the research, which was conducted at 25 medical centers in the United States and Canada, was made this week by the U.S. National Heart, Lung, and Blood Institute (NHLBI).
Researchers compared monthly blood transfusions with daily hydroxyurea pills among children with sickle cell anemia who were at high risk of stroke. To determine this, they measured the velocity of blood flow to the brain in these young patients.
With sickle cell anemia, red blood cells become stiff and sickle-shaped, blocking blood flow throughout the body. Hydroxyurea was first developed as a cancer drug, but with sickle cell anemia it reduces the number of these abnormally shaped red blood cells, the researchers said.
Early results showed that hydroxyurea "works as well as blood transfusions which lowers the risk of the child having a stroke," principal investigator Dr. Russell Ware, director of hematology at Cincinnati Children's Hospital Medical Center, said in a center news release.
"This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease," NHLBI Director Dr. Gary Gibbons said in the news release.
The study began in September 2011 and enrolled 121 children, aged 4 to 16, with sickle cell anemia who showed an increased risk of stroke.
SOURCE: Cincinnati Children's Hospital Medical Center, news release, Nov. 19, 2014

HealthDay

TIF Launches “ThaliMe” App for Thalassemia Patients

The Thalassemia International Federation (TIF) is taking on a new project to develop and deploy an innovative mobile program to greatly aid and improve the lives of people living with thalassemia. The envisioned program, delivered via mobile app, has the potential to reach millions of people around the world living with this challenging disease. (A video demonstration is available by clicking here.)

The overall goals of this program are to give people living with thalassemia, their families and caregivers, a private mobile support network and a suite of tools to simplify daily management and inspire overall health. The ThaliMe app helps to connect the thalassemia community to one another and to those that care for them. The application will be designed with active input from the thalassemia community to ensure value, ease of use and applicability.

ThaliMe App will be easy to use, personalized and provide users with helpful tools to manage everything from medication reminders to appointment scheduling, from mood and mobility levels, to transfusion dates and accessing the latest research. TIF views this approach to patient care and the use of mobile technology for patient empowerment and outreach as a critical component of the overall thalassemia care ecosystem.

More specifically, the goals for the program are to develop a cross-platform mobile tool that enables:
• Private, peer to peer and peer to caregiver support networks to reduce isolation and improve patients sense of support;
• Easy to use, simple health tracking and information management functionality that eases the daily challenges of disease management;
• Data visualization tools that translate health tracking into visual format thus providing an easy and motivating way to chart personal health;
• Medication and appointment reminders to encourage adherence and timely care;
• Educational and research information channel that users can post to privately or share to their social networks, more broadly, like Facebook, Twitter etc. to improve awareness, empowerment and prevention.
The App can be downloaded from the Apple store or Google Play. For more information, contact TIF at thalassaemia@cytanet.com.cy.

Correcting the genetic error in sickle-cell disease might be as simple as amending text.

After some tragic early setbacks techniques that allow precise genetic manipulation have created a surge of research.

 Tiny changes in DNA can have huge consequences. For years, scientists have been trying to 'fix' these mutations in the hope of treating and potentially curing some of humanity's most devastating genetic diseases. After some tragic early setbacks , techniques that allow precise genetic manipulation have created a surge of research.



 DNA sequences showing the sickle-cell disease mutation (marked with an asterisk, top) and the sequence corrected (below) using gene-editing technology.

Although most existing treatments for genetic diseases typically only target symptoms, genetic manipulation or 'gene therapy' goes after the cause itself. The approach involves either inserting a functional gene into DNA or editing a faulty one that is already there, so the conditions most likely to prove curable are those caused by a single mutation. Sickle-cell disease is a perfect candidate: it is caused by a change in just one amino acid at a specific site in the β-globin gene. This results in the production of abnormal haemoglobin proteins that cause the red blood cells that house them to twist and become sickle shaped. The distorted cells get sticky, adhere to each other and block blood vessels, preventing oxygenated blood from flowing through.

Gene therapy has been used successfully in a handful of patients with immune disorders, and sickle-cell disease is among researchers' next targets. The most advanced of these projects is slated to begin clinical trials by the end of the year, and other trials are set to follow. The approaches being developed to treat sickle-cell disease take one of two forms. Conventional gene therapy, also known as gene addition, typically involves inserting new genes. Usually, a harmless virus is modified with the gene to be inserted, and this 'viral vector' is mixed with cells from the patient in vitro. The virus searches out the cells and inserts the gene into the cells' DNA, after which the cells are transplanted into the patient. Conversely, gene editing is more nuanced: in a molecular cut-and-paste, researchers cut out the faulty DNA sequence and then insert a piece of laboratory-created DNA. In both approaches, the modified DNA dictates the formation of a normal, working protein.
In sickle-cell disease, the only cells that need their DNA edited are blood stem cells — also known as haematopoietic stem cells — which are found in bone marrow. These cells continually form new red blood cells to replace those that are lost, and reprogramming just a small fraction of them will create enough perfectly formed red blood cells to eliminate disease symptoms. “Achieving genome editing via direct repair of blood stem cells represents a high hurdle,” says George Daley, director of the Stem Cell Transplantation Program at Boston Children's Hospital in Massachusetts, “but perhaps not an impossible one.”

Although these approaches are promising, several important issues must be addressed before they can be used to treat patients, such as ensuring that the therapies accurately hit their targets and do not cause irreparable harm to the cells or introduce additional genetic information that could cause problems such as cancer.

Injecting genes

Gene addition is poised to become the first sickle-cell gene therapy to be tested in humans. At the regenerative medicine and stem cell research centre of the University of California, Los Angeles, molecular geneticist and physician Donald Kohn is developing protocols for a clinical trial of this technique that is due to start enrolling patients by the end of 2014. Doctors will first harvest bone marrow from the hip bones of patients with sickle-cell disease and then extract haematopoietic stem cells from the marrow. Using a viral vector, they will insert a new, working haemoglobin gene into the cells' DNA; the old, faulty haemoglobin gene will still be present, but it will go silent as the new gene takes over. The modified cells will then be infused back into the patient's bloodstream and will migrate to the bone marrow, where they can provide a continual source of healthy red blood cells.
Kohn says that this approach has the potential to cure sickle-cell disease, and with significantly fewer side effects than a bone marrow transplant — currently the only cure (see page S14). He has tested the technique by injecting modified human haematopoietic stem cells into mice, and found that they were free of sickle cells 2 to 3 months later¹. The limiting factor in mice, Kohn says, is that they can only sustain human grafts for that long. In humans, he thinks the correction should last a lifetime — as long as 50 to 70 years.

One of the challenges in treating sickle-cell disease with gene therapy is that it is necessary to extract bone marrow to retrieve haematopoietic stem cells. With most other diseases, patients can be given drugs that entice these cells to leave the marrow and enter the bloodstream, where they can be easily harvested. But in patients with sickle-cell disease, these drugs can trigger sickle-cell crisis, an acutely painful episode during which the damaged cells stick together and block blood vessels; the crisis can be accompanied by anaemia, chest pain, difficulty breathing, blood trapped in the spleen and liver, even stroke. So researchers must harvest the bone marrow itself, which can be difficult and slow, and limits the number of cells that can be collected at one time. Kohn says that they still do not know whether this approach will yield enough haematopoietic stem cells for reprogramming. And, like other bone marrow transplant procedures, the patient still needs to undergo chemotherapy to kill off the remaining bone-marrow cells to help the genetically altered ones survive once they are reintroduced into the body.

Talented fingers

Further away from clinical trials, but potentially a lot more exciting, is gene editing. The concept was introduced in the 1990s, when artificial DNA-cutting enzymes known as zinc finger nucleases (ZFNs) were first engineered. ZFNs bind to a specific section of DNA and create a break at both ends (see 'Molecular cut-and-paste'). Cells will start to repair the break, at which point a specific sequence of laboratory-made DNA can be slotted into the gap. After the DNA is repaired, the cells start to create healthy copies of the gene.

In parallel to his work on gene addition, Kohn is exploring the use of ZFNs to edit sickle-cell genes. In collaboration with the firm Sangamo BioSciences in Richmond, California, he has shown that around 7% of haematopoietic cells can be repaired in culture using this technique, using a viral vector to get the ZFNs into the cells. Because the repaired cells continue to replicate, this small proportion could be enough to eventually produce a sufficient amount of working red blood cells. Kohn says that patients have shown major improvements when just 10–20% of their donor cells successfully engrafted and started to make new, healthy cells.

The advantage of gene editing over gene addition (a less complex approach) is that it provides an actual fix rather than a work around. But ZFNs are expensive and difficult to program. In 2010, a gene-editing protein called TALEN (transcription activator-like effector nuclease) was developed, which uses a similar mechanism as ZFNs but is cheaper and easier to work with. It was quickly adopted for use in sickle-cell disease.

At the Salk Institute for Biological Studies, in La Jolla, California, stem-cell biologist Juan Carlos Izpisua Belmonte uses TALENs in concert with viral vectors called HDAdVs (helper-dependent adenoviral vectors) to correct the sickle-cell mutation. Instead of harvesting haematopoietic stem cells from bone marrow, Izpisua Belmonte's team takes easily harvestable cells, such as blood, skin or fat cells, and then turns them into induced pluripotent stem (iPS) cells, which can be converted into any cell type. The researchers correct the haemoglobin gene defect in vitro using gene editing, then differentiate the repaired iPS cells into blood stem cells. From there, the researchers have a couple of choices. The repaired cells could simply be infused into a patient's bloodstream, where they would make their way into the bone marrow and start to make healthy haematopoietic cells.

But Izpisua Belmonte is also working on a cure that could work inside the bone marrow itself. His team is combining TALENs with a different viral vector, HDAdVs, to boost the success rate of gene editing, and the researchers are working on a plan to administer their hybrid vector directly into the bone marrow, so the genetic fix would take place inside the patient's body. Although each infusion into the marrow might correct only 1% of the cells, ten such procedures over the course of several months — something Izpisua Belmonte and his research associate Mo Li think is feasible in terms of time and cost — could alleviate the symptoms of sickle-cell disease. “Little by little, you are correcting the disease in vivo,” says Izpisua Belmonte. So far, this 'hybrid vector' technique has shown promising efficacy in umbilical-cord blood stem cells.

Sickle-cell disease results when both copies of the haemoglobin gene are faulty, and fixing just one of the genes is sufficient to make a big health improvement. As Li points out, people who carry one copy of the mutated gene, a genetic condition referred to as 'sickle-cell trait', do not show symptoms. “In fact, many of the world's best sprinters have the sickle-cell trait, he says. “Our approaches will most likely restore one mutated copy to its wild-type sequence, leaving the other copy untouched.”
CRISPRs (clustered regularly interspaced short palindromic repeats) are the most recent addition to the gene-editing toolbox. Whereas ZFNs and TALENs use a protein to lock on to a specific section of DNA, CRISPRs use a 'guide RNA'. These guide RNAs are much easier to program than the proteins in TALENs and ZFNs, as well as being cheaper and more efficient. CRISPRs also make it possible to perform multiple genetic manipulations in one go. CRISPRs work in combination with the Cas9 (CRISPR-associated 9) nuclease: after the CRISPR locks on to the target gene, Cas9 snips both strands of the DNA, disabling the gene. The approach is less than two years old, yet many researchers are now working with CRISPRs in parallel with other in vitro techniques.

Chris Calleri/Georgia Institute of Technology

A researcher corrects a mutation in the β-globin gene that causes sickle-cell disease.

There are safety hurdles to be overcome before gene editing is used in humans, especially because it involves a permanent change in the genome. The thorniest issue is 'off-target activity' — unintended changes to the genome away from the target gene.

Gang Bao, a biomedical engineer at the Georgia Institute of Technology in Atlanta, is developing gene-editing strategies for sickle-cell disease and is paying particular attention to the challenge of limiting off-target effects. He notes that if erroneous cuts happen in a cancer-causing gene, they could potentially trigger tumour growth. Even a rate of off-target activity lower than 1% could still pose serious health risks. So that the technology can move forward, researchers need to have a better understanding of off-target effects. There are two main issues: determining exactly where the off-target cuts occur and at what rate.

Bao's group has created software to predict where the off-target effects might occur for the different gene-editing techniques. In a paper published in May, his team reported that their software predicted 114 potential off-target sites across the whole genome for the CRISPR/Cas9 system, and experiments confirmed 15 of them by sequencing the cleaved DNA².

Izpisua Belmonte's team is also looking at the rate of unwanted mutations caused by gene-editing techniques. The group created iPS cell lines and then edited half of the cells using HDAdVs and TALENs³, but left the other half unedited. The edited cells had no more mutations than the unedited ones, indicating that — in contrast to Bao's findings for CRISPRs — the use of TALENs does not seem to make cells any less safe. Although human testing is still a few years off, they say that these results give them optimism about the potential for gene editing to work.
The other major challenge for gene-therapy researchers is ensuring that the edited stem cells survive and generate healthy red blood cells after they are reinserted into the bone marrow. Edited cells often die because of the amount of stress they undergo during therapy. Researchers might be able to improve the cell-survival rate by delivering other types of cells at the same time, and the speed of gene editing also seems to be important: the longer the cells are cultured in vitro, the less likely they are to survive. “Let's see if we can perform the whole procedure in four hours instead of four days,” says Bao.

Future repair toolboxes

Based on his research so far, Bao thinks that CRISPRs are the best method for generating DNA breaks, but they are also more likely to cause off-target activity. TALENs are less efficient than CRISPRs, but they seem to have fewer off-target effects. The rate of on-target activity for CRISPRs is between 40% and 80%, whereas the on-target rate for TALENs is between 20% and 50%, Bao says. The rate of off-target activity varies depending on the type of cells and the nuclease used. “If we have a way to overcome the off-target and [cell-survival] problems, CRISPR is a very promising technology,” he says.

Kohn has compared ZFNs, TALENs and CRISPRs, and thinks all three have therapeutic potential for patients with sickle-cell disease. The techniques are all good at slicing DNA; now the remaining challenges are delivering them to the target cell and accurately repairing the gene after the break.
Ultimately, for sickle-cell gene therapy to become reality, the details must be sorted out on a large scale. Tinkering with human genes can yield both devastating and remarkable results, and the difference between the two often lies in a single nucleic acid of a single gene. This places a heavy responsibility on the shoulders of every researcher in the field, but the vast potential of gene therapy makes that burden worthwhile.

East and West African sickle cell anaemia are genetically similar

African collaboration unpicks disease variations by combining local genomic research with large-scale genome-wide association techniques

 Sickle cell anaemia is most common in Africa and up to 11,000 children are born with the condition every year in Tanzania alone. Yet most of what is known about the genetic basis of this inherited disease comes from studies of US-based or UK-based African-Caribbean populations.

In African-American populations genetic variations can influence the ability to produce foetal haemoglobin by as much as 50 per cent, but knowledge of this effect in East African populations is scant. A collaboration between research teams in Tanzania and the UK applied the power of the genome-wide association techniques to the genomes of 1,213 individuals in Tanzania to confirm whether or not the same variations are at work in an East African population and to identify possible new ones.

Sickle cell anaemia is painful and disabling disease caused by variations in a gene involved in producing adult haemoglobin. But people who have greater levels of the foetal form of haemoglobin in their bloodstream are less affected. This first large-scale genomic study based in Tanzania has revealed a number of regions in the genome that appear to have an effect on foetal haemoglobin levels and will guide future research into African populations.

"By carrying out a large-scale genome-wide association study we have, for the first time, been able to identify powerfully the prevalence of genetic variants involved in sickle cell anaemia in the Tanzanian population and how that compares with other populations," says Siana Nkya Mtatiro, co-first author of the paper from Muhimbili University of Health and Allied Sciences. "We have also identified suggestive additional variants, which can now be studied further by the research community in the search for interventions for sickle cell anaemia in patients in Africa and worldwide."
 
The research confirmed the association of genetic variations near the genes BCL11A and HBS1L-MYB with sickle cell anaemia in the Tanzanian population but found that variations in HBB, which are associated with the disease in African-American populations, are not significant in East African populations. In addition, the study hinted at additional associations that require confirmation in other populations.









  The collaboration between research teams in Tanzania and the UK carried out a genome-wide association study of 1,213 individuals in Tanzania with sickle cell anaemia and confirmed that BCL11A and HBS1L-MYB are connected with the disease. [Muhimbili University of Health and Allied Sciences]

"We were unable to validate any of our new suggestive associations in a group of UK samples we used for comparison. This suggests we need bigger studies to more completely understand the genetics of this disorder," says Jeff Barrett, senior author from the Wellcome Trust Sanger Institute.
The work was a joint effort drawing on the skills and techniques developed by Tanzania- and UK-based teams and the free flow of information between them. The samples were gathered in Tanzania and genotyped at the Sanger Institute, the genome-wide scan was carried out by the UK-based team and subsequent data analysis was carried out the African-based researchers.

"This work demonstrates how scientists in Africa can collaborate both with one another and with colleagues in Europe to provide greater insight into the genomic landscape of health and disease in Africa, the cradle of humanity," says Julie Makani, senior author on the study from Muhimbili University of Health and Allied Sciences. "We hope that our approach could be used as a model for other researchers working to understand the genetic basis of health and disease in Africa."
The research was supported by the Wellcome Trust, which encourages collaborations between researchers on different continents to apply cutting-edge genomic techniques in low- to middle- income countries. Trust-funded research in this area aims to increase our understanding of diseases that might otherwise be neglected.

"This is an important contribution to sickle cell disease research, which clearly demonstrates how successful genomics research collaborations - in this case between researchers in Tanzania and the Wellcome Trust Sanger Institute - can be achieved," says Jimmy Whitworth, Head of Population Health at the Wellcome Trust. "The results of this study will form a firm foundation for further studies of the genetic basis for sickle cell disease and potential avenues for treatment in sub-Saharan Africa."