Three people with inherited diseases successfully treated with CRISPR

By Michael Le Page

Sickle cell disease can distort red blood cells

Stocktrek Images, Inc/Alamy

Two people with beta thalassaemia and one with sickle cell disease no longer require blood transfusions, which are normally used to treat severe forms of these inherited diseases, after their bone marrow stem cells were gene-edited with CRISPR.

Result of this ongoing trial, which is the first to use CRISPR to treat inherited genetic disorders, were announced today at a virtual meeting of the European Hematology Association.

“The preliminary results… demonstrate, in essence, a functional cure for patients with beta thalassaemia and sickle cell disease,” team member Haydar Frangoul at Sarah Cannon Research Institute in Nashville, Tennessee, said in a statement.

Beta thalassaemia and sickle cell disease are conditions caused by mutations that affect haemoglobin, the protein that carries oxygen in red blood cells. Those with severe forms require regular blood transfusions.

However, a few people with the disease-causing mutations never show any symptoms, because they keep producing fetal haemoglobin in adulthood. Normally, fetal haemoglobin stops being produced soon after birth.

This discovery has inspired the development of treatments based on boosting fetal haemoglobin. In this trial, run by collaborating companies CRISPR Therapeutics and Vertex, bone marrow stem cells are removed from people and the gene that turns off fetal haemoglobin production is disabled with CRISPR.

The remaining bone marrow cells are killed by chemotherapy, then replaced by edited cells. This is done to ensure that new blood cells are produced by the edited stem cells, but the chemotherapy can have serious side effects including infertility.

The first two patients with beta thalassaemia no longer need blood transfusions since being treated 15 and five months ago. Nor does the patient with sickle cell disease, nine months after treatment.

The results are excellent, says Marina Cavazzana at the Necker-Enfants Malades Hospital in Paris, France, whose team has treated a 13-year-old boy with sickle cell disease using a different approach.

Although the three patients did experience some adverse effects due to the chemotherapy, the CRISPR gene editing appears safe. However, the patients may need to be monitored for the rest of their lives to be sure it has no adverse effects, says Cavazzana.

Altogether five people have now been treated. The trial was put on hold because of the coronavirus pandemic, but has now resumed.

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Are patients with thalassemia more susceptible to serious COVID-19 disease?

COVID-19 and Thalassemia: Frequently Asked Questions

(last updated June 8, 2020)

Input from Drs. Maria Cappellini, Antonio Piga, Janet Kwiatkowski and Alexis Thompson

Note: Please review ASH's disclaimer regarding the use of the following information.

Are patients with thalassemia more susceptible to serious COVID-19 disease? Does splenectomy confer a higher risk?

Thalassemia patients, especially young adults/adults, have a chronic condition which may be associated with several co-morbidities linked to the underlying disease as well as complications of chronic transfusions, including heart failure, pulmonary hypertension, and diabetes. Thus, it seems possible that there could be an increased risk of more severe COVID-19 disease in some patients. Nonetheless, outcomes were recently reported from a small cohort of Italian patients followed in the northern part of Italy, where the pandemic has been the most widespread, showing most experienced relatively mild to moderate COVID-19 disease.¹ The number of infected thalassemia patients was lower than expected, likely due to earlier and more vigilant self-isolation compared to the general population.

Splenectomy is not known to increase the general risk of viral infection or severe viral disease, but no specific data exists for SARS-CoV-2. Splenectomized patients who develop fever should be evaluated for possible bacterial infection and should receive antibiotics to cover secondary bacterial infections.

Should any changes in transfusion schedules or thresholds be made in the context of the COVID-19 pandemic?

At present there is no evidence that the SARS-CoV-2 virus may be transmitted through donated blood. It is advisable to maintain the individual’s chronic transfusion regimen. Clinics and infusion centers should offer patients the safest possible environment for receiving transfusions, in areas free of COVID-19 patients or those being screened for respiratory symptoms and providing health care personnel protective equipment.

Hematologists and other thalassemia care providers should continue to follow local and national developments related to possible blood shortages related to COVID-19. Clinical sites and blood banks should develop contingency plans for adjusting transfusion regimens and obtaining appropriate donor units for individuals with alloimmunization in the event a significant shortage develops. 

Should thalassemia patients continue iron chelation if they are exposed to or have confirmed COVID-19 disease?

No data are available regarding iron chelation and susceptibility to COVID-19 or severity of infection. If a patient is exposed but asymptomatic there is no reason to interrupt iron chelation. If a patient becomes symptomatic, particularly with moderate to severe disease, then interruption of iron chelation is advisable, with ongoing communication between the treating physicians and the hematologist.

Many comorbidities in thalassemia are related to iron overload. Patients should be reminded that adherence to the iron chelation dose and schedule recommended by their thalassemia care provider will reduce organ injury and thalassemia complications.

What about treatment with the recently approved disease-modifying drug luspatercept during the COVID-19 pandemic?

Luspatercept has been approved for adults with transfusion dependent beta thalassemia and has been shown to significantly reduce transfusion burden in this population. No data are available to date on luspatercept and COVID-19. If patients are currently taking luspatercept, there are no theoretical reasons to stop treatment. If the drug has decreased transfusion frequency, then continuing treatment would be beneficial in terms of avoiding prolonged clinic visits for transfusions and decreasing utilization of a limited blood supply.

What are the recommendations for stem cell transplantation or gene therapy for thalassemia during the COVID pandemic?

Due to high risk of infection in hospital settings and the risk of myeloablation, most allogeneic stem cell transplantation and gene therapies were postponed during the initial phases of the pandemic. In localities with a fall in COVID-19 hospitalizations, patients and their physicians can begin to discuss moving forward with planned procedures, particularly in patients with gene therapy cell products already prepared or with limited allogeneic donor availability. There is no evidence that SARS-CoV-2 can be transmitted via hematopoietic stem cell grafts.

References

1. Motta et al, Am J Hematol, 2020 SARS‐CoV‐2 infection in beta thalassemia: preliminary data from the Italian experience. https://doi.org/10.1002/ajh.25840
2. Karimi M, et al. Prevalence and Mortality due to Outbreak of Novel Coronavirus Disease (COVID-19) in β-Thalassemias: The Nationwide Iranian Experience. Br J Haematol. 2020 Jun 2.
3. Roy NBA, et al. Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID-19 pandemic. Br J Haematol. 2020 May;189(4):635-639.

For additional information, see:

• Resources for providers to share with their patients
  • Cooley Anemia Foundation
  • Thalassemia International Federation

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Public Health Webinar Series on Blood Disorders

CDC’s Division of Blood Disorders (DBD) is proud to offer its Public Health Webinar Series on Blood Disorders. The purpose of this series is to provide evidence-based information on new research, interventions, emerging issues of interest in blood disorders, as well as innovative approaches in collaborations and partnerships. We invite you to join us in this series.

Archives for 2020

Sujit Sheth, MD
Harold Weill Professor, Chief of Pediatric Hematology and Oncology, and Vice Chair for Clinical Research, Department of Pediatrics, Weill Cornell Medicine

Director, New York Comprehensive Thalassemia Center, New York-Presbyterian Hospital/Weill Cornell Medical Center

Overview of Novel Thalassemia Treatments

The thalassemia syndromes are among the most common genetic disorders. Homozygous or compound heterozygotes have a wide spectrum of clinical severity, with the most severe requiring regular blood transfusions to maintain health and prevent morbidity. Transfusion-associated iron overload and its complications result in significant morbidity and mortality, thus disease-modifying treatments are a major unmet need in the management of these individuals.

During the past five years, novel approaches to treatment have been possible with advances in technology. In this webinar, Dr. Sheth will discuss the basic pathophysiology of the disease and specific targets for novel therapies. He will review data from trials of the newer agents aimed at reducing or abolishing the transfusion burden and mention additional strategies that are in early stage development that have the potential to completely change the landscape of thalassemia care.

Longer Life Expectancy is Possible for Some Sickle Cell Disease Patients, Case Study Contends

By Alice Melao

A published case study reports that patients with mildly symptomatic sickle cell disease (SCD) can exceed the U.S. median life expectancy  of 47 years for patients with the disease if it is managed properly.

The report published in Blood, the Journal of the American Society of Hematology, “Case series of octogenarians with sickle cell disease,” analyzes four women diagnosed with milder forms of SCD who have lived as long as 86 years.

“For those with mild forms of SCD, these women show that lifestyle modifications may improve disease outcomes,” stated Samir K. Ballas, MD, professor emeritus in the Department of Medicine at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, and principal author of the case study.

Ballas went on to explain that strong and long-term family support are important factors for the reported long life expectancy and high quality of life of the SCD patients. Moreover, strict adherence to medication and appointments also were reported as being highly important for the disease outcome.

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“It is very likely that their healthy lifestyles were important contributors to their longevity,” said Ballas. “All of the women were non-smokers who consumed little to no alcohol and maintained a normal body mass index. This was coupled with a strong compliance to their treatment regimens and excellent family support at home,” he said.

The four cases studied in this report were considered by Ballas to be “desirable” disease states. “These women never had a stroke, never had recurrent acute chest syndrome, had a relatively high fetal hemoglobin count [which helps to prevent cells from sickling], and had infrequent painful crises. Patients like this usually — but not always — experience relatively mild SCD, and they live longer with better quality of life,” Ballas said.

Nevertheless, Ballas points out that this study included only four participants and all were women. Given so, more studies with a broader group of study is still required.

In summary, Ballas is hopeful that the stories of these four women can serve as examples for SCD patients. “I would often come out to the waiting room and find these ladies talking with other SCD patients, and I could tell that they gave others hope, that just because they have SCD does not mean that they are doomed to die by their 40s — that if they take care of themselves, and live closely with those who can help keep them well, that there is hope for them to lead long, full lives,” the author concluded.

Promising Gene Therapy For Sickle Cell Ready for Clinical Trial

By Alexandra Anderson PhD

A new engineered gene therapy virus, inserted into blood stem cells and then transplanted into mice with sickle cell disease, markedly reduced red blood cell damage according to the study “Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype,” published in theJournal of Clinical Investigation.

A clinical gene therapy trial is expected in the coming year in which researchers will use a gene manipulated harmless virus to prevent the “sickling” of red blood cells. The new gene therapy is based on research going back to the 1980s which revealed that people with a milder form of sickle cell disease carried a fetal form of hemoglobin.

Hope and Destiny: The Patient and Parent's Guide to Sickle Cell Disease and Sickle Cell Trait
This form is present in the human fetus and normally tapers off after birth. It differs most from “adult” (beta) hemoglobin because it is able to bind oxygen to a larger extent and is not seen to “sickle”.

In later studies, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center researchers showed that suppressing a gene (BCL11A) that acts as an “off-switch” on the fetus hemoglobin, could restart the production again. With this approach the team was able to replace much of adult hemoglobin with the fetus form, in mice with sickle cell disease.

Dr. David A. Williams and colleagues from the center later adopted the approach.

“BCL11A represses fetal hemoglobin and also activates ‘adult’ hemoglobin, which is affected by the sickle-cell mutation,” Williams, the study’s senior author, said in a news release. “So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

The new team tried to turn this insight into a therapy approach but they faced a problem. They discovered that the BCL11A gene also plays an important role in blood stem cells — which caused serious problems with the general blood development.

After some engineering in which the team used different gene techniques to silence the “switch-off” gene, without influencing the general blood development, they inserted the whole package into a lentivirus made for safe use in humans. Blood stem cells treated with this gene therapy were then successfully transplanted into mice and reduced the signs of sickle cell disease.

Additionally, in red blood cells from mice and four patients with the disease, the fetal hemoglobin surpassed the sickling “adult” hemoglobin, making up at least 80 percent of the total hemoglobin in the cell. According to the researchers, these results are more than enough to avoid the disease.

Williams believes this gene therapy approach will substantially increase the ratio of non-sickling versus sickling hemoglobin in patients, and his team is now taking the final steps toward FDA clearance for a clinical gene-therapy trial in sickle cell disease, that is expected to begin in early 2017.

New Biophysical Markers Could Help Develop Treatments for Sickle Cell Disease

by Dr. Trupti Shirole

Sickle cell disease is an inherited blood disorder that affects an estimated 80,000 to 100,000 Americans each year. People with sickle cell disease have an abnormal form of hemoglobin, a protein found in red blood cells that carry oxygen throughout the body.

Normal red blood cells are flexible discs that easily bend and stretch to flow through the body's narrow blood vessels. In sickle cell disease, the abnormal hemoglobin forms fibers that cause the blood cells to take on a flattened, sickled shape and stiffen when they lose oxygen. This change in shape and rigidity causes the red blood cells to be stuck in the blood vessels and prevents the transport of oxygen to the surrounding tissue. This can cause anemia and extreme pain and impact the health of the body's tissue and organs. 

Currently, hydroxyurea is the only FDA-approved drug for sickle cell disease. The drug reduces sickling in red blood cells and is used to treat pain and reduce the need for blood transfusions in some patients, but it does not work in all patients. Researchers have been divided over what mechanisms cause the drug to work. Some believe it works by reactivating fetal hemoglobin, which is better at transporting oxygen than the abnormal hemoglobin that causes sickling. Others believe it works by increasing the volume of red blood cells, reducing the concentration of sickle hemoglobin. 
An interdisciplinary, international group of researchers has found new biophysical markers that could help improve the understanding of treatments for sickle cell disease, a step toward developing better methods for treating the inherited blood disorder.

"There is a critical need for patient-specific biomarkers that can be used to assess the effectiveness of treatments for sickle cell disease," said Subra Suresh, president of Carnegie Mellon University and co-author of the study. "This study shows how techniques commonly used in engineering and physics can help us to better understand how the red blood cells in people with sickle cell disease react to treatment, which could lead to improved diagnostics and therapies."

The findings from engineers, physicists and clinicians from Carnegie Mellon, the University of Pittsburgh, the Massachusetts Institute of Technology, Florida Atlantic University, Korea University, the Korea Advanced Institute of Science and Technology, and Harvard University will be published this week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).

In the current study, the international research team evaluated the biophysical properties - shape, surface area and volume - and biomechanical properties - flexibility and stickiness - of red blood cells under normal oxygenated conditions using electromagnetic waves to measure small differences in physical properties. The technique, known as common-path interferometric microscopy, allowed researchers to get a three-dimensional view of the cells.

Using blood samples from patients with sickle cell disease, the researchers separated red blood cells into four groups based on their density. Normal, disc-shaped red blood cells were the least dense, while severely sickled cells were the most dense. They then took samples from people receiving hydroxyurea treatment and those not receiving treatment. The red blood cells of those receiving treatment showed an improvement in all of the biophysical and biomechanical properties tested across all density levels. Furthermore, improvement in the physical properties of red blood cells of people treated with hydroxyurea correlated more with an increase in the red blood cell volume than with levels of fetal hemoglobin.

"Our findings shine a light on the mechanism behind hydroxyurea action, which has long been debated in the scientific community," said Ming Dao, principal research scientist in MIT's Department of Materials Science and Engineering and co-author of the study. "It's exciting to see that using the latest optical imaging tools, we can now confirm which one is the dominating mechanism. Understanding the key mechanism of action will allow us to explore novel and improved therapeutic approaches for sickle cell disease."

The researchers hope that these biophysical markers can be combined with biochemical and molecular-level markers to assess things like the severity of a patient's sickle cell disease, determine whether or not a patient will respond to hydroxyurea treatment and monitor the effectiveness of that treatment.

Sickle Cell Natural Healing: A Mother's Journey
 Source: Eurekalert

Gene editing of blood stem cells can correct disease-causing mutations

Recent advances in gene editing technology, which allows for targeted repair of disease-causing mutations, can be applied to hematopoietic stem cells with the potential to cure a variety of hereditary and congenital diseases. Gene editing can overcome many of the obstacles associated with gene addition therapies, but this young field still faces many challenges before it is ready for human testing, as discussed in a Review article published in Human Gene Therapy.

The article entitled "Gene Editing of Human Hematopoietic Stem and Progenitor Cells: Promise and Potential Hurdles" is part of a special joint issue on stem cell gene therapy in Human Gene Therapy and Stem Cells & Development guest edited by Luigi Naldini, MD, Scientific Director, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy. A special "upside-down" print issue will be distributed at ESGCT/ISSCR Florence 2016 in October.
Gene Editing, Epigenetic, Cloning and Therapy 

Kyung-Rok Yu, Hannah Natanson, and Cynthia Dunbar, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, describe how earlier gene addition strategies and the hurdles they encountered have informed the current development of gene editing approaches. The authors present the state-of-the-art in gene editing technology and the potential to apply these novel techniques to repair genetic flaws in hematopoietic stem cells, which give rise to the different types of cells in blood, and then to test those strategies in human clinical trials.
"Gene editing is the hottest new technology in gene therapy. The use of this approach to genetically modify hematopoietic stem and progenitor cells is very promising, but requires a careful assessment," says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. "This mini-review by Dr. Dunbar's group at NIH provides a very insightful analysis of recent advances and current limitations of this approach

Smartphone App may offer needle free way to screen Blood for Anemia

Carolina Henriques:

Engineers and computer scientists from the University of Washington (UW) have developed what they are calling a HemaApp, designed to detect hemoglobin concentration using simply a smartphone camera and a little extra lighting — rather than needles or an expensive, specialized machine.

Measuring hemoglobin, a protein found in red blood cells, is particularly important for people with anemia and other blood disorders, who require frequent blood draws. The app is also thought to detect abnormal hemoglobin properties, which could help screen for diseases such as sickle cell anemia.

Described in an article that won a  ‘Best Paper’ award, HemaApp will be presented at the Association for Computing Machinery’s 2016 International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp 2016), taking place on Sept. 15 in Germany.

Healthcare providers now measure hemoglobin levels by drawing blood with a needle or an intravenous line, or by using Masimo Pronto, an U.S. Food and Drug Administration (FDA)-approved device that measures hemoglobin noninvasively by clipping a sensor onto a person’s finger. The device, however, is too expensive for many medical facilities worldwide.

“In developing countries, community health workers have so much specialized equipment to monitor different conditions that they literally have whole bags full of devices,” Edward Wang, the study’s lead author and UW electrical engineering doctoral student, said in a press release. “We are trying to make these screening tools work on one ubiquitous platform — a smartphone.”

HemaApp works by analyzing the color of  blood when light is shone from the phone’s camera — with a little help, for now, from external lighting — through a patient’s fingers, and then estimating hemoglobin concentrations. By analyzing how colors are absorbed and reflected across wavelengths, it can detect concentrations of hemoglobin and other components, like plasma.

HemaApp was tested in an initial trial including 31 patients. Requiring only one smartphone modification, HemaApp performed as well as the Masimo Pronto, the researchers said.

To make sure that the technology works on different skin tones and body masses, the team developed processing algorithms that use the patient’s pulse to differentiate between the properties of the patient’s blood and the physical aspects of the patient’s finger.

The UW team tested the app under three different scenarios: using the smartphone camera’s flash alone, in combination with a common incandescent lightbulb, and with a low-cost LED lighting attachment – additional light sources fall onto other sections of the electromagnetic spectrum that aren’t now found on all smartphone cameras.

“New phones are beginning to have more advanced infrared and multi-color LED capabilities,” said Shwetak Patel, the paper’s senior author and an endowed professor in Computer Science and Engineering and Electrical Engineering at UW. “But what we found is that even if your phone doesn’t have all that, you can put your finger near an external light source like a common lightbulb and boost the accuracy rates.”

In the initial studies, HemaApp’s hemoglobin measurements had a 69% correlation to a patient’s complete blood count (CBC) test, a 74% correlation when using a common incandescent light bulb, and an 82% correlation using a small circle of LED lights attached to the phone. Masimo Pronto scored an 81% correlation to the blood test.

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The app is not meant to replace blood tests, but results suggest that it could be an effective and affordable screening tool to determine if blood testing is needed.  When used in anemia screening, HemaApp accurately identified 79% of the cases of low hemoglobin levels and 86% when aided with light sources.

“Anemia is one of the most common problems affecting adults and children worldwide,” said Doug Hawkins, a UW Medicine, Seattle Children’s Hospital, and Seattle Cancer Care Alliance pediatric cancer specialist. “The ability to screen quickly with a smartphone-based test could be a huge improvement to delivering care in limited-resource environments.”

MegaFood - Blood Builder, Promotes Healthy Blood Cell Production & Circulation, 90 Tablets (Premium Packaging) Further research steps include further testing of HemaApp to collect additional data and improve accuracy rates. The research project received financial assistance from the Washington Research Foundation.

Stem cell transplant cures children with sickle cell anemia, says Alberta hospital

7 girls, 2 boys cured in what lead doctor considers unprecedented treatment

By Lisa Monforton,

Cardelia Fox has a tattoo on the inside of her right forearm with the words "Set free." 

It's a reminder of how a cutting-edge transplant at the Alberta Children's Hospital cured her of sickle cell anemia and a life of hospital stays and blood transfusions.

The chronic genetic blood disorder caused Fox to have three childhood strokes — the first when she was only six months old. She would have two more at age six and 10.

Until the age of 17, she had been in and out of hospital and previously needed to have monthly life-saving blood transfusions.

The year Fox turned 17 she was one of the first patients to undergo the stem cell transplant procedure at the Alberta Children's Hospital.

The success of the procedure has captured interest from around the world, says Dr. Greg Guilcher, a pediatric oncologist who leads the sickle cell blood and marrow transplant program in Calgary.

Dr. Greg Guilcher is the lead doctor for the stem cell transplant procedure at Alberta Children's Hospital.

"To our knowledge, no one else is offering this protocol in children with sickle cell anemia," said Guilcher, who is also an assistant professor in the departments of oncology and pediatrics at the University of Calgary's Cumming School of Medicine.

What sets the Calgary procedure apart from other sickle cell anemia cures in young children is the lead up to the transplant. 

"​This protocol uses the 'lightest' doses of medication — no chemotherapy but immune suppressing drugs only, with a low dose of radiation," said Dr. Guilcher in a statement. 

While the protocol was developed and is used in the U.S., Dr. Guilcher said he's not aware of any other hospital using it on children.

More exciting is the fact that there have been no incidents of stem cell rejection. 

"We're getting phone calls and emails from around the world from interested parents and other doctors. We think we're ahead of the curve in offering this curative therapy as a standard of care."

Sickle cell anemia is a chronic illness where blood vessels can become blocked when blood cells change into a sickle shape, potentially affecting every organ and causing strokes, lung disease heart strain and spleen and bone damage. With advanced drug therapy treatment, life expectancy is 55- to 60-years-old.

The success of the procedure, which was first performed in Calgary in 2009, has cured seven girls and two boys to date.

Life-changing, says patient

"Before the stem cell transplant I felt like I was trapped," says Fox, whose sister Tamika Allen was a perfect match — a rare one in five occurrence within families. "Without this treatment I would likely still be at Foothills getting blood transfusions every month."

Tamika Allen, left, was a perfect stem cell match to her sister Cardelia Fox, which allowed her to have a procedure curing her of sickle cell anemia. (CBC)

Once Allen found out she was a full match, she didn't think twice about helping her sister.

Without a family match, the transplant procedure is generally considered too risky to perform.

"When we learned I was a match there was never any question of whether or not I'd do it," said Tamika, now 22. "Of course I'm going to do this for my sister. It was such a good feeling to be able to help make her life better — now I call her my mini-me."

Rising incidence in Canada

People of African descent are most often affected by sickle cell anemia. One parent can pass on the mutation and not cause the illness, but the illness results when both parents pass it on.

Fox's grandmother died at the age of 35 because of complications from the disease.

In 2008, the Sickle Cell Clinic at the children's hospital regularly treated 16 children.

Now there are more than 80, primarily because of immigration, says Dr. Mike Leaker. He is the head of the clinic, which sees patients from Alberta, Saskatchewan and eastern B.C.

"We now have some excellent medications that can change the course of the illness for many patients," said Leaker. "But a drug is still a treatment, not a cure. For families the word 'cure' is incredibly powerful."

Guilcher is expecting continued interest in the procedure from around the world

Sickle Cell Anemia: From Basic Science to Clinical Practice

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.