Wednesday, 12 Dec 2018
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Gene therapies could transform the treatment of sickle cell disease

Erica Esrick examines Manny Johnson during a check-up at the Dana-Farber / Boston Center for Cancer and Blood Disorders. Johnson is the first subject in the Esrick and David A. Williams sickle cell trial using gene therapy. (Sam Ogden / Dana-Farber Cancer Institute) Manny Johnson does not stop getting herself rubbing a stain on the upper right side of her chest. At age 21, then a 21-year-old from Boston, was dependent on an implanted port to facilitate his monthly blood transfusions for sickle cell disease, a genetic disorder causing a stroke. at the age of three. But in November, six months after Johnson became the first patient to receive experimental treatment to cure his illness, the port that was part of it – requiring special permission to play sports, used when it was dispensed from school for a day or more. two per month for treatment – has been removed. Johnson has not needed transfusions or symptoms since May. "It's like, wow, that fascinates me," said Johnson, who said he hardly knew what to think when his medical team told him she would not need to see him. before three full months "I'm so used to being next to them, it's like: freedom." Johnson's doctors, who had to present case of his late treatment Monday at the annual meeting of the American Society of American Hematology, warn them that they do not know how long it will remain without transfusion or whether other patients will experience a similar experience. "He's a patient. . . but it's a very impressive result, "said John F. Tisdale, principal investigator at the National Heart, Lung and Blood Institute, who was not involved in the work and was expected to present distinct results from a Different gene therapy testing for sickle cell disease. For patients and researchers, this is an exciting and unprecedented moment. Johnson's experimental therapy is only one of many approaches using advanced genetic techniques to try to cure a disease known for nearly 70 years as the first "molecular disease." In 1949, Nobel laureate Linus Pauling traced sickle cell disease. an aberrant form of hemoglobin, a protein in red blood cells that carries oxygen. It has helped pave the way for the modern era of medicine, focusing on the use of the biological roots of disease to untangle diseases – yet, sickle cell anemia, widespread in the people of African descent, has also become a flash point of medicine at the intersection of race and health care. According to one study, doctors often tend not to believe patient reports of pain caused by the disease. President Richard M. Nixon said it was "a sad and shameful fact that the causes of this disease have been largely neglected in our history." There was only one drug approved for the disease until last year. "This is an incredible new situation, in which there are people who have to choose between clinical trials, after having access to none," said Erica Esrick, hematologist at Dana-Farber / Boston Children's Cancer Treatment and Blood Disorders Center. who directed the work. "From a historical perspective, the most affected African-American population is the African-American population – who have not really received the medical care they deserved." In the case of sickle cell disease, a typo of a letter buried in the Billions of DNA letters that spell out the instruction manual in genetics intended for a human cause the formation of red blood cells in a form crescent moon. These malformed blood cells can get stuck in the blood vessels and cause inflammation, infections and organic lesions. In the United States, about 100,000 people have sickle cell disease. They are usually identified during neonatal screening and tend to receive good care as children. But as they grow up and move into adulthood, the effects of the disease begin to accumulate at a time when sickle cell patients often have trouble finding specialists, because of the fragmentation of the health care system. Patients with organic lesions and debilitating chronic pain without a competent physician often consult the emergency department. At a time when society is undergoing an epidemic of analgesic abuse, they are often confused with drug seekers. The fact that people with sickle cell disease are mainly African-American adds another layer of potential discrimination to the way they are treated. A cure is possible for those who can find a compatible donor to do a bone marrow transplant and endure the procedure. But it was not until now – with the age of the multitude of genetic techniques – that the idea of ​​repairing the disease at the root, with a patient's own cells, had become plausible. "We are at such a turning point," said Biree Andemariam, chief physician of the Sickle Cell Disease Association of America, not only to cure their disease, but also to change the way people are treated in society. In addition to genetic therapies, new drugs are being developed. "When they [doctors] feel that they have something to offer, I think that will really change the deal. . . This will further encourage hematologists to care for this population, "said Andemariam. "We provide comprehensive care to our patients, but honestly, much of what we do is like palliative care."
Manny Johnson (Sam Ogden / Dana-Farber Cancer Institute)

Erica Esrick (Sam Ogden Institute / Dana-Farber Cancer) Potential therapies developed and tested for sickle cell disease manipulate genes in different ways, providing researchers with a multitude of options and a reason for hope. Esrick and his colleagues have worked to increase the levels of a form of fetal hemoglobin that normally functions and is usually closed after birth. They removed the stem cells from Johnson's blood and modified them in the lab, using a virus to insert a molecule that toggles a genetic switch to reactivate the fetal hemoglobin. They administered a form of chemotherapy to Johnson, and then reinjected it with the altered cells. At six months of absence, they found no sickle cell in his blood and he no longer needed transfusions. They plan to give treatment to the next patient in February, followed by another in March. If all goes well, they plan to seek the ethical approval to try treatment in younger patients. This is a promising result, but the real reason researchers are optimistic is that this is just one of many possible ways to achieve a cure. The biotechnology company Bluebird Bio uses a virus to transmit a gene to generate functional red blood cells and was to present the updated results of its ongoing clinical trial at Monday's conference. Other companies and university teams use to use gene editing tools to correct the gene mutation responsible for sickle cell disease or increase fetal hemoglobin levels. "Genetic tools have evolved, in an exponential manner," said W. Keith Hoots, director of the Division of Blood Diseases and Resources at the National Heart Institute, Lung and blood, which is leading a new initiative to accelerate the development of cures for sickle cell disease. The National Institutes of Health spends about $ 100 million on sickle cell research each year. But the problems of success could be particularly serious because the burden of disease is greatest in developing countries. The price of the few gene therapies sold in the United States is several hundred thousand dollars, and an estimated 20 million people with sickle cell disease worldwide. David A. Williams, hematologist at Dana-Farber / Boston Children's Working with Esrick, said that the team was already thinking about access and had received a grant from the Bill & Melinda Gates Foundation for see if it was possible to develop useful ways to apply their approach in developing countries. Johnson, who has spent a lot of time since graduation to receive medical treatment, said he hoped to inspire others and pave the way for his 7-year-old brother, Aiden, so that he would never feels limited by this disease. "I can not complain. I just hope everything goes as planned. I hope I do everything I should do and pray for the best, "said Johnson. "It's a 15-year study, but the first year is everything."

Erica Esrick speaks with Manny Johnson at Dana-Farber / Boston Children's. (Sam Ogden / Dana-Farber Cancer Institute) Learn more
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