Stories about: sickle cell disease

Stopping the pain of sickle cell disease at its source

sickle cell pain
The pain of sickle cell disease can be unbearable. But there’s a new view emerging on how that pain comes about, one that has spurred a new clinical trial aimed at stopping the pain at its source. (stevendepolo/Flickr)

If there’s one thing most patients with sickle cell disease will agree on, it’s that sickle cell hurts. A lot.

The characteristic rigid, sticky, C-shaped red blood cells of this inherited disease tend to get stuck in the small blood vessels of the body. If so many get stuck in a vessel that they cut off blood flow, the body sends out a warning signal in the form of searing pain that doctors call a pain or vaso-occlusive crisis (at least, that’s the historic view; more on that in a minute). The pain can happen anywhere in the body, but most often occurs in the bones of the arms, legs, chest and spine.

Preventing flare-ups—and stopping them when they happen—is a major part of the care plan for any patient with sickle cell. Right now doctors try to avoid pain crises largely by diluting a patient’s blood with fluids or transfusions, thereby keeping the numbers of sickled cells relatively low.

What these treatments don’t do is tackle the pain directly. Doctors can use pain medications, but over time, patients can become tolerant to painkillers, requiring ever-larger doses. What’s needed is something that can stop the complex cascade of events that ignite a pain crisis.

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Getting iron out after putting blood in: Transfusions and iron overload

Frequent transfusions can leave the body overloaded with iron. Ellis Neufeld is helping find new ways of scrubbing that extra iron from the blood. (Research Indicates/Flickr)

In some children the body’s machinery for making red blood cells just doesn’t work right. Conditions like Diamond Blackfan anemia or thalassemia can leave the body anemic, struggling to keep up with its own demands for oxygen. And the misshapen red blood cells of sickle cell disease can get stuck in small blood vessels and cause anemia, organ damage and great pain.

Right now, the most effective way to care for these blood disorders is with blood transfusions. But unlike trauma or surgery, a single transfusion doesn’t solve the problem for people with life-long anemias or sickle cell. Most people with thalassemia, for example, have transfusions every month for their entire life.

“After about 20 transfusions, you reach a point where the body is overloaded with iron from all of the extra hemoglobin that’s been introduced into it,” says Ellis Neufeld, MD, PhD, director of the Thalassemia Program at Dana-Farber/Children’s Hospital Cancer Center (a partnership of Boston Children’s Hospital and Dana-Farber Cancer Institute). “The body has no way to actively remove iron on its own, so the iron starts to build up.” Over time, this can damage the liver, heart, pancreas and other major organs.

Over the last 40 years, a lot of work at DF/CHCC and elsewhere has gone into what’s called chelation therapy: drug-based treatments that scrub the blood of excess iron. Right now there are three chelating drugs in broad use: deferoxamine, deferasirox and deferiprone. They work well for many patients, but have their disadvantages.

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Sickle cell disease and the thalassemias: The advantages of staying forever young

Flipping a single molecular switch could turn off the mutation that causes sickle cell diseae. Stuart Orkin has already done it in mice. (CDC PHIL)

What if we really could turn our bodies’ clocks back? In some cases, that could be a really good thing. Take sickle cell disease. A scourge of tens of thousands worldwide, it stems from a genetic defect in hemoglobin, the oxygen-carrying protein in red blood cells.

Normally, our bodies can produce two forms of hemoglobin: adult hemoglobin, the form susceptible to the sickle cell mutation; and fetal hemoglobin, which is largely produced during development and for a short time after birth. Our bodies finish making the switch from fetal to adult hemoglobin production by about four to six months old – the same time frame when children with the sickle cell mutation first start to show symptoms of the disease.

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Moving gene therapy into high gear

A healthy copy of the affected gene is introduced into the patient's stem cells by means of a vector, a genetically altered virus that does not cause ongoing infection. The stem cells, corrected for the defect, are infused back into the patient. (Click to enlarge.)

Gene therapy, still experimental but beginning to enter the clinic, attempts to utilize advanced molecular methods to treat and even reverse genetic diseases. The field started in earnest about 25 years ago and has had many setbacks along the way to its recent earliest successes.

International collaboration has been critical. Children’s Hospital Boston is one of the founding members of the Transatlantic Gene Therapy Consortium (TAGTC), a new collaboration that seeks to facilitate a more rapid advancement of this technology for treating human diseases. It was initiated shortly after the first trials of gene therapy for X-linked Severe Combined Immunodeficiency (X-SCID) (in both Paris and London) reported leukemia as a serious side effect. The TAGTC was formed to address this setback, developing safer gene therapy reagents, sharing the costs of their development, and then implementing new gene therapy trials for rare diseases across multiple international sites.

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Fetal DNA tests: Are we finally entering an era of eugenics?

Eugenics, 1919. (Photo: A.M. Kuchling/Flickr)

As an Ashkenazi Jew planning to have a baby, I sure as heck wanted carrier screening for Tay-Sachs disease. But that disease is incurable and lethal. What about diseases that don’t severely limit lifespan and aren’t that disabling? During my pregnancy, I went on to have amniocentesis, which included testing for Down syndrome and – because of my family history — for a few genes associated with autism and mental retardation. But even as I was tested, I had no idea what I’d do if results came back positive.

Sometime soon, almost every expectant family may be faced with such life-and-death decisions. New tests are arriving that can detect Down syndrome by analyzing fetal DNA in the mother’s blood during the first trimester of pregnancy.

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Sickle cell: New looks at a neglected disease

sickle cell disease red blood cells
(OpenStax College/Wikimedia Commons)

Sickle-cell anemia was the first disease to have its genetic cause identified, in the 1950s — a milestone in human genetics. Yet today, there’s just one FDA-approved drug, hydroxyurea, developed 20 years ago at Children’s. Though it’s a mainstay of treatment, reducing the frequency of severe pain, acute chest syndrome and the need for blood transfusions, it can cause toxicity, and about half of patients aren’t helped by it. Only a hematopoietic stem-cell transplant is curative.

Research on sickle-cell disease has generally been underfunded compared with other genetic diseases like cystic fibrosis that aren’t as common. But Children’s has been exploring new treatment approaches for decades, and two exciting possibilities have emerged.

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