Stories about: blood disorders

Is obesity on the rise among children with sickle cell disease?

Obese child on a scale
Obesity is more common in sickle cell disease than thought. Why?

Ask many doctors about their image of a child with sickle cell disease (SCD), and they’ll describe a short, skinny child, perhaps almost malnourished. For decades, that image was accurate.

That perception needs to change, though. A group of sickle cell specialists from hospitals in New England—members of the 11 institutions in the New England Pediatric Sickle Cell Consortium (NEPSCC)—recently made a surprising observation: Nearly a quarter of children with SCD are overweight or obese. The question is, why?

The answer may start with their red blood cells (RBCs).

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Customized cell therapy for untreatable diseases: Your tax dollars at work

Leonard Zon (top) and Massachusetts Lt. Governor Timothy Murray in the Stem Cell Program's zebrafish facility. (Courtesy MLSC)
Ed. Note: Leonard Zon, MD, is founder and director of the Boston Children’s Hospital Stem Cell Program, which yesterday was awarded $4 million by the Massachusetts Life Sciences Center to build the Children’s Center for Cell Therapy.

As a hematologist, I see all too many children battling blood disorders that are essentially untreatable. Babies with immune deficiencies living life in a virtual bubble, hospitalized again and again for infections their bodies can’t fight. Children disabled by strokes caused by sickle cell disease, or suffering through sickle cell crises that drug treatments can’t completely prevent. Children whose only recourse is to risk a bone marrow transplant—if a suitably matched donor can even be found.

Over the past 20 years, my lab and that of George Daley, MD, PhD, at Boston Children’s Hospital have worked hard to give these children a one-time, potentially curative option—a treatment that begins with patients’ own cells and doesn’t require finding a match.

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There is a cure for sickle cell disease…for some

Maryam Idan (center), a young Iraqi girl with sickle cell disease, was lucky: she could be cured with a stem cell transplant. Leslie Lehmann, MD, wants to make such transplants an option for more sickle cell patients.

I was surprised when chatting recently with Leslie Lehmann, MD, clinical director of the Stem Cell Transplantation Program at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). She turned to me and asked, “Did you know there’s been a cure for sickle cell disease for nearly 40 years?”

I had to admit that I didn’t. I’ve always thought of sickle cell—a painful and debilitating disease caused by an inherited mutation that makes red blood cells stiffen into a characteristic sickled shape—as a chronic disease to be managed, not one that could be cured.

I’m not alone in that belief. Lehmann often asks this question when she give talks for medical students, residents and other physicians. Their reaction is puzzlement, then a shaking of heads.

The cure is there, though. It’s a stem cell (aka bone marrow) transplant. The catch is that it’s not available to everyone—but for reasons that Lehmann thinks can be overcome.

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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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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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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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Stem cell experiments in genetic blood diseases

The green tips of these chromosomes are telomeres, whose length is a measure of cellular "aging" and determines how many times a cell can divide.

In a roomful of kids’ cancer specialists, like those listening to the keynote speech by George Daley, closing an international pediatric oncology meeting in Boston, the Myc gene is better known as a mutated weapon of mass destruction.

But this driver of cancer growth is also part of a four-gene cocktail that can reprogram an adult skin cell back into an embryonic-like stem cell that holds great therapeutic potential.

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Helping disease cells handle the stress of reprogramming

Fanconi anemia cells have multiple defects in response to DNA damage, making it hard to create iPS cells from them.

I’m attending an international pediatric oncology meeting in Boston with about 2,000 other people. In a session on gene therapy, David Williams, chief of Hematology/ Oncology at Children’s, talked about trying to treat a rare inherited bone marrow failure syndrome, Fanconi anemia, by correcting the gene in the patient’s blood stem cells. It didn’t work the first time, but he has a new tactic.

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