Stories about: gene therapy

BCL11A-based gene therapy for sickle cell disease passes key preclinical test

sickle cell gene therapy coming

Research going back to the 1980s has shown that sickle cell disease is milder in people whose red blood cells carry a fetal form of hemoglobin. The healthy fetal hemoglobin compensates for the mutated “adult” hemoglobin that makes red blood cells stiffen and assume the classic “sickle” shape.

Normally, fetal hemoglobin production tails off after birth, shut down by a gene called BCL11A. In 2008, researchers Stuart Orkin, MD, and Vijay Sankaran, MD, PhD, at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center showed that suppressing BCL11A could restart fetal hemoglobin production; in 2011, using this approach, they corrected sickle cell disease in mice.

Now, the decades-old discovery is finally nearly ready for human testing — in the form of gene therapy. Today in the Journal of Clinical Investigation, Dana-Farber/Boston Children’s researchers report that a precision-engineered gene therapy vector suppressing BCL11A production overcame a key technical hurdle.

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Mom-entrepreneur forms gene therapy company to tackle Sanfilippo syndrome

Karen and Ornella Aiach Sanfilippo gene therapy

Sanfilippo syndrome A is a neurodegenerative condition caused by a genetic error in metabolism: because of a missing enzyme, long-chained sugar molecules cannot be broken down. Toxic substrates accumulate in cells, causing a rapid cognitive decline and, later, motor decline. Most affected children die in their teens or earlier.

There is no treatment, and when Karen Aiach’s daughter Ornella was diagnosed with Sanfilippo syndrome A, no companies were even working on the disease.

As a mother, Aiach could not accept that.

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Wine used to toast CGD gene therapy trial linked to decades-long scientific journey

Brenden Whittaker (left) and David Williams, MD (photo: Sam Ogden)

When Brenden Whittaker of Columbus, Ohio, the first patient treated with gene therapy for chronic granulomatous disease (CGD), showed successful engraftment last winter, the gene therapy team lifted glasses for a celebratory toast. The wine they sipped was no ordinary wine. The 2012 Bordeaux blend came from an award-winning California vineyard owned and operated by Robert Baehner, MD, a pioneering pediatric hematologist with ties to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Decades before, Baehner had done fundamental research in CGD, an inherited immune system disorder that occurs when phagocytes, white blood cells that normally help the body fight infection, cannot kill the germs they ingest and thus cannot protect the body from bacterial and fungal infections.

Children with CGD are often healthy at birth, but develop severe infections in infancy and early childhood from bacteria that would cause mild disease or no illness at all in a healthy child. This was true for Whittaker. Diagnosed with CGD when he was 1, his disease became increasingly severe, forcing him to quit school several years ago.

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Forty years waiting for a cure: ALD gene therapy trial shows early promise

Ethan and me, June 1977
Ethan and me, June 1977

A small piece of notepaper, folded twice, sits tucked in a slot of the secretary desk in the living room. Every so often, I pull it out, read it, then reread.

Addressed to my mom, the paper has a question and two boxes, one “yes” and one “no,” written with the careful precision of a 7-year-old.

I am sad of Ethan. You too?

A check marks the box.

Yes. Yes, I am sad too.

Learning about adrenoleukodystrophy

My brother Ethan Williams was 9 years old in the fall of 1976, when he began to lose his sight. For my parents, that winter brought an endless round of doctor visits, therapists and lab tests.

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Drug ‘cocktail’ could restore vision in optic nerve injury

regenerating optic nerves cropped
Gene therapy achieved extensive optic nerve regeneration, as shown in white, but adding a potassium channel blocking drug was the step needed to restore visual function. In the future, it might be possible to skip gene therapy and inject growth factors directly. (Fengfeng Bei, PhD, Boston Children’s Hospital)

When Zhigang He, PhD, started a lab at Boston Children’s Hospital 15 years ago, he hoped to find a way to regenerate nerve fibers in people with spinal cord injury. As a proxy, he studied optic nerve injury, which causes blindness in glaucoma — a condition affecting more than four million Americans — and sometimes in head trauma.

By experimenting with different growth-promoting genes and blocking natural growth inhibitors, he was able to get optic nerve fibers, or axons, to grow to greater and greater lengths in mice. But what about vision? Could the animals see?

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Storify: The science and business of cystic fibrosis

Cystic Fibrosis panelWhat happens when you put a doctor who specializes in cystic fibrosis in the same room as two biotech executives, one of whom is a ‘dadvocate’ of a teenager with CF? View the highlights and reactions to a a dynamic panel discussion at the Boston Children’s Hospital Global Pediatric Innovation Summit + Awards with Gregory Sawicki, MD, MPH, director of the Boston Children’s Cystic Fibrosis Center; David Meeker, MD, Genzyme president and CEO; Bob Coughlin, Massachusetts Biotechnology Council president and CEO; and moderator Luke Timmerman, founder and editor of The Timmerman Report.

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So far, so good for gene therapy patient Emir Seyrek

Emir Seyrek gene therapy Wiskott-Aldrich ThrivingRemember Emir Seyrek, the Turkish boy who last year was the first patient in gene therapy trial for a genetic immunodeficiency called Wiskott-Aldrich Syndrome? Emir traveled back to the U.S. earlier this month for an annual follow-up visit with his care team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. The news was quite good.

“Emir is the star of the trial,” Sung-Yun Pai, MD—a Dana-Farber/Boston Children’s gene therapy and immunodeficiency transplant specialist and lead (along with David Williams, MD, and Luigi Notarangelo, MD) of the U.S. arm of the trial—tells our sister blog, Thriving. “He has the highest platelet count of all of the children who have gone through gene therapy with this vector so far. His immune function is excellent, and we have no worries whatsoever from a bleeding standpoint. He’s perfectly safe to play like a normal child.”

Learn more about Emir’s progress on Thriving.


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Gene therapy restores hearing in deaf mice

A closeup of the sensory hair bundles in the cochlea (inverted v's), each containing 50 to 100 microvilli tipped with TMC proteins. Cell bodies are below the bundles. (Gwenaelle S. Geleoc & Artur A. Indzhykulian)
The inverted V’s above are sensory hair bundles in the ear, each containing 50 to 100 microvilli tipped with TMC proteins. Gene therapy restores hearing by providing working copies of those proteins. (Gwenaelle Geleoc & Artur Indzhykulian)

More than 70 different genes are known to cause deafness when mutated. Jeffrey Holt, PhD, envisions a day when patients with hearing loss have their genome sequenced and their hearing restored by gene therapy. A proof-of-principle study published today by the journal Science Translational Medicine takes a clear step in that direction, restoring hearing in deaf mice.

“Our gene therapy protocol is not yet ready for clinical trials—we need to tweak it a bit more—but in the not-too-distant future we think it could be developed for therapeutic use in humans,” says Holt, a scientist in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and an associate professor of Otolaryngology at Harvard Medical School.

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Advances in SCID (“bubble boy” disease): A Q&A with a child hematologist/oncologist

David Williams, Luigi Notarangelo and Sun-Yung PaiSung-Yun Pai, MD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, was lead author on two recent articles on severe combined immune deficiency (SCID) in The New England Journal of Medicine. The first reviewed outcomes after bone marrow transplantation; the second reported the first results of a new international gene therapy trial for X-linked SCID. Here, she discusses what’s known to date about these therapies.

Q: What is SCID?

A: SCID is a group of disorders that compromise the blood’s T cells, a key component of the immune system that helps the body fight common viral infections, other opportunistic infections and fungal infections. T-cells are also important for the development of antibody responses to bacteria and other microorganisms. A baby born with SCID appears healthy at birth, but once the maternal antibodies that the baby is born with start to wane, the infant is at risk for life-threatening infections. Unless diagnosed and treated—with a stem cell transplant from a healthy donor or a more experimental therapy like gene therapy—babies with SCID typically die before their first birthday.

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Five new developments in hemophilia

Ellis Neufeld hemophiliaEllis Neufeld, MD, PhD, is a hematologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

From new longer-acting drugs to promising gene therapy trials, much is changing in the treatment of hemophilia, the inherited bleeding disorder in which the blood does not clot. Hemophilia Awareness Month comes at a time of both progress and remaining challenges.

1. Many more treatment products are being introduced, including some that last longer.

People with hemophilia lack or have defects in a “factor”—a blood protein that helps normal clots form. Of the approximately 20,000 people with hemophilia in the U.S., about 80 percent have hemophilia A, caused by an abnormally low level of factor VIII, and most of the rest have hemophilia B, caused by abnormally low levels of factor IX. Many patients with severe hemophilia give themselves prophylactic IV infusions of the missing factor to prevent bleeding (which otherwise can lead to crippling joint disease when blood seeps into the joint and enzymes released from blood cells erode the cartilage).

Hemophilia factors traditionally have such a short half-life that we tend to treat patients every other day with factor VIII and twice a week with factor IX. The first two longer-lasting products came onto the market within the past year, and more are on the way. So now, with factor IX, it is possible to get an infusion just once a week and not bleed. This is really changing how we think about the disease. So far, the longer-acting factor VIII products are not yet long-lasting enough to make as dramatic a difference in the frequency of infusions. And creating really long-acting factors remains a challenge.

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