Stories about: David Williams

Gene therapy halts progression of cerebral adrenoleukodystrophy in clinical trial

David Williams, MD, the principal investigator of the clinical trial, discusses gene therapy and its impact on children with adrenoleukodystrophy

Adrenoleukodystrophy — depicted in the 1992 movie “Lorenzo’s Oil” — is a genetic disease that most severely affects boys. Caused by a defective gene on the X chromosome, it triggers a build-up of fatty acids that damage the protective myelin sheaths of the brain’s neurons, leading to cognitive and motor impairment. The most devastating form of the disease is cerebral adrenoleukodystrophy (CALD), marked by loss of myelin and brain inflammation. Without treatment, CALD ultimately leads to a vegetative state, typically claiming boys’ lives within 10 years of diagnosis.

But now, a breakthrough treatment is offering hope to families affected by adrenoleukodystrophy. A gene therapy treatment effectively stabilized CALD’s progression in 88 percent of patients, according to clinical trial results reported in the New England Journal of Medicine. The study was led by researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Massachusetts General Hospital.

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Landmark moment for science as the FDA approves a gene therapy for the first time

Leukemia blast cells, which could now be destroyed using a first-of-its-kind, FDA-approved gene therapy called CAR-T cell therapy
Leukemia blast cells.

Today, the Food and Drug Administration approved a gene therapy known as CAR T-cell therapy that genetically modifies a patient’s own cells to help them combat pediatric acute lymphoblastic leukemia (ALL), the most common childhood cancer. It is the first gene therapy to be approved by the FDA.

“This represents the progression of the field of gene therapy, which has been developing over the last 30 years,” says gene therapy pioneer David A. Williams, MD, who is chief scientific officer of Boston Children’s Hospital and president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s a realization of what we envisioned to be molecular medicine when this research started. The vision — that we could alter cells in a way to cure disease — is now coming true.”

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Rare disease therapies: Three strategies to bridge the gap between research and industry

Rare disease research: DNA helix pictured here
Genetic mutations underpin many rare diseases.

Right now, there are about 7,000 rare diseases affecting 10 percent of Americans. Only five percent of these diseases have any FDA-approved treatment options.

Panelists:
David Williams, MD: President, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Senior VP, Chief Scientific Officer and Chief of Hematology/Oncology, Boston Children’s
Wayne Lencer, MD: Chief of Gastroenterology, Hematology and Nutrition, Boston Children’s
Phil Reilly, MD, JD: Venture Partner at Third Rock Ventures
Alvin Shih, MD, MBA: Chief Executive Officer at Enzyvant

Even at a place like Boston Children’s Hospital, where doctors regularly see children with rare diseases from all over the world, there are big challenges when it comes to drug discovery and treatment.

“Roughly 70 percent of drugs to treat children are used off-label,” says David Williams, Boston Children’s chief scientific officer. “That’s because these drugs were initially developed for adults and have not been tested formally in children.”

In order to cure rare diseases in children and adults, scientists must bridge the gap between research and industry. On May 25, Boston Children’s Technology and Innovation Development Office (TIDO) and MassBio held a candid panel discussion about what it will take to advance the development of rare disease therapies. Here are three of the biggest takeaways

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Gene therapy: The promise, the reality, the future

gene therapy
(Graphs courtesy Alexandra Biffi, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

Gene therapy stalled in the early 2000s as adverse effects came to light in European trials (leukemias triggered by the gene delivery vector) and following the 1999 death of U.S. patient Jesse Gelsinger. But after 30 years of development, and with the advent of safer vectors, gene therapy is becoming a clinical reality. It falls into two main categories:

  • In vivo: Direct injection of the gene therapy vector, carrying the desired gene, into the bloodstream or target organ.
  • Ex vivo: Removal of a patient’s cells, treating the cells with gene therapy, and reinfusing them back into the patient, as in hematopoietic stem cell transplant and CAR T-cell therapy.

A recent panel at Boston Children’s Hospital, hosted by the hospital’s Technology and Innovation Development Office (TIDO), explored where gene therapy is and where it’s going. Here were the key takeaways:

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Science to care: Q&A with Boston Children’s Hospital’s new Chief Scientific Officer

David Williams, MD
David Williams, MD

When Boston Children’s Hospital decided to hire its first chief scientific officer (CSO) in eight years, the institution sought an individual who could spotlight the hospital’s robust scientific enterprise and effectively connect it to clinical medicine and industry. David Williams, MD, president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and director of clinical and translational research at Boston Children’s, was the ideal choice.

An award-winning researcher, Williams trained in the clinic but also pursued basic science, developing techniques for introducing genes into mouse and human blood cells. He focused on blood stem cell biology, leukemia and gene therapy to correct genetic blood disorders, becoming a 16-year Howard Hughes Medical Institute Investigator, a Member of the National Academy of Medicine and a Fellow of the American Association for the Advancement of Science. He has secured multiple patents for techniques still in use today.

Williams spoke about his vision as CSO to align basic research and clinical care at Boston Children’s and the challenges ahead.

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2017 predictions for biomedicine

2017 predictions for biomedicine

David Williams, MD, is Boston Children’s Hospital’s newly appointed Chief Scientific Officer. He is also president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and director of Clinical and Translational Research at Boston Children’s. Vector connected with him to get his forecast on where biomedical research and therapeutic development will go in the year ahead.

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

sickle cell gene therapy coming
(unsplash/Pixabay)

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

CGD
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, who was diagnosed with ALD when he was 9, with his sister Emily
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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Give childhood cancer a place on the cancer ‘moonshot’

cancer moonshot

Cancer remains the leading disease-related cause of death in children in the United States. Yet, when it comes to cancer research funding and drug development, pediatric cancer is often left behind, writes David A. Williams, MD, president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, in Boston Globe Media’s STAT.

Although there are more than 150 types of childhood cancer, pediatric cancer receives only a small fraction of NIH and National Cancer Institute funding, Williams writes. Yet, he points out, just as breakthroughs in adult cancer research can help children, breakthroughs in pediatric cancer can also benefit adults.

Williams and other members of the Coalition for Pediatric Medical Research recently met with the staff of Vice President Joseph Biden, leader of the federal government’s cancer moonshot. Their message? Make sure that pediatric cancer is represented on the moonshot.

Read Williams’s STAT piece.

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