Gene therapy effectively stabilizes progression of cerebral adrenoleukodystrophy, trial reveals

In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) -- a neurodegenerative disease that typically claims young boys' lives within 10 years of diagnosis -- effectively stabilized the disease's progression in 88 percent of patients, researchers from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Massachusetts General Hospital report today.

According to their results, published in the New England Journal of Medicine, 15 of 17 patients had stable neurologic functioning more than two years on average after receiving the gene therapy, which was administered in a clinical trial sponsored by bluebird bio. It is one of the largest gene therapy trials targeting a single-gene disease to be published to date.

"Although we need to continue to follow the patients to determine the long-term outcome of the gene therapy, so far it has effectively arrested the progress of cerebral adrenoleukodystrophy in these young boys," says David A. Williams, MD, chief scientific officer and senior vice-president for research at Boston Children's Hospital and president of Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the lead author of the study. "This is a devastating disease, and we are all quite grateful that the patients and their families chose to participate in the trial."

The treatment leverages bluebird bio's proprietary Lenti-D gene therapy to deliver the functional gene to patients' stem cells in the laboratory.

"The clinical experience with Lenti-D demonstrates the potential for gene therapy to benefit patients with CALD," said David Davidson, MD, chief medical officer of bluebird bio. "Early intervention is important to optimize outcomes, so the recent implementation of newborn screening in many states will improve the ability to provide timely treatment to preserve neurologic function in affected boys."

Bluebird bio is engaged in ongoing discussions with the FDA and European regulators on their plans to bring the therapy to market.

"This treatment results from more than two decades of investment in basic gene therapy research by the NIH and others," Williams says. "It really demonstrates that research funding is essential to developing the next generation of therapies for devastating childhood diseases."

"Since it was first described 100 years ago, adrenoleukodystrophy has robbed the function of children who, up until the disease's onset, had been developing normally," says Florian Eichler, MD, co-lead author on the study and the director of the Leukodystrophy Service at Massachusetts General Hospital. "These are children who have been growing and thriving, and then suddenly, their parents witness this devastating decline that starts with personality changes and then progresses to motor problems and loss of their ability to walk and talk."

Adrenoleukodystrophy (ALD) -- featured in the 1992 movie "Lorenzo's Oil" -- is an X-linked genetic disease that usually affects boys. It causes a build-up of fatty acids that damage the myelin sheaths of nerves in the nervous system and also results in adrenal insufficiency. The most devastating form of the disease is CALD, marked by demyelination and inflammation in the patients' brains.

Until now, stem cell transplantation using cells donated by another person has been the only known effective therapy for CALD. Yet, its efficacy is drastically reduced if performed during later stages of neurodegeneration and usually works best with a disease-free matched sibling donor, which fewer than one-quarter of CALD patients have.

To perform the gene therapy, clinicians first collect a patient's blood stem cells, which give rise to all mature blood cells. In a highly-specialized laboratory that contains a clean room for preparation of medicines, a viral vector is used to insert a correct version of the faulty gene into the patient's stem cells. Then, after the patient receives chemotherapy to make room for the genetically altered blood stem cells in the bone marrow, the cells are infused back into the patient's bloodstream via an intravenous line.

"In my clinic, the impact of this trial has been phenomenal," Eichler says. "Boys without a donor match for stem-cell transplant were often passing away within a year or two of their diagnosis. Now, with early diagnosis and gene therapy, these boys are living longer and some are thriving enough to play sports and participate in other normal day-to-day activities."

At the latest follow-up, all patients who participated in the clinical trial were expressing functional ALD protein, which their bodies had been unable to produce prior to gene therapy. The trial is ongoing and has received regulatory approval to expand patient numbers.

"There are two great advantages to gene therapy," Williams says. "The first is that patients don't have to wait to find a donor match. The second is that, because we use their own, gene-modified stem cells, there's no risk of graft-versus-host-disease and the patients do not require any immunosuppression drugs, which can have very significant, even fatal, side effects."

The ALD gene therapy trial is part of a robust and growing portfolio of pediatric gene therapy trials at Dana-Farber/Boston Children's that also includes clinical trials for X-linked severe combined immune deficiency ("bubble boy" disease), chronic granulomas disease, a recently completed trial in Wiskott-Aldrich Syndrome and the use of gene therapy to treat some types of childhood leukemia using "CAR T cells". In addition, the Food and Drug Administration has just approved a ground-breaking study at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center for the use of gene therapy to cure sickle cell disease.

"We are excited to provide this cutting-edge therapy to patients afflicted with cerebral adrenoleukodystrophy and other life-threatening diseases," says Christine Duncan, MD, co-lead author on the study, who is a pediatric hematologist/oncologist at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "The work is the result of robust collaboration and years of work by teams dedicated to improving the lives of children."