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Neurology Today At the Meetings: CNS Annual Meeting

Tuesday, October 23, 2018

Gene Therapy Halts Impairments in Cerebral Adrenoleukodystrophy


CHICAGO—Delivering a functional copy of a crucial gene using a patient's own hematopoietic stem cells (HSC) and a lentiviral vector has kept children with early cerebral adrenoleukodystrophy (CALD) mostly free of major functional disability for more than three years following the procedure, researchers said here at the Child Neurology Society annual meeting.

Fifteen out of 17 patients in the initial cohort that were given the investigational Lenti-D gene therapy are alive and do not have the devastating impairments seen in the disease, such as loss of ability to communicate, cortical blindness, tube feeding, total incontinence, wheelchair dependency, and complete loss of voluntary movement. Without treatment, patients become severely debilitated soon after disease onset.

Two children did not make it to two years of follow-up — one died because of disease progression and another withdrew from the study to undergo allotransplantation instead, the researchers reported.

"For a disease that frequently progresses to vegetative state or death within two years, being able to prevent loss of neurological function in most boys is quite a dramatic result," said Patricia L. Musolino, MD, PhD, assistant professor of neurology at Harvard, who presented the findings.

To be enrolled in the trial, patients had to be 17 or younger with evidence of active but early disease on brain imaging and no matched sibling donor. The drug has been granted breakthrough status by the US Food and Drug Administration.

CALD is the brain form of adrenoleukodystrophy, in which mutations of the ABCD1 gene brings about impaired expression of a protein needed to degrade very long chain fatty acids, leading them to build up to toxic levels. ALD affects about 1 in 17,000 children; approximately 40 percent of boys with the mutation will develop the cerebral form in early childhood. 

The standard treatment for ALD has been allotransplantation of bone marrow healthy cells (allo-HSCT) from a donor with the non-mutated gene, but these transplants involve risks, especially when there are no healthy sibling cells available and the donor is someone else. The allo-HSCT procedure has a more than 10 percent treatment-related mortality, with grade 2 to 4 graft-versus-host disease in 10- to 40-percent of cases and requires prolonged immune suppression post-transplant, which can elicit the risk of severe infections.

Bone marrow transplantation with a compatible sibling donor is only available to a limited number of boys with cerebral ALD. Families become aware of the genetic mutation in a child because an older sibling has already suffered irreversible disabilities and death.  

Twelve more patients given the therapy also have not exhibited those major disabilities, but are still in early follow-up, except for one patient whose family chose to have the child undergo allotransplantation. 

"We are hopeful that as newborn screening continues to expand early detection of these mutations, many more boys will be able to be followed and treated before any symptoms occur," Dr. Musolino said. "Lenti-D gene therapy stabilized neurologic disease progression and may offer an alternative to allo-HSCT in patients with early cerebral disease, particularly for patients with no matched sibling donors."

Joshua Bonkowsky, MD, PhD, chief of pediatric neurology at the University of Utah who specializes in CALD, said the therapy is encouraging on several fronts.

"First, this approach uses the patient's own cells, so finding a donor is not an issue," he said. "And the long-term risk for graft-versus-host disease seems to be resolved. Second, the effectiveness including mortality appears as good as standard HSCT."

Outcomes after standard HSCT, he added, "are not ideal — there continues to be some disease progression while the transplant becomes effective, and children with CALD who have HSCT will still develop peripheral neuropathy as adults."

He said that while the data suggest the results on the new gene therapy are better than for standard HSCT, the small number of patients makes it "hard to be certain."

There is also the question of cost. "Is the expense that will be charged to patients, families, and the health care system proportionate?" Dr. Bonkowsky asked. "We are all aware now of the conundrums regarding price and access to medicines: Companies need to pay for the development of these medicines, but are the prices so high that we are essentially limiting access to children living in a first-world country? This question of price has become very contentious in the field."


Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 2017; 377:1630-1638.