Treatment Success in Fatal Disorder in Children

October 12, 2017

A gene therapy for a fatal neurologic degenerative condition affecting children has shown major success in a clinical trial.

In the STARBEAM trial, adrenoleukodystrophy  stabilized in 15 of 17 children who received the gene therapy, with no major functional disability at 24 months after infusion.

"Adrenoleukodystrophy is a devastating disease," senior author, David Williams, MD, Boston Children's Hospital, Massachusetts, commented to Medscape Medical News. The condition usually presents in early childhood and progresses quickly, leading to loss of function and eventual death, normally within a few years, he said. Until now, the only treatment has been donor stem cell transplant, but only about 20% of patients have a suitable match, and there can be many severe complications, he noted.

"Our study with the gene therapy was a great success. For the first time we have something to offer the 80% of children who don't have a good match for a donor transplant. This gives them a real hope of life," he said.

"So far, the gene therapy looks as effective as donor stem cell transplants, but its safety looks far better. There are much fewer complications," he added.

The STARBEAM study was presented at the 2017 Child Neurology Society Annual Meeting and was published simultaneously October 4 in the New England Journal of Medicine.

In an accompanying editorial, Marc Engelen, MD, Academisch Medisch Centrum–Emma Children's Hospital, Amsterdam, the Netherlands, says the gene therapy "appears to be poised as a real treatment option for cerebral adrenoleukodystrophy, and it might even become the first gene therapy approved by the Food and Drug Administration."

Dr Williams explained that adrenoleukodystrophy is an X-linked genetic disease and so affects mainly boys. It is a rare disease, affecting 1 in every 21,000 males. It is caused by a defect in the ABCD1 gene encoding for the ALD transporter protein, which removes long-chain fatty acids from cells.

In this condition, the build-up of long-chain fatty acids in the brain causes inflammation and eventually neuronal death. The condition develops in about 35% of boys with the abnormal gene younger than 12 years of age and in a smaller percentage of affected patients over age 12 years.

Allogeneic (donor) stem cell transplantation is the only effective therapy for cerebral adrenoleukodystrophy that has been identified to date, the authors write. and it is more likely to be effective if it is performed at an early stage of neurodegeneration, before symptoms have developed, so rapid identification of potential highly matched hematopoietic stem-cell donors is important.

The best results with this approach have been achieved with the use of cells from HLA-identical, unaffected related donors (normally a sibling), but these are available in only around 20% of cases. Stem cell transplants from unrelated donors have a much higher risk for complications, including graft failure and graft-vs-host disease, which are often fatal, Dr Williams noted.

For the current study, the researchers evaluated a different approach: the use of the patients' own CD34+ hematopoietic stem cells carrying a gene therapy —– the correct ABCD1 gene. The gene is transduced into the cells ex vivo with a lentiviral (Lenti-D) vector.

"There are two very cool parts to this therapy," Dr Williams commented. "The first is the genetic engineering of the correct gene and delivery into the patients' own cells with a viral vector, and the second part is after transplanting the gene therapy stem cells into the patient, they travel into the brain and deliver the protein to its target."

For the study, 17 boys between aged 4 to 13 years received the gene therapy. All patients had gene-marked cells after engraftment and measurable ALD protein. No treatment-related death or graft-vs-host disease was reported. At the time of the interim analysis — a median follow-up of 29.4 months since the treatment — 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms.

Treatment was not successful in two patients. One patient progressed rapidly after enrollment but before the therapy was given, so the disease had probably progressed too far by the time the treatment was administered, Dr Williams said.

"The second patient showed some signs of progression on brain MRI, and the treating physician was concerned that the therapy wasn't working so withdrew the patient from the trial so he could receive a donor transplant, but very tragically, he died from complications of that transplant," he said.

MRI brain scans showed limited progression of disease as compared with the known rates of lesion progression among untreated boys (mean increase in Loes score, 2.2 and 2.3 points per year for the posterior and anterior patterns, respectively), the researchers report.

They point out that neither donor hematopoietic stem cell transplantation nor gene therapy appear to prevent white-matter lesion progression during the initial 12 to 18 months after treatment.

They explain that microglial cell death appears to play an important role in the disease, and therefore disease may progress during the time before replacement of microglial cells. "This reinforces the urgency in identifying cerebral disease early and treating it swiftly. Infusion of autologous stem cells may have an advantage over allogeneic transplantation in this sense, because of the time saved by not needing to find a donor," they state.

"One of the things we need to do more work on is how to enhance the brain uptake of these cells," Dr Williams added. "Currently it appears to take 12 to 18 months for this to happen fully, during which time the disease can progress." 

He noted that two major issues still need to be addressed: (1) how long the treatment effect will last (ie, whether the effect will be permanent or another treatment will be necessary)  and (2) whether there will be any long-term side effects.

He pointed out that in previous trials of gene therapy using a different viral vector, the vector resulted in integration of viral genes, causing leukemia and myelodysplastic syndrome.

"However, we used a different viral vector — Lenti D — which has been used in other gene therapy trials as well and so far looks safe, but there have only been small numbers of patients treated so far and we have to follow up closely long term."

In his editorial, Dr Engelen asks whether this gene therapy will replace allogeneic transplantation as the standard treatment for cerebral adrenoleukodystrophy. He says the gene therapy "certainly has potential, but some concerns remain." These include the observation that only about 19% of CD14+ cells were positive for ALD protein 24 months after the treatment.

Responding to this, Dr Williams told Medscape Medical News: "We do need to establish what level you need to stop disease progression, but from this study it appears that 19% is enough."

Dr Engelen also raises the issue of cost, pointing out that a previous gene therapy developed for a different condition has had to be discontinued because the price of approximately $1 million per patient was prohibitive.

Dr Williams said the price has not been established. "This will be set by the company commercializing the treatment — Bluebird Bio — after negotiations with third-party payors if the therapy is approved." But he pointed out that donor stem cell transplants can cost several hundred thousand dollars if there are complications.

A Case for Routine Screening

Because both the gene therapy and the allogeneic transplant need to be given very early in the course of the disease, preferably before symptoms appear, Dr Williams believes that there is a case for routine genetic screening of infants to identify those at risk for the condition. 

"Not all children with the genetic mutation will develop the condition but they can be monitored with MRI scans to detect brain inflammation and then the treatment given as soon as this starts. The fact that this gene therapy has been successful strengthens the case for such genetic screening," he said.

He added that the success of the current study had been built on years of basic research funded mainly by government sources. "In the current political environment, it is imperative that we keep investing in basic science so that these types of breakthroughs continue to occur," he stressed.

The STARBEAM trial was supported by Bluebird Bio; the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health; the Patient-Centered Outcomes Research Institute; and the Great Ormond Street Hospital and University College London Great Ormond Street Institute of Child Health Biomedical Research Centre. Dr Williams reports grant support and nonfinancial support from Bluebird Bio during the conduct of the study; grant support from Bluebird Bio outside the submitted work; and a patent related to compositions and methods to treating hemoglobinapathies licensed to Bluebird Bio.

N Engl J Med. Published October 4, 2017.  Abstract, Editorial 

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