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In the Pipeline – Neurogenetics

In Small Study, Gene Therapy Found Safe and Well-Tolerated for Sanfilippo Type B

Talan, Jamie

doi: 10.1097/
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In a small trial of children with Sanfilippo type B, investigators in France were able to introduce a gene therapy — replacing a defective enzyme — that was found to be safe and well-tolerated.

Gene therapy to deliver a missing enzyme that causes mucopolysaccharidosis (MPS) type IIIB syndrome, also called Sanfilippo type B, was found safe and well-tolerated in an early phase 1-2 trial in four children. The gene therapy seems to slow the cognitive deterioration that is the devastating hallmark of the lysosomal storage disease for which there is no treatment, according to the study published online July 13 in The Lancet Neurology.

Marc Tardieu, MD, PhD, professor of pediatrics and head of the neuropediatric unit at the Ho^pitaux Universitaires Paris-Sud, said that the youngest of the four children in the study is now around 6 years old and is attending school.

“That is the best proof that something good is happening,” he said. “Plus, all of the children are doing better than anyone would have expected.”

Children born with this condition seem to develop normally until 2 to 3 years old, Dr. Tardieu explained. They are missing the enzyme, N-acetylglucosaminidase (NAGLU); without the enzyme, patients accumulate cellular debris that induces apoptosis.

If scientists can prove that gene therapy works, it may be possible to initiate screening and identify children before symptoms develop, he said. Patients would do best if they could be treated under 20 months old, as the early treatment could prevent the toxic effects of the missing enzyme, NAGLU.

After an initial symptom-free interval, the study authors explained, children experience slowed development and behavior problems, followed by progressive intellectual decline. Speech acquisition is often slow, and as the disease progresses, so too does the manifestation of behavioral disturbances, including hyperactivity, pica, and aggressive behaviors.

“My colleagues have worked for 15 years in animals before we were ready to do gene therapy in these children,” Dr. Tardieu said. “We are hoping for a good long-term outcome.”

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The French researchers were given permission from European health regulatory officials to conduct a gene therapy trial on up to four children. Two of the children were from France, one from Italy, and one from Greece, and their ages ranged from 20 to 53 months old.

The children were given immunosuppressive therapy 14 days before the brain surgery to deliver the gene therapy, which was packed inside a recombinant adeno-associated viral vector serotype 2/5 (rAAV2/5) encoding human NAGLU. They delivered the viral vector to 16 different areas in the brain, including the cerebellum. Most of the sites were in white matter.

The team assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in cerebrospinal fluid (CSF), and specific anti-NAGLU immune response for 30 months after surgery.

The team also assessed neurological, behavioral, and developmental features at one month before the treatment, and then again at one year and 30 months. They compared the findings to what they would expect in children with this condition. They determined a developmental quotient: the ratio of developmental age to chronological age × 100.

Throughout the study, they conducted continuous blood tests and viral serology to look for varicella zoster, Epstein-Barr virus, and cytomegalovirus. They collected cerebrospinal fluid (CSF) a month before and at four times during the study. The children had repeated magnetic resonance imaging scans.

The scientists reported that the vector genomes were detected in blood around two days after the surgery. NAGLU activity was detected in lumbar CSF and was 15 to 20 percent of the levels that are present in unaffected children.

Those levels remained over the course of the 30-month follow-up. The youngest patient, a girl who had an older brother with the same disease, improved the most. Her function is close to the development expected in a healthy child. By comparison, her brother is very impaired. Her MRI on follow-up also looked normal, Dr. Tardieu said.

The other three children also had more stable cognitive scores that suggested that they were not deteriorating as fast as others of the same age. The decrease in the developmental quotient was –11 points in patient one, –23 in patient two, –29 in patient three, and –17 in patient four, compared with –37.7 in the natural history of the disease.

The MRI did not detect edema, inflammation, or signs of local necrosis at the vector delivery sites.

The scientists did find NAGLU antigen in the children up to one year, but then immune antigen was not present at 30 months in three of the four patients. Dr. Tardieu said that this is a good sign that most of the children appear to develop immune tolerance to NAGLU, the enzyme missing in the disease. And that could mean that patients may not need long-term immunosuppressive therapy.

Throughout the course of the study, there were 125 reported adverse effects, everything from runny noses to colds. Six were classified as severe, including raised aminotransferase in one patient, respiratory tract infection during follow-up in three, and diarrhea in two.

Most of the other children are making some progress, the scientists said. “They seem better than they would have been,” said Jean-Michel Heard, MD, PhD, a clinician-scientist at the Institut Pasteur in Paris and co-author of the study. “Their cognitive scores appear stable.”

Dr. Tardieu told Neurology Today that the research team will continue to follow the children and expand the study to include more patients, especially younger ones who may benefit the most. They will also add more injection sites outside of the brain to expand coverage. (For more on the animal studies that prompted the small clinical study, “Bench Research on Sanfilippo Type B.”)

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“The most impressive finding is the sibling pair where we have the same mutation and two children following different trajectories,” said Maria L. Escolar, MD, associate professor of pediatrics at the University of Pittsburgh and director and founder of the Program for the Study of Neurodevelopment in Rare Disorders at Children's Hospital of Pittsburgh.

“In this form of disease there is a severe and a mild presentation, so having in this cohort the younger and least symptomatic patient compared to the sibling's natural history makes this result especially exciting. In addition, we know from studies in other MPS disorders that the earlier treated patients have the best outcomes and those who are already affected only stabilize. This is in treatments that we now know are effective because we have two decades of follow-up.”

“I am impressed by the findings,” said Jean-Baptiste Le Pichon MD, PhD, associate professor in pediatrics and program director for the child neurology residency program at Children's Mercy Hospital in Kansas City, MO. “It's a treatment with potentially significant consequences. The gene therapy seemed to be well-tolerated, and the authors show that the patients continue producing at least some enzyme activity throughout the course of the study, with all children showing enzyme activity at the end of the 30-month follow-up.”

“They did a heroic effort at documenting cognitive changes over time,” he continued. “Notably, the youngest child in the study acquired the skills of a normal developing child. This is a small but very promising phase 1 to 2 study.”

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Jean-Michel Heard, MD, PhD, a clinician-scientist at the Institut Pasteur in Paris and co-author of the study, has been working on gene therapy techniques for lysosomal storage diseases since the late 1990s. The challenge was getting the enzyme into the brain. He started with mice, and was successful. Then, he worked with dogs. The dogs also had about 20 to 30 percent of normal NAGLU activity in their CSF and 100 percent inside the brain.

The enzyme was enough to clear the lysosomal storage lesions throughout brain parenchyma neurons, astrocytes, and microglia.

“There was no biological defect and no pathology in the brain,” said Dr. Heard. They delivered the gene therapy to chimps, too.

He said it has been “tricky to study cognitive decline in the children, because it is so variable...We have to compare what happens with treatment to what we think would have happened,”

The tests on the youngest child suggest the benefits of the therapy. “She is progressing like a normal kid,” he said. “She is in a regular school and doing well. This has never happened in this disease. We are pretty confident that this treatment has changed the normal course of the disease.”

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•. Tardieu M, Zerah M, Gougeon M-L, et al Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: An uncontrolled phase ½ clinical trial http:// Lancet Neurol 2017; Epub 2017 Jul 13.
    © 2017 American Academy of Neurology