Gene therapy slowed the pace of decline among children diagnosed with Batten's disease, according to findings presented at the virtual 2020 conjoint annual meeting of the International Child Neurology Association (ICNA) and Child Neurology Society (CNS).
"The therapy was tested for effectiveness and safety in extensive preclinical studies before moving forward to the first-in-human clinical trial," said the first study author Emily de los Reyes, MD, attending pediatric neurologist at Nationwide Children's and professor of clinical pediatrics and neurology at The Ohio State University College of Medicine in Columbus.
Batten's disease, or neuronal ceroid lipofuscinosis, is an autosomal recessive, lysosomal storage disease, Dr. de los Reyes explained. "Nerve cells and other cells of the nervous system are very sensitive to accumulation of trash such as misfolded or old proteins, lipids, and other components of the cell since they are highly active," she told Neurology Today At the Meetings. "The accumulation and lack of clearance of these components from the cells are hallmarks of all Batten diseases."
The gene therapy trial focused on CLN6 type Batten's disease, one of 13 genotypes of the disorder. CLN6 type Batten's disease—which is caused by mutations in the CLN6 gene that encodes for a protein with unknown function called CLN6 protein— is characterized by progressive declines in language, motor skills, cognitive abilities, visual loss, and intractable myoclonic epilepsy, Dr. de los Reyes said.
"The symptom onset of variant late infantile CLN6 is approximately 3 to 4 years of age. There is rapid clinical deterioration of their abilities to walk and talk. Most children die during late childhood or in their early teens," she added.
The researchers injected AT-GTX-501, a non-replicating, recombinant, self-complementary adeno-associated virus-9 vector containing the human CLN6 gene, into the lumbar spinal cord of children. The patients were followed weekly for the first month after gene transfer, and every three months after, Dr. de los Reyes said.
After 12 months, the 12 children treated with gene therapy experienced a 0.4-point decline in the validated Hamburg Motor and Language Scale, compared with a 1.2-point decline observed in the natural history decline seen in 16 children who were also diagnosed with CLN6 type Batten's disease.
Despite the small numbers of patients in the study, the difference achieved statistical significance (p<0.01), Dr. de los Reyes said.
At two years, eight children treated with the gene therapy experienced a 0.6-point decline in function compared to a projected 2.4-point decline in the natural history of the disease (p>0.0001), she said.
"We continue to follow the last patients enrolled in the protocol, which involves monitoring safety and efficacy, in addition, to collecting further natural history data, to which we will compare our clinical results, " Dr. de la Reyes said. "Next steps will be informed by this data in the near future."
This study was funded by Amicus Therapeutics, Inc.
Commenting on the study, Bruce H. Cohen, MD, FAAN, director of the NeuroDevelopmental Science Center at Akron Children's Hospital and professor of pediatrics at Northeast Ohio Medical University, noted how devastating the illness is to the children and their families. "These children are healthy during their first few years of life but then develop regression in cognitive and language skills, changes in behavior and seizures, followed by a sleep disturbance and vision loss. Death generally occurs in early adolescence."
Dr. Cohen, who was not involved with the study, said the disease usually occurs by inheriting a mutation from each parent in the CLN6 gene, which is on chromosome 15. He noted that the vector could be used to treat only one form of the disease.
The study aimed to uncover "the safety and effectiveness of this gene therapy," he said. "Using a scale of motor and language function, the eight children [out to 24 months] treated with the gene therapy had a dramatically slower rate of disease progression when compared to the natural history of 16 children cared for before this therapy was available.
Five patients had adverse events, four of whom had side effects possibly related to the therapy (vomiting, fever, and abdominal pain), and all four children recovered, he noted.
"These are preliminary findings, and it is very encouraging that the therapy has benefited the patients," he said. "There is a lot of work to do, and issues such as if earlier treatment may provide greater benefit is still not known."
Dr. de los Reyes received grants and consulting fees from Amicus and Biomarin. Dr. Cohen had no relevant disclosures.
Link Up for More Information:
CNS-ICNA PL67: de los Reyes E, Meyer K, Lehwald L, et al. Single-dose AAV9-CLN6 gene transfer stabilizes motor and language function in CLN-6 Batten disease: Interim results from the first clinical gene therapy trial.