In a groundbreaking effort, twins with an ultra-rare genetic disorder, juvenile Batten disease, have received a personalized treatment developed and fast-tracked by researchers at the University of North Carolina (UNC) and the University of Michigan. The treatment, an antisense oligonucleotide (ASO) named Zebronkysen, targets a unique mutation in the CLN3 gene responsible for the twins' condition.
Understanding Juvenile Batten Disease
Juvenile Batten disease, or CLN3 disease, is a rare and fatal neurodegenerative disorder affecting approximately 1 in 100,000 births. The disease typically manifests around the age of six or seven, with symptoms including vision loss, paralysis, cognitive decline, seizures, and speech impairment. The CLN3 gene, located on chromosome 16, encodes a protein crucial for waste management within cells' lysosomes. Mutations in this gene lead to the accumulation of cellular waste, causing cell death in the brain and eyes.
The Discovery of a Novel Mutation
Amelia and Makenzie Kahn, diagnosed with juvenile Batten disease, were found to have a previously unobserved genetic variant in the CLN3 gene. This discovery prompted their family to collaborate with Michelle L. Hastings, PhD, at the University of Michigan, to develop a personalized ASO therapy.
Developing a Personalized Treatment
Hastings, an expert in ASO therapeutics, leveraged FDA guidance on individualized investigational ASOs for severe genetic diseases to create Zebronkysen. Jessica Centa, PhD, in the Hastings lab, used cells from skin biopsies of the twins to identify a potent ASO capable of restoring expression from their mutated gene.
"Drug development and medicine is changing," said Hastings. "It’s not just drug companies developing drugs for large patient populations. It’s also family members, doctors that are seeing the patients, and basic scientists coming together to apply new technologies to treat disease."
Rapid Approval and Clinical Implementation
The ForeBatten Foundation established an N-of-2 study development team, with UNC serving as the clinical site and Yael Shiloh-Malawsky, MD, as the primary investigator. The team secured FDA approval for the investigational drug in late May 2024, just over a year after initiating the process.
"This is the first time this kind of N-of-1, or N-of-2, personalized treatment is going through the UNC system," said Dr. Shiloh-Malawsky. "This is an extraordinary example of how incredible talent, investment, and collaboration with multiple scientists can come together to bring new and innovative treatments to pediatric patients in need. It’s incredible."
Treatment and Future Implications
In June 2024, Amelia and Makenzie received their first doses of Zebronkysen via spinal tap. The treatment aims to restore the function of the CLN3 gene and prevent further neurodegeneration. While long-term effects are still being monitored, the initial signs are promising.
This study could serve as a proof-of-concept for personalized treatments for other patients with variants in the CLN3 gene, other subtypes of Batten disease, or other pediatric genetic disorders. The collaborative effort underscores the potential of personalized medicine in addressing rare and devastating conditions.
"This probably isn’t a cure, and we are aware of that," said Karen Kahn, mother of Amelia and Makenzie and co-founder of the ForeBatten foundation. "I think this is a major step in the right direction. When there is no treatment available for children, to finally have something with promise, is exciting."
