Newswise — When Karen and David Kahn’s daughters, Amelia and Makenzie, were born in 2010, they knew life with twins would be different. But after just 18 months, the Kahn family was forced onto an unexpected and harrowing path. Amelia began failing her speech and behavior milestones. At age two, she was diagnosed with autism. Then, at 7-years-old, both girls started experiencing unexplained vision loss and were declared legally blind.
Desperate to find a diagnosis, the Kahns reached out to a geneticist for testing, eventually learning that both girls had an extremely rare and progressive genetic disorder of the nervous system called juvenile Batten disease, or CLN3, for which there is no cure.
They refused to give in to the disease and worked to find a treatment, and now – seven years after diagnosis – the family is part of a first-in-kind clinical study at UNC Health, led by Yael Shiloh-Malawsky, MD, associate professor of neurology.
A New, Personalized Treatment for Two
Juvenile Batten disease is a rare neurodegenerative condition affecting as little as 1 of every 100,000 births. Around the age of six or seven, patients typically begin experiencing vision loss, followed by paralysis, cognitive decline, seizures, and loss of speech. Because the condition causes rapid brain cell death, life expectancy is from the teens to early twenties.
The disease is linked to genetic changes in a gene called CLN3. Located on chromosome 16, the CLN3 protein, which is encoded by the gene, is important for directing the body to store and break down cellular waste in cellular organs called lysosomes. When this waste builds up in the body’s cells, it causes cell death in the brain and eyes.
The Kahn girls underwent further genetic testing. Geneticists confirmed that Amelia and Makenzie had the common genetic changes seen in CLN3 Batten disease.
But geneticists also found something else. The girls had another genetic variant in the CLN3 gene – one that had never before been observed in a person with Batten disease.
Not long after diagnosis, the Kahns formed the ForeBatten Foundation, a nonprofit that funds juvenile Batten disease research and support for families whose lives have been affected by the disease. It was at this point that the Kahn family reached out to Michelle L. Hastings, PhD, the Pfizer Upjohn Research Professor of Pharmacology at the University of Michigan Medical School, to discuss antisense oligonucleotide treatments.
Hastings has been studying short RNA molecules called antisense oligonucleotides (ASOs) for more than 20 years. Much like a pair of teeny molecular tweezers, the short RNA molecules can target specific sites on genes and correct the gene expression to restore protein function.
By January 2021, Hastings was working on a therapy for pediatric patients with the common CLN3 genetic variant in parallel with a therapy for the Kahn girls’ specific variant. She was able to do this work thanks to newly released guidance from the U.S. Food and Drug Administration (FDA), which gave researchers directions on how to develop individualized investigational ASOs for those with severely debilitating or life-threatening genetic diseases.
This new type of personalized trial, frequently referred to as an “N-of-1” study, is a type of clinical trial that focuses on just one individual rather than a large group of people. In the case of Makenzie and Amelia, the specific treatment is created and tested for two patients, an “N-of-2” study.
Jessica Centa, PhD, a senior postdoctoral research fellow in the Hastings lab, took cells recovered from skin biopsies from both girls, and grew them in culture dishes in the lab and used them to test a series of ASOs to determine which ones were capable of recovering expression from the girls’ mutated gene. They identified a highly potent and effective ASO as their lead candidate for development of personalized treatment.
After researchers developed the ASO drug that had the potential to be effective, it was time to name it. Inspired by the girl’s favorite animals, zebras and monkeys, the customized treatment was named Zebronkysen. With guidance from the ForeBatten Development team, the personalized drug was manufactured and bottled for use.
“Drug development and medicine is changing,” said Hastings, who is also the director of the RNA Therapeutics Initiative at the University of Michigan. “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.
“As we see more success with individualized treatments using ASOs, I think that will drive support, which we hope will lead to more treatments of this kind to children with juvenile Batten disease and other ultra rare conditions.”
A Quick Transition from Bench to Bedside
In May 2022, the Kahn family moved cross-country from Scottsdale, AZ to Chapel Hill, NC to be closer to family. Amelia and Makenzie’s Phoenix neurologist reached out to Dr. Shiloh-Malawsky, an expert in child neurodegenerative disorders at the UNC School of Medicine, to assist in their transition of care to UNC and to establish a new medical home for the girls in North Carolina.
Dr. Shiloh-Malawsky became their new neurologist, forming part of a multidisciplinary team at UNC that helped treat the twins’ myriad symptoms, which included seizures, muscle spasms, and anxiety. However, later in 2022, the disease progressed further. Feeding and mobility became more challenging for the girls, increasing the urgency for treatment.
Fortunately, Hastings’ ASO drug was developed for the specific gene altered in Amelia’s and Makenzie’s genomes. But before Dr. Shiloh-Malawsky could bring the treatment to the clinic, she had to obtain approval from UNC’s Institutional Review Board (IRB), UNC’s Ethics Review Committee, and the FDA. Typically, this process takes a very long time.
“This is not like other study drug approvals, in the sense that the treatment is being created only for these two patients,” said Dr. Shiloh-Malawsky. “Most importantly, we have to do it quickly if we want to help them before they lose any more abilities.”
In spring 2023, the ForeBatten Foundation established the N-of-2 study development team, with UNC serving as the clinical site of the study, and Dr. Shiloh-Malawsky the primary investigator. The team was able to develop individualized ASO and clinical trial protocol, submit for FDA approval of new investigational drug, and gain institutional and FDA approvals in a little over a year. The FDA officially approved the new investigational drug in late May 2024.
“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.”
A New Proof of Concept
In June 2024, just two weeks after the study drug was approved by the FDA, Amelia and Makenzie received their first dosages of Zebronkysen. Their ASO drug is provided as an “N-of-2” clinical trial, with UNC serving as the study site.
The drug is injected into the cerebrospinal fluid via spinal tap while the girls are under general anesthesia. The girls’ treatment is provided under a study protocol with close monitoring to assess tolerance to the drug and observe whether it has staved off further neurodegeneration.
Dr. Shiloh-Malawsky is hopeful that restoring the function of Amelia and Makenzie’s CLN3 gene can prevent further decline. If it proves beneficial, the girls will use the drug for the rest of their lives.
But this latest drug development impacts more than just the Kahn family. This study could be used as a proof-of-concept for other personalized treatments to help patients who have other variants in the CLN3 gene, other subtypes of Batten disease, or other pediatric genetic disorders.
“There are other patients who could benefit if a drug affecting the common juvenile Batten mutation was created,” said Dr. Shiloh-Malawsky. “This is why I’m at UNC, to be at a place that has the knowledge, the systems, and the interest in taking scientific advancements and giving applying them to the development of intervention for our patients, giving them hope of treatment.”
It is too early to tell what long-term effects the treatment will have on the girls, but so far, the signs are positive.
“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.”
The N-of-2 study team is a collaboration of clinical research organizations, laboratories, and drug development specialists, including Vanguard Clinical Inc., SciLucent, Charles River Laboratories, Avecia, Argonaut Manufacturing Services, and additional consultants. UNC co-investigators for the clinical trial include Zheng (Jane) Fan, MD, Jamie Capal, MD, and Elizabeth Jalazo, MD.
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