BCH N of 1 Trial Yields Approved Therapy for Single Rare Disease Patient

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Illustration of a damaged ribonucleic acid or  dna strand

The promise of precision medicine is focused on providing the right drug to the right patient at the right time. Usually that means matching patients, based on their molecular profiles to specific approved drugs. But precision medicine has never created a unique drug intended to treat one—and only one—patient.

Until now.

In what is likely the first instance of a drug being specifically designed for a single patient, researchers at Boston Children’s Hospital (BCH) have reported in the New England Journal of Medicine the one-year development process of a drug custom-designed—and approved by the FDA—to bypass a unique mutation and treat an 8-year-old girl’s CLN7 Batten disease.

The team at BCH was led by Timothy Yu, M.D., Ph.D., a neurologist and genetics researcher.

“One of the unique things about this trial is that, due to clinical urgency, we were starting a first-in-human trial with a drug that had only been tested in our patient’s cells in a dish,” said Yu in a press release. “What was also unique is that we have a drug that is targeted to a mutation seen to this date only in one patient.”

Mila, the patient, was diagnosed in late 2016 with Batten disease, a rare neurodegenerative disease that is marked by rapid progression and is ultimately fatal. Mila’s form of the disease is called CLN7 Batten disease as those suffering from this have inherited a bad copy of the CLN7 gene. CLN7 Batten disease has no known cure, and Mila’s form of the disease is caused by a mutation in the gene not previously observed.

Mila’s family first became concerned about her health around the age of 3 when her right foot began to turn inward. Her disease continued to progress over the next few years with additional signs including pulling books close to her face as a 4-year-old, and beginning to stumble when she was 5.

By the time Mila was first seen at BCH two years ago, Mila was blind, was experiencing seizures, was barely speaking and showed signs of both developmental and neurologic regression. Despite her difficulties, the BCH team reported, she remained alert, happy and able to respond to favorite activities and people.

Finding the mutation in the dark

CLN7 Batten disease is recessive, and while the mutation Mila inherited from her father was readily identified in her CLN7 gene, the mutation from her mother could not be found. To try to find an answer for her ill daughter Mila’s mother posted on Facebook, looking for a lab that could quickly do whole-genome sequencing. Yu’s wife saw the ad in January 2017, brought the appeal to his attention since his lab specializes in WGS and finding unusual mutations.

Within three months Yu and his colleagues found the mutation, residing in the “dark matter” of the genome—affecting a regulatory piece of DNA that controls splicing of the CLN7 gene. Even more unusual, it consisted of a “jumping gene”—a rogue piece of DNA known as a retrotransposon that inserted itself into the genome, altering how the splicing machinery read CLN7 resulting in the production of an abnormal, truncated protein.

Designing Mila’s drug

As Yu and colleagues wrestled with how to use this information to treat Mila, they decided a good approach was to design a number of antisense oligonucleotide drugs, one of which they hoped would help bypass her unique mutations. The oligonucleotides were designed to find the CLN7 gene and act as a bandage to cover the malfunctioning gene so that the CLN7 gene could be read normally.

By September, 2017, Yu’s team had showed that several of their candidate oligonucleotide drugs could repair the splicing defect in Mila’s CLN7 gene. One month later, they showed that the drugs also corrected the lysosomal abnormalities in Mila’s cells. They named their best candidate milasen and sent it to contract research organizations for animal testing and manufacturing.

“n of 1” trial

In January 2018, the FDA granted permission to test milasen as a Single-Patient Compassionate-Use Investigational New Drug and by the end of the month, Mila began her single-patient clinical trial, a short eight months after her diagnosis.

Every two weeks Mila received a total of nine escalating doses of milasen, which was given via spinal injection to target it to the brain. Since August 2018, she has received maintenance treatments every two to three months.

Since beginning treatment on milasen, Mila’s seizure frequency has decreased from roughly 30 seizures per day to 5-10 per day.  Further, the duration of her seizures decreased significantly from one to two minutes to only a few second each.

Looking ahead

As the first instance of a team creating a customized drug for a single patient, the development of milasen, over such a short time span, could give new hope to how rare genetic diseases are treated.

“Everyone knows that the future of precision medicine in pediatrics is developing treatments for kids one at a time, the way this work has done,” said Christopher A. Walsh, M.D., Ph.D., chief of the Division of Genetics at Boston Children’s Hospital in a prepared statement, “but until now no one had a real-life case where everything lined up in a way to allow them to do it.”

Based on his team’s work, Yu believes other cases could also be treatable with oligonucleotides. He and Mila’s mother recently met with the FDA to discuss a new regulatory model for offering custom antisense oligonucleotide treatments for patients with rare or seemingly one-of-a-kind conditions. However, many questions and obstacles remain to be addressed before widespread adoption of this approach.

“There are whole categories of diseases with populations too small to attract industry effort,” Yu said. “But in the hospital where research is a major focus, we can go one step, one patient at a time. I think that some of the most exciting parts in science are when you try to do something new, when there isn’t a recipe.”

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