By Daniel S. Levine

The earliest signs of Mila’s condition became apparent at age 3 when her right foot began to turn inward. By age 4, her vision was declining, and at 5 she showed trouble walking. When she was first seen at Boston Children’s Hospital at age 6, she had grown blind, was having seizures, and lost almost all of her ability to speak.

Physicians diagnosed Mila with a form of the rare neurodegenerative disorder Batten disease. She could have been one more example of how so-called n-of-1 patients—patients who are the only ones with a given condition—are destined to a cruel fate because of the economics of drug development and the long time it takes to develop a therapy.

Instead, her story has become an example of the potential for ways to rethink the traditional drug development process to speed needed therapies to patients with rare genetic conditions, even if they are the only ones with a specific mutation.

In December 2016, Mila (now 8) was diagnosed with the CLN7 form of Batten disease, a lysosomal storage disorder that is fatal and had no treatments. Mila’s form of the condition is caused by a mutation unique to her.

A team at Boston Children’s Hospital led by neurologist and genetics researcher Timothy Yu identified her mutation, designed a customized drug to treat it, manufactured and tested the drug, and secured approval from the U.S. Food and Drug Administration to treat her in less than a year. Mila’s case and the potential for single-patient clinical trials are reported in an article in the New England Journal of Medicine, published online October 9.

Yu and his colleagues determined that Mila’s mutation existed in a regulatory part of the genome that controlled splicing of the CLN7 gene. It involved a retrotransposon, a piece of DNA that jumps from its correct location in the genome and inserts itself elsewhere. As a result, the retrotransposon causes Mila’s CLN7 gene to produce a truncated version of the protein it should make.

Yu and his colleagues designed a series of antisense oligonucleotides to bypass the unique piece of genetic code driving Mila’s disease. These are designed to carry short pieces of synthetic genetic code complementary to Mila’s retrotransposon. In essence, they patch the malfunctioning genetic code so that the CLN7 gene can be read normally.

By September 2017, Yu’s team had identified their best drug candidate. A month later, they demonstrated that the drug corrected the lysosomal abnormalities in Mila’s cells. They named their best candidate milasen. They found a contract research organization to help manufacture the drug candidate and conducted safety testing in animals. In January 2018, the U.S. Food and Drug Administration granted permission to test milasen in a single-patient clinical trial with Mila, eight months after her diagnosis.

While Mila’s disease was progressing quickly in the months leading up to treatment, it has slowed or stabilized since treatment began. Her seizure frequency has decreased from about 30 seizures daily to 5-10 per day, and seizure duration has decreased from 1-2 minutes to typically a few seconds each.

“There are whole categories of diseases with populations too small to attract industry effort,” Yu says. “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.”

In an accompanying editorial, FDA Director of the Center for Drug Evaluation and Research Janet Woodcock and FDA Director of the Center for Biologics Evaluation and Research Peter Marks offer a set of issues that will need to be addressed to make the approach in Mila’s case a more common occurrence for rare diseases.

Among the questions the FDA officials highlight for such N-of-one situations include, what type of evidence is needed before exposing a patient to a new drug? What is the minimum assurance of safety needed? How should dose and regimen be selected? How will efficacy be determined? And how should the urgency of the patient’s situation be weighed, or the number of people who could ultimately be treated affect the decision-making process?

They also note that there are societal and ethical issues raised by this approach, including such things as what the criteria for stopping the use of a therapy that caregivers might believe is providing benefit but there is not apparent evidence to investigators, and the need for finding sustainable funding for such approaches.

Yu and Mila’s mother Julia Vitarello have 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.

As Mila’s case shows, the pieces are in place to diagnose, formulate therapies, produce them, and treat patients. While there are regulatory questions that need to be addressed, the editorial makes clear the FDA is beginning to think through these issues. The FDA is opening the door for patient advocates, academics, industry, and others to weigh in on these issues.

As with the pioneering work of Yu and his team, this is moving fast. There is a potential here to not just to provide treatments for patients with ultra-rare conditions, but create a roadmap for doing so.

Photo: Timothy Yu, Mila, and Mila’s mother
Julia Vitarello courtesy of Boston Children’s Hospital