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The researchers who developed a personalized antisense oligonucleotide (ASO) for a little girl with a form of Batten disease -- all in record time -- have in the New England Journal of Medicine.

Timothy Yu, MD, PhD, of Boston Children's Hospital, and colleagues explained how they characterized then-6-year-old Mila Makovec's mutation, developed therapeutic candidates, sped up institutional review board (IRB) and FDA timelines, and started treatment in just over a year -- with the promising result of reduced seizures.

"[T]his experience indicates that antisense oligonucleotides may deserve consideration as a platform for the rapid delivery of individualized treatments," Yu and colleagues wrote, cautioning that the approach "is at present probably scalable to only a limited number of patients, given current limitations on systemic and infrastructural issues (e.g. regulatory burden, manufacturing capacity, cost, and reimbursement)."

番茄社区app recently reported on a handful of patients and parents who, like Mila, were seeking personalized treatments with ASOs for various conditions.

Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, and Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, cited that story , saying Yu's work "illustrate(s) how recently developed technologies permit the delineation of pathways for truly individualized drug development."

Details of Mila's Case

Mila, whose story was first , developed normally until age 3, when her parents noticed that her foot was turning inward, according to the NEJM paper.

At age 4, she started holding books close to her face at bedtime. At age 5, her language and social skills regressed and she became physically clumsy. She was hospitalized at age 6 after she rapidly lost her vision and was having frequent falls, dysarthria, and dysphagia.

She was eventually diagnosed with neuronal ceroid lipofuscinosis 7 (CLN7), a form of .

Genetic testing revealed a single point mutation in the MFSD8 gene (which is also known as CLN7), but Mila was heterozygous for it; one of the alleles didn't have the expected mutation. (Both alleles must be defective to produce this form of Batten disease.)

So Yu's team then sequenced the girl's entire genome to find the missing second mutation. They discovered a previously undescribed insertion of a retrotransposon in the other copy of Mila's MFSD8 gene. (Retrotransposons are stretches of DNA that can move around the human genome, to a new location like the middle of a gene.)

In this case, that retrotransposon led to a mis-splicing of MFSD8 messenger RNA (mRNA). Yu and colleagues reasoned that an ASO could correct the mis-splicing and restore MFSD8 expression.

They designed a few versions of an ASO that used the same molecular backbone and glycosylations as nusinersen (Spinraza), an FDA-approved ASO for spinal muscular atrophy.

Yu and colleagues tested those candidates in vitro, in patient fibroblasts, and saw three that worked well; but the one that was the most efficacious became the lead candidate, which the team dubbed milasen in Mila's honor.

They then ran abbreviated toxicologic evaluations in rats for safety, with the FDA's okay. With satisfactory results, they started Mila on the therapy just one month after those studies.

Mila's regimen was modeled "roughly" after that of nusinersen because of the parallels between the drugs: they're the same size, they have identical chemical modifications, and they both target the central nervous system.

Dose escalation started at 3.5 mg, increasing every 2 weeks up to 42 mg. Then, Mila received two additional loading doses, followed by maintenance dosing approximately every 3 months.

Overall, Yu and colleagues found that Mila's neurologic measurements stabilized and her seizures were vastly diminished, with no serious adverse events through the first year.

Testing with the Vineland Adaptive Behavior Scale 2nd edition (Vineland-II) starting 3 months before the clinical study initially showed declines in seven of 11 neurologic and neuropsychological subscores. These represented "ongoing losses of some of the patient's few remaining adaptive skills in the domains of communication, daily living skills, and socialization," they wrote.

However, those subscores tended to stabilize, both from the start of the clinical study to 3 months (three declined, six remained the same, and two improved) and from 3 to 6 months (four declined, two remained the same, and five improved).

Tests of infant/toddler development, motor function, and sensory threshold testing also remained stable throughout treatment, Yu and colleagues reported.

Whereas Mila had 15 to 30 seizures per day before treatment, with each lasting 1 to 2 minutes, that frequency fell to 0 to 20 per day, with an average duration of less than 1 minute, over the course of the study, they reported.

MRI did show continued brain volume loss 7 months after treatment initiation, as expected, which extended the trend seen over the previous 3 years.

Despite the generally favorable outcomes, Yu and colleagues warned that this therapy isn't for all patients with Batten disease since it's so specific to Mila's mutation, and not all genetic mutations are amenable to ASO therapy. "Only a minority of patients are likely to have mutations that are amenable to the 'mRNA splice-switching' strategy deployed here," they wrote.

Who Pays?

While ASOs could be tailored for other eligible conditions, costs would likely be prohibitive for wider application. Mila's family raised millions of dollars to pay for all of the expertise and services involved.

Yu did not return a 番茄社区app request for comment, but in supplemental material, the researchers noted the future challenges in scaling these therapies to include regulatory hurdles, streamlining the development process, and "wrestling with the underlying issue of jurisdiction: what constitutes the practice of medicine vs. what constitutes commercial development for drugs to market."

"We believe that innovations in technology and regulation will make it possible to scale this process to benefit a large number of patients without putting an excessive financial burden on families or the system," they wrote.

In their editorial, Woodcock and Marks noted that "finding sustainable funding for such interventions may prove challenging, because the cost of production can be quite substantial."

She said the agency will be considering the issues around these kinds of tailored therapies "in the upcoming months." An FDA spokesperson previously confirmed to 番茄社区app that the agency was "seeing more of these requests" and that figuring out how best to handle so-called N-of-1 trial requests "has been a work in progress."

Woodcock and Marks noted that although ASOs have most frequently appeared in these requests, "other types of treatments, including individualized cell and gene therapies, are following closely behind."

The FDA has its work cut out, with Woodcock and Marks listing scores of questions that must be considered, including what type of evidence will be required before exposing a human to a new drug; how persuasive should the mechanistic or functional data be; and whether the urgency of a patient's situation or the number of people who could ultimately benefit should affect the decision-making process.