Efforts to make ultra‑rare disease therapies more accessible have accelerated after the pioneering case of a three‑year‑old girl whose family helped create the first individualized antisense oligonucleotide (ASO) treatment for Batten disease.
From a single patient to a growing pipeline
When Mila Makovec’s parents first noticed her speech and vision problems, doctors eventually diagnosed her with CLN7‑type Batten disease, a fatal neurodegenerative disorder.
ASOs are short synthetic strands of nucleic acids that bind targeted RNA sequences, altering gene expression or prompting the breakdown of harmful messenger RNA. They differ from other nucleic‑acid therapies like small interfering RNAs (siRNAs) and aptamers, but share the advantage of being reversible; a dose can be stopped if adverse effects appear.
Regulatory and reimbursement hurdles
Scientists and parents alike agree that the scientific challenges are no longer the primary obstacle. “The science isn’t the limiting factor, it’s the system … meaning primarily regulation and reimbursement payments—these are the big barriers,” said Julia Vitarello, Mila’s mother and a leading advocate for individualized medicines.
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In the United States, FDA approval typically triggers insurance reimbursement, but Europe’s process is more fragmented. After a therapy gains European Medicines Agency (EMA) approval, each country must decide on pricing and market entry, often using criteria that differ from the regulators’ safety assessments. This mismatch can leave patients without coverage even after a drug is deemed safe.
Payment models also need rethinking.
Cost reduction is essential.
Professor Aidan Hollis of the University of Calgary suggests a cost‑based approach that values patient outcomes without seeking high profit margins, noting that “you’re not going to turn this into a profit‑making venture if the justification for the high price is that it’s a rare disease.”
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Manufacturing costs could be reduced if hospitals invested in in‑house synthesizer machines capable of producing oligonucleotides under good manufacturing practice (GMP) standards. Aartsma‑Rus estimates such a setup might cut expenses by a factor of ten to twenty, though the upfront capital required remains a barrier for many academic centers.
These systemic changes are essential because timing is critical. Mila received her treatment at age seven, but experts say earlier intervention—ideally at birth—offers the best chance of preserving neuronal function. “We probably got to Mila too late,” Vitarello recalled, echoing a sentiment shared by many families handling ultra‑rare diseases.
One reason ASOs remain attractive for early‑stage intervention is their ability to reach the central nervous system via intrathecal injection. “The cells in the central nervous system will actually take up the ASOs very efficiently,” she explained, noting that the long half‑life of these molecules can allow dosing as infrequently as three times a year.
Building a collaborative future
Beyond regulatory reform, collaborative networks are emerging to streamline therapy development. The N = 1 Collaborative, founded in 2021, brings together scientists, clinicians, and families to create standardized guidelines for assessing ASO eligibility. Marlen Lauffer of the University of Oxford, who advises the group, emphasizes the need for consistent communication so families receive uniform answers.
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Vitarello’s own nonprofit, Mila’s Miracle Foundation, works to amplify the voices of families affected by ultra‑rare conditions. She also helped launch EveryONE Medicines with Harvard’s Timothy Yu, although the venture closed in March due to funding shortfalls. Still, the experience “put on the table the concept of a viable business model for individualized medicines,” she said, noting that other companies have since entered the space.
From a broader perspective, the shift toward personalized molecular treatments reflects a gradual alignment of scientific capability with policy mechanisms. As regulators adapt and reimbursement schemes evolve, the hope is that the current “icebreaker”—ASOs—will pave the way for more complex approaches like CRISPR‑based editing, which already showed promise in a recent case involving a baby with CPS1 deficiency.
While Mila’s story ended with her passing at age 10, her legacy continues to influence a growing community striving to turn rare genetic diagnoses into treatable conditions. Ongoing pilots, such as the Rare Therapies Launch Pad in the U.K., aim to prove that the infrastructure for rapid, patient‑specific drug development can be built and scaled.
Experts remain cautiously optimistic. “It’s really a change in the way that we see drug development … There is a true commitment, I feel, from the regulator to rare diseases across the world,” said Vincent Forster, CEO of Zurich‑based Nerai Bioscience, which focuses on next‑generation CRISPR platforms. If regulatory pathways keep pace, more families may see the promise of individualized therapies become a practical reality.
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