The Endgame Is N-of-One: Why Ultra-Rare Failures Are a Warning to Everyone
For decades, rare disease families have been told to be patient, to trust the system, to believe that scientific progress moves at the pace it must. But in 2025, with AI-designed antibodies emerging overnight, CRISPR systems rewriting DNA in a single injection, and gene editing platforms capable of building cures targeted to a single mutation — patience is no longer a neutral ask.
It is a cost.
And the children living with ultra-rare diseases Classic Galactosemia, Barth syndrome, Sanfilippo syndrome, Prader–Willi syndrome are the ones paying it. These are just a few examples.
The truth is simple, and uncomfortable for the system to admit:
N-of-one medicine is not a fringe idea.
It is the endgame.
Everything we are doing now is just the scaffolding.
And the cracks in the scaffolding are starting to show.
The Pattern No One Wants to Name
Families hear different diagnoses. Different organs involved. Different genes. Different specialists.
But the system failure is the same.
Galactosemia, with its 3,500 U.S. patients, has no FDA-approved treatment and on the lowest estimate lifetime economic burden of $7.23 million per patient a preventable cost rooted in diagnostic delays, missed therapies, and the consequences of untreated cellular toxicity .
Barth syndrome lost a decade of therapeutic momentum when a promising mitochondrial drug was stalled over endpoints that could never be met in a population of fewer than 130 boys worldwide.
Sanfilippo syndrome saw one of the most hopeful gene therapies — ABO-102 — freeze behind statistical thresholds impossible to reach once the sponsor was told to expand a trial in a disease where expansion is mathematically impossible.
Prader–Willi families watched the first drug to meaningfully reduce hyperphagia crash into a Complete Response Letter because COVID-interrupted data didn’t rise to traditional significance, even though parents saw their children stabilize for the first time in their lives.
These aren’t isolated stories. They are warnings.
They reveal a system designed for common adult diseases being forced onto micro-populations of children — where replication is impossible, where p-values warp under small-sample pressure, and where a single missing assessment can erase ten years of science.
This rigidity isn’t just unhelpful.
It is harmful.
CRISPR, AI, and the World That’s Already Here
While regulators cling to frameworks written before the iPhone existed, science is sprinting ahead at a speed medicine has never seen.
David Baker’s lab just dropped AI-designed antibodies directly to GitHub.
No animals. No immunization. No guesswork.
Just a protein target → an antibody generated from scratch.
CRISPR variants now allow single-base editing, RNA-guided repair, and combinatorial approaches unimaginable five years ago.
Gene therapy manufacturing is becoming modular, scalable, and in some cases — nearly on-demand.
Artificial intelligence can model folding, predict pathogenicity, and simulate treatment response faster than some IRBs approve consent forms.
If the regulatory system does not evolve, innovation will bypass the patients who need it most.
Not because the science isn’t ready —
but because the system isn’t.
N-of-One Isn’t Radical. It’s Inevitable.
N-of-one therapies used to be whispered as science fiction. Now they are a scientific inevitability:
Personalized antisense oligos for unique mutations
CRISPR edits tailored to a single child’s exact variant
AI-designed biologics tuned to a pathological pathway
Gene delivery vectors modified for individual tolerability profiles
When a disease affects 10 children in the world?
Or 100?
Or even 3,500?
The population is the outlier.
The individual is the constant.
The system has it backwards.
The goal is not squeezing micro-populations into an industrial framework built for statins and hypertension.
The goal is building a regulatory framework that recognizes reality:
The smallest population is one person.
The future of therapeutics is individualized.
Imagine a World Where Individualized Medicine Is Standard
Imagine a world where:
A child receives a molecular diagnosis and in the same month an individualized RNA therapy is generated from their exact mutation.
Where a newborn’s genome is sequenced, and disease-specific gene editing is scheduled before symptoms emerge.
Where emergency rooms open AI-driven dosing pathways tailored to metabolic disorders like Galactosemia, preventing the toxic damage outlined in the burden report .
Where a parent no longer has to ask whether an FDA CRL is political, statistical, or just outdated because the criteria are transparent, adaptive, and written for populations measured in dozens, not hundreds of thousands.
Where a single child doesn’t lose a therapy because a dataset dropped during a vendor transition.
Where regulators, researchers, and families sit at the same table — not as adversaries, but as co-designers of a future that uses law the way it was intended:
To protect life, not delay it.
This is not fantasy.
It is timeline alignment.
And right now, the scientific timeline is far ahead of the regulatory one.
Why Ultra-Rare Failure Is Everyone’s Warning
When ultra-rare pathways fail, the public thinks it only affects the 3,500 living with Galactosemia. Or the 130 with Barth. Or the children with Sanfilippo or Prader–Willi.
But the truth is this:
Ultra-rare disease is the canary in the coal mine.
How these children are treated is a preview of how everyone will be treated in the era of individualized medicine.
If the FDA can’t accommodate a trial of 50 children, it will not be able to accommodate a future where every therapy is modeled, edited, and manufactured at the individual level.
If regulators cannot accept surrogate endpoints for micro-populations, they will not survive an era where “population-level” endpoints no longer exist.
If agencies cannot adjust rigidity now, they will be irrelevant later.
The ultra-rare space isn’t fringe.
It is the blueprint for what is coming.
The Ask
What ultra-rare families are really asking for is not pity, or miracles, or special treatment.
They are asking for alignment.
Between science and regulation.
Between authority and action.
Between what is possible and what is allowed.
They are asking for laws that already exist —
FDA Modernization Act §112, FDASIA §901, Accelerated Approval, RWE integration, HEART Act-
to be used the way Congress intended: for populations where traditional trials are impossible.
They are asking for leadership that understands what’s at stake.
They are asking for a future where individualized medicine is not a loophole or an exception —
but the standard of care.
Because in the end, the truest form of medicine has always been N-of-one.
