Stanley Crooke and the n-of-many foundation

In April 2026, the n-Lorem Foundation announced that the 50th nano-rare individual had received a personalized antisense oligonucleotide medicine. The Foundation reported more than 440 applications received since founding, more than 240 individuals approved, more than 260 doses administered, approximately 45 patient-years of cumulative follow-up, and no ASO-related serious adverse events.

Stanley Crooke is 81. He founded n-Lorem in 2020, after retiring from Ionis Pharmaceuticals, the antisense oligonucleotide company he had founded in 1989 and run for 31 years. The 50-individual milestone is the proof he had been arguing for since the 1980s: that the chemistry he spent his career building can now be applied at one-individual scale, in a charitable model, with a safety database that holds.

Training

Crooke received his M.D. and Ph.D. degrees, and completed his house-staff training, at Baylor College of Medicine. He held faculty appointments at Baylor and at the University of Pennsylvania School of Medicine, training graduate students and winning teaching awards in both places. His early industry work was at Bristol Laboratories, where he helped build the oncology research program. He moved to Smith Kline Beckman, a predecessor to GlaxoSmithKline, where he led research and development.

The biographical detail that matters most for the rest of the story is that Crooke had been working on antisense oligonucleotides since the early 1980s, before there was any consensus that nucleic-acid drugs could be made to work as therapeutics. The chemistry that the field uses today, the 2'-O-methoxyethyl (2'-MOE) phosphorothioate platform that produced nusinersen and milasen, was developed under his leadership at Ionis between 1989 and the mid-2000s.

Ionis Pharmaceuticals

Crooke founded Isis Pharmaceuticals in San Diego in 1989, leaving his R&D leadership role at Smith Kline. The company was renamed Ionis Pharmaceuticals in 2015. Its founding thesis was that synthetic oligonucleotides could be designed to bind specific RNA sequences and modify gene expression with greater specificity and lower toxicity than small-molecule drugs. The thesis was widely doubted in the early years, in part because of repeated failures in the broader oligonucleotide-therapeutics field through the 1990s and early 2000s.

The first FDA approval for an Ionis-developed drug was mipomersen (Kynamro) in 2013, a phosphorothioate gapmer ASO targeting apolipoprotein B for familial hypercholesterolemia. Mipomersen was a commercial disappointment but a chemistry validation: the systemically delivered ASO worked, the safety profile was characterizable, and the regulatory pathway was traversable.

The transformative approval came in December 2016: nusinersen, marketed by partner Biogen as Spinraza, the splice-switching ASO for spinal muscular atrophy. Adrian Krainer's lab at Cold Spring Harbor and Frank Bennett's group at Ionis had identified the mechanism, designed the candidate, and run the placebo-controlled phase 3 trial. The trial was stopped early for benefit. Spinraza became the most successful nucleic-acid drug ever launched.

By the time Crooke retired from Ionis as chairman and chief executive in early 2020, the company had brought several additional ASOs to FDA approval, including inotersen for hereditary ATTR amyloidosis (2018), volanesorsen for familial chylomicronemia syndrome (2019), and tofersen for SOD1-mutant ALS (later, in 2023). Ionis was no longer a niche oligonucleotide company; it was the established commercial home of an entire drug class.

n-Lorem Foundation

Crooke's argument for n-Lorem was that the commercial drug-development model Ionis had spent three decades building could not address people whose mutations were too rare to support a commercial drug. A pharmaceutical company can justify the cost of a phase 3 trial when the eventual addressable population is in the thousands. It cannot justify that cost for a population of one, or two, or eight. The mathematics of commercial drug development structurally excludes those with the rarest mutations, and the chemistry that would help them is the same chemistry the commercial business has already validated.

The n-Lorem solution is a foundation that develops experimental ASO medicines for individual nano-rare patients (Crooke's coinage for the population with mutations affecting fewer than 30 people worldwide), provides the medicine free of charge for the patient's lifetime, and funds the work through philanthropic donations. The foundation was incorporated in 2020 in San Diego. Crooke serves as founder and chief executive.

The mechanics of how a case proceeds through n-Lorem are formalized. A treating physician submits an application on behalf of an identified patient. The foundation evaluates the application against a standardized set of criteria, including the molecular mechanism of the variant and the clinical urgency. If the application is accepted, n-Lorem designs a candidate ASO, validates it in patient-derived cells when possible, manufactures it under good manufacturing practices through partners, and submits a sponsor-investigator IND on behalf of the treating physician. The patient receives the drug through the treating institution. n-Lorem covers the development and manufacturing cost; the institution covers the dosing and clinical follow-up.

The structural argument is that the foundation amortizes its infrastructure across many individual programs. The chemistry is shared. The manufacturing relationships are shared. The regulatory playbook is shared. The safety database is shared, and grows with each patient treated. The first ASO program a foundation runs is expensive on a per-patient basis. The hundredth program benefits from the cumulative data and the matured infrastructure.

What the numbers look like in 2026

The n-Lorem milestones reported as of April 2026:

• More than 440 applications received from treating physicians worldwide
• More than 240 nano-rare patients approved for the foundation's pipeline
• 50 patients treated with their personalized ASO medicines
• More than 260 doses administered across multiple routes
• Approximately 45 patient-years of cumulative safety follow-up
• No ASO-related serious adverse events reported

The 50-patient milestone is the bar Crooke had been arguing the chemistry could clear, and the no-ASO-related-SAE figure across 45 patient-years is the reason the FDA's 2021-2022 guidance series for individualized ASOs is willing to allow abbreviated nonclinical packages and simplified CMC requirements for the chemistry class. The safety database itself is the regulatory argument.

What is not yet working

The constraints Crooke and the n-Lorem leadership have publicly identified are scale, geography, and durability.

Scale is constrained by manufacturing capacity. The academic-affiliated and contract GMP facilities that produce small-batch ASOs for n-Lorem and for individual academic programs at Boston Children's and elsewhere are running at high utilization. Increasing throughput from approximately 50 patients per year to 500 per year, which is the implied scale needed to address the global nano-rare population in any meaningful timeframe, requires manufacturing investment the foundation does not currently have.

Geographic access skews to North America and Europe. Treating physicians in the United States and Western Europe submit most of the applications, in part because the regulatory framework that allows compassionate-use ASO programs is most developed in those jurisdictions. Latin America, Africa, and most of Asia have far fewer applications relative to population.

Durability is the open clinical question. The n-Lorem patients dosed earliest are now five or more years out from first treatment. The longer-term efficacy of repeated intrathecal ASO administration in different disease contexts is still being established. Re-dosing schedules, dose adjustments, and the question of whether the safety profile holds over decades all require longer follow-up than any of these programs has yet accumulated.

The institutional argument

The model Crooke has built, of a non-profit foundation that aggregates demand for patient-specific ASO drugs, partners with academic groups for case-by-case development, and operates under a shared chemistry platform, is the closest thing the field has to an n-of-many infrastructure for the nano-rare population. It is the institutional answer to the commercial-drug-development gap, and its viability depends on three things continuing to hold: the chemistry remaining safe at the population scale the foundation has now validated; donor funding continuing to grow at the rate the patient pipeline grows; and manufacturing capacity expanding to meet demand.

Crooke's career arc, from the 1980s laboratory work establishing the chemistry, through the commercial company that produced nusinersen and the broader ASO drug class, to the foundation that now treats individual patients no commercial company would address, is the closest thing the rare-disease field has to a complete pipeline from chemistry to one patient. The question Crooke is now answering is whether the pipeline scales beyond 50.