FDA’s New Plausible Mechanism Guidance for Implementing Gene Editing and RNA Therapies is Good News for the Rare Disease Community

Last year, nine-month-old KJ Muldoon made history when a variation of CRISPR gene editing, called base editing, swapped one DNA building block for another at a specific part of his mutant gene. He had inherited a urea cycle disorder called carbamoyl-phosphate synthetase 1 (CPS1) deficiency. It hampers the ability to digest protein and is among the rarest of the rare, affecting only about one in 800,000 to one in 1.2 million newborns, in different populations.

The boy had inherited one mutation from each parent; they are unaffected carriers. His liver couldn’t produce the crucial enzyme CPS1, and as a result, ammonia released from the breakdown of the amino acids in dietary proteins was accumulating in his bloodstream. Organ failure and, ultimately, brain swelling and coma would follow. Half of the babies with the condition do not survive infancy.

KJ’s case was reported in The New England Journal of Medicine May 15 of last year, “Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.” DNA Science covered it here.

More recently, KJ appeared at a news conference March 2, 2026, to celebrate Rare Disease Day. The toddler demonstrated his ability to walk. He has very mild symptoms of the ultrarare disease.

The event coincided with FDA’s release of new guidance that will enable a clinical trial to embrace multiple mutations in one registered effort, without requiring a separate application for each way (almost limitless!) that a gene can be mutant. I’ve been writing about rare diseases for decades, and I’m excited by this revamping of a sometimes maddeningly sluggish system.

The “Plausible Mechanism” Concept Expands Possibilities

A February 23 news release from FDA announced publication of a full Guidance document, “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause.“

“Plausible mechanism” echoes the NEJM article, and is a term that at first puzzled me – why would a scientist hypothesize a mechanism if it wasn’t plausible? But it means adding a mutation to those covered in a specific clinical trial if the mutation is predicted to alter cells in the same or a similar way.

According to the Guidance, “nonclinical and clinical data could be collected using a defined set of mutations to support product licensure. A highly supported ‘plausible’ mechanism of action may then be used to support the addition of other such GE (genome edited) product variants, intended to treat patients with mutations that were not included in the clinical trial used to support the original approval.”

The guidance also applies to RNA-targeted therapies. These include antisense oligonucleotides (ASOs), ribozymes, small interfering RNAs (RNAi), and microRNAs, such as the new treatment for Huntington’s disease, which I covered recently here.

I think the idea is brilliant.

With AI able to reveal what a particular mutation, even a hypothetical one never seen in a patient before, will do, the plausible mechanism approach seems a straightforward way to quickly broaden the scope of clinical trials to include more patients under a single regulatory “umbrella” or “basket” study. One review puts the strategy in plain language: removing red tape.

Gene editing via CRISPR made the plausible mechanism approach feasible, because it replaces an errant DNA base, rather than sending a bit of DNA into a genome, willy nilly, like original gene therapy did. Plus, the components of a CRISPR-based treatment are modular, a little like a screwdriver or hairdryer with several attachments. Different “guide RNAs” can be swapped in to direct the basic molecular machinery to precise targets, corresponding to different mutations in the same gene – or even mutations in different genes.

My Unusual Optimism Reflects the History of Gene Therapy

In my decades of science writing, textbooks and articles, I’ve never used the “c” word – cure – or the “b” word – breakthrough. But CRISPR base editing just may earn both designations. The plausible mechanism approach adds to the potential and excitement.

First, a glimpse of history.

Background

The idea for gene therapy emerged in the late 1950s, just after Watson and Crick discovered the structure of DNA. Soon after, Crick and many co-workers deciphered exactly how a gene encodes a protein – via the genetic code of DNA base triplets corresponding to the amino acids that build proteins.

French Anderson, who conducted the very first gene therapy trial in 1990, told me that he’d had the idea of a genetic code back in 1958, but I’m pretty sure it occurred to others too. If I wasn’t four years old at the time, I might have thought of it.

The invention of CRISPR will surely come to occupy a place in the history of genetics equal to that of the 1953 description of DNA’s structure. Curiously, my book The Forever Fix: Gene Therapy and the Boy WHo Saved It, which covers the history of gene therapy, was published at a crossroads in biotechnology, in 2012. That year was when Jennifer Doudna and Emmanuelle Charpentier published their seminal paper in Science on harnessing a bacterial immune defense to create a sharp gene-editing tool, CRISPR. I interviewed the inventors when I found myself one of only two journalists in the press room at a conference where they were honored.

Since then, CRISPR has taken off at an astonishing rate.

Expanding Clinical Trials to Embrace More Mutations: N-of-1 and Bespoke Buzzwords

Because a gene is an informational molecule, its sequence can be altered in many ways. CRISPR gene delivery would enable a single clinical trial to target and fix specific mutations.
The idea isn’t new, just the tool.

Past clinical trials could be amended to accommodate a single patient, such as someone missing part of a gene (a deletion mutation) while others in the trial share the same single-base mutation. Such individualized branches of clinical trials have been called “n-of-1” or “bespoke.” Back when I started my career, “orphan disease” was popularly used to denote rare genetic conditions, until it was deemed offensive.

N-of-1 is science-speak for an experimental group consisting of a single individual. The practice has been around since at least 2011, when personalized medicine became a buzzword. For example, in a clinical trial for the neurological condition giant axonal neuropathy, one participant was placed in her own outside group to attempt to treat her peripheral nervous system, in addition to the central nervous system focus of the original clinical trial.

Then in 2018, a seven-year-old, Mila, made headlines when she received a novel treatment tailored to another ultrarare neurological condition, a form of Batten disease. The first drug was named milasen in her honor. The case led to the founding of the N=1 Collaborative in 2021, from a taskforce and the Chan Zuckerberg Initiative. Now, a team from The N=1 Collaborative, including KJ’s physicians, are calling the plausible mechanism framework “an important advance toward fulfilling the potential of targeted technologies … to treat serious genetic diseases at their source.”

The other term for individualized therapy testing, “bespoke,” comes from tailoring in the 1600s and refers to choosing fabric for creation of a specific, personalized garment. NIH’s Bespoke Gene Therapy Consortium launched in 2021. It has been used for rare instances when patients have been admitted to ongoing clinical trials with a “compassionate use” designation.

Correcting Past Inconsistencies in Genetic Terminology

The new guidance from FDA spells out requirements for applicable “severely debilitating or life-threatening diseases” that could be candidates for a plausible mechanism approach. The focus is on identifying specific mutations, rather than relying on descriptions of symptoms. This new precision can clear up some longstanding inconsistencies in the peculiar history of genetic terminology. They’ve been a challenge for me as a textbook author.

Compare cystic fibrosis to sickle cell disease.

More than 2,500 distinct mutations are recognized in the gene that encodes the CFTR ion channel protein behind cystic fibrosis. Under the new guidance, hundreds, even perhaps thousands, of mutations could be embraced in a single clinical trial for cystic fibrosis using CRISPR.

In contrast, sickle cell disease is the consequence of a change in just one DNA base in the beta globin gene. Yet a mutation elsewhere in the very same gene causes beta-thalassemia, a different blood condition and distinct clinical entity.

Other Considerations

In addition to vastly improved classification and specificity of disease targets, the new guidance emphasizes the importance of natural history studies. These are key parts of clinical trials that follow untreated individuals to document and measure disease progression. Responses to experimental therapies are compared to natural disease progression.

The guidance also calls for evidence of confirmation that the mutation has been replaced and that the patient improves in some measurable way. Have symptoms improved? The disease course slowed? Biomarkers indicate improvement? “Real-world evidence” would continue to be collected to monitor safety and efficacy over the long term.

The National Organization for Rare Disorders issued this statement:

“For families facing a rare disease, regulatory policy isn’t abstract. It is life-defining. It can mean the difference between watching a disease progress with no options and finally having a treatment that improves quality of life and restores hope. The Plausible Mechanism Framework offers promise, and its impact will depend on consistent, transparent implementation that drug developers and patients can trust.”

CODA

The ability of CRISPR and RNA technologies to broaden clinical trial design for rare diseases was perhaps expected. But what I didn’t expect was glowing comments in the FDA’s news release from RFK Jr:

“We are cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most.”

The Secretary of Health and Human Services then praises the President for being on top of seeking cures for rare diseases!

If only they would turn their attention, in addition, to the once-vaccine-vanquished infectious diseases that are returning due to ignorance of basic science.