The FDA’s recent NEJM1 commentary on the “plausible mechanism pathway” represents a pivotal moment in how individualized therapies may advance from concept to clinic. It offers a window into the agency’s thinking as it confronts the rise of bespoke, patient-specific therapeutics, which are treatments that often cannot be assessed through traditional randomized clinical trials or development frameworks.
At the heart of the FDA’s perspective is a message that is both simple and consequential: individualized therapies will only scale if the platforms they rely on are adaptable, predictable, and mechanistically coherent across variations. In other words, adaptability and safety are no longer separate metrics, they reinforce one another. The more easily a technology can be tuned to the specific biology of an individual mutation, the more confidently developers and regulators can predict its mechanistic behavior.
This marks a meaningful evolution in what “precision” must mean in the next era of genome editing.
What the FDA is signaling about the future of individualized therapies
In their NEJM article¹, Prasad and Makary outline several cornerstone expectations for bespoke or ultra-rare therapies:
- A therapy must target a specific, well-understood biological abnormality. The disease-causing variant must be clearly defined.
- The therapy must directly address that mechanism. Approaches that do not engage the causal lesion are unlikely to qualify.
- Mechanistic confirmation is essential. Regulators want evidence that the intended molecular event occurred.
- Clinical improvements must be attributable. Even if only one patient is treated, clinical benefits must align with mechanistic plausibility.
- Real-world evidence becomes critical. Sponsors must confirm durability, monitor for unexpected effects, and verify the absence of off-targets.
- Platform-based efficiencies are expected. Reusing a consistent therapeutic architecture across variants may enable more efficient review.
Taken together, these expectations point to a future where control, mechanism-driven architecture, and adaptability become central regulatory priorities. This is especially relevant in gene editing, where patient numbers may be small but biological diversity is substantial.
Why adaptability matters more than ever
Developers working on precision therapeutics face a familiar challenge: the optimal edit for patient A is not the same as for patient B, even within the same gene. Editing efficiency, bystander risk, and off-target propensities vary across loci.
This means no single editor will be “one size fits all.” Not for rare diseases, n-of-1 therapies, or even many common indications. As the FDA’s NEJM commentary makes clear, individualized therapies must be built on systems that can be tuned to the specific biological context of each variant. And in gene editing, adaptability and safety are inseparable, because the safest edit is the one that fits the biology precisely.
Base editing already offers an advantage in this regard. By avoiding double-strand breaks, base editors reduce many of the well-characterized risks associated with DSB repair: stochastic indels, large deletions, rearrangements, chromothripsis, p53 activation, and loss of cellular fitness2-6. But even within the class of DSB-free technologies, safety is not uniform across loci. The bystander window, local sequence context, and off-target propensities can shift dramatically from site to site.
This is why adaptability becomes a safety requirement. If an editing system cannot be adjusted to minimize bystanders or off-target events at a specific locus, developers are forced to accept avoidable risks. The inverse is also true: the more an architecture allows developers to configure catalytic components to the local sequence environment, the more precisely it can be tuned toward a safer profile.
Modular, reconfigurable architectures matter for this reason, not because they eliminate variability (they don’t), but because they organize and contain biological variability within a predictable mechanistic framework. They allow developers to optimize the editing footprint around a stable framework, rather than redesigning an entirely new fusion protein with each change.
Base editors built by tethering deaminases directly to nickases can certainly be adapted with different Cas variants or deaminase domains. Technically, nothing prevents such modifications. However, because the catalytic and targeting functions are entangled in a single protein, changing any component creates a new molecular entity with new folding characteristics, new kinetic behavior, new off-target profiles, and new manufacturability considerations. Even small adjustments can redefine therapeutic identity.
In contrast, modular architectures can deliberately separate the stable therapeutic core from the variable catalytic component. Within the Pin-point™ base editing platform7, for example, the core consists of a defined recruitment architecture, a reproducible assembly and QC framework, and a shared biological mechanism driven by directed deamination rather than double-strand break repair.
Yes, each catalytic module will have its own performance profile. But those differences occur around a consistent, reusable mechanistic backbone, not within a newly designed fusion protein each time. This distinction becomes meaningful when the regulatory conversation shifts to platform-level evaluation, because a consistent framework supports both adaptability and safety simultaneously.
A platform mindset for a platform era
The FDA’s draft guidance on “Platform Technology Designation”8 outlines a program intended to encourage the development of consistent, reusable therapeutic architectures that can efficiently support multiple products. While still evolving, the direction is clear. A platform is defined not by identical payloads, but by a consistent framework that can support a range of variant-specific interventions without rebuilding the therapeutic from scratch.
Under this definition, payload variability is not disqualifying. For example, mRNA vaccines vary in sequence, AAV gene therapies vary in transgenes, and CAR T therapies vary in their antigen-binding domains. What persists is the structural and mechanistic continuity of the platform. This regulatory lens is why the field is beginning to differentiate between systems that entangle variability and systems that modularize it. From a scientific standpoint, both remain valid; from a development standpoint, their implications diverge.
While it is far too early to claim that any editing system qualifies for platform designation, the emerging direction is noteworthy. The FDA is placing value on mechanistically coherent platforms, enabling individualized therapies built on shared architectures, and encouraging technologies that can adapt across variants without reinventing the therapeutic entity each time.
For organizations developing modular editing systems, and for therapeutic developers designing patient-specific interventions, this is a space worth watching closely as the regulatory landscape continues to mature.
If you’re thinking about how adaptable editing architectures might support your therapeutic programs, we’d be glad to explore the possibilities with you and how the Pin-point platform can help.
Pin-point base editing reagents are available for research use only and are not for diagnostic use or direct administration into humans or animals. The Pin-point base editing platform technology is available for clinical or diagnostic study and commercialization under a commercial license from Revvity.
References:
- Prasad V, Makary MA. FDA’s New Plausible Mechanism Pathway. New England Journal of Medicine. 2025.
- Kosicki M, Tomberg K, Bradley A. Repair of CRISPR–Cas9–induced double-strand breaks leads to large deletions and complex rearrangements. Nat Biotechnol. 2018.
- Cullot G et al. CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations. Nat Commun. 2019.
- Leibowitz ML et al. Chromothripsis as a result of CRISPR–Cas9 genome editing. Nat Genet. 2021.
- R. Blassberg et al. Minimal activation of the p53 DNA damage response by a modular cytosine base editor enables effective multiplexed gene knockout in induced pluripotent stem cells. bioRxiv. 2025.
- Porreca et al. An aptamer-mediated base editing platform for simultaneous knockin and multiple gene knockout for allogeneic CAR T cells generation. Mol Therapy. 2024.
- Pin-point™ Base Editing Platform. Revvity. 2025. https://www.revvity.com/category/pin-point-base-editing-platform
- Platform Technology Designation Program for Drug Development Guidance for Industry. May 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/platform-technology-designation-program-drug-development
