The FDA has proposed a new approval pathway called the "plausible mechanism" for individualized gene therapies for rare diseases where randomized controlled trials are not possible due to small patient numbers.[1][3] This pathway focuses on genome editing and RNA-based methods, such as antisense oligonucleotides, that target a specific genetic, cellular or molecular abnormality and correct the underlying cause of the disease.[1][3] The proposal allows for approval based on data from small, well-controlled studies, a biological rationale for therapy, and favorable early signals of efficacy.[2][3] It requires identification of the abnormality, demonstration of targeting the root cause, use of data on the natural history of the disease, and confirmation of successful targeting.[3] An example is the bespoke CRISPR therapy for the child KJ with the Q335X mutation in CPS1 deficiency, where 42% of liver cells in mice were modified.[1] Once approved, manufacturers must collect real-world data, monitor safety, and conduct confirmatory studies or face product recall.[2] The FDA expects a large number of applications for such therapies for ultra-rare diseases.[1][2]