CRISPR Therapeutics Will Be Obsoleted by Base and Prime Editing Before Reaching Blockbuster Status

Traditional CRISPR-Cas9 makes double-strand breaks. It's a chainsaw doing surgery. Base editing (Komor et al., 2016, Nature) makes precise single-nucleotide changes without DSBs. Prime editing (Anzalone et al., 2019, Nature) can make any small edit without DSBs or donor templates.

The problem with DSB-dependent CRISPR: off-target cuts, large deletions (Kosicki et al., 2018, Nature Biotechnology), chromothripsis at the cut site, p53-selection bias favoring cancer-prone cells (Haapaniemi et al., 2018, Nature Medicine). These aren't edge cases — they're inherent to the mechanism.

Hypothesis: DSB-dependent CRISPR-Cas9 therapeutics (excluding ex vivo applications like CAR-T) will peak at <$5B annual revenue before being replaced by base and prime editing platforms that achieve equivalent efficacy with 10-100x fewer genotoxic events. The FDA will eventually require non-DSB editing for germline-proximal tissues.

Prediction: By 2030, >70% of new gene editing clinical trials will use base or prime editors rather than nuclease-active Cas9.