Base and Prime Editors Are Too Large for Single-AAV Delivery

Base editors (~5.2 kb) and prime editors (~6.3 kb) exceed AAV's 4.7 kb packaging limit. Split-intein dual-AAV approaches work but lose 40-70% of activity. This means the safest, most precise editing tools can't use the most established delivery vehicle.

CBE is ~5.2 kb, ABE ~5.1 kb, PE ~6.3 kb (editor protein alone). Split-intein dual-AAV reconstitution achieves 30-60% of unsplit activity. LNP delivery of editor mRNA works for liver (Verve achieved ~60% editing of PCSK9 in NHP liver) but drops dramatically in non-liver tissues. Compact Cas proteins — Cas12f (~1.5 kb from Arbor), CasX (~2.8 kb from Scribe) — could make single-AAV editors possible but with different PAM requirements and potentially lower activity.

Why It Matters

Base/prime editors are theoretically ideal — no dangerous DSBs. But if they can't be efficiently delivered, their safety advantage is moot. Beam, Prime Medicine, and others have multi-billion valuations built on in vivo precision editing that doesn't yet work efficiently enough outside the liver.

Startup Approach

Engineer compact editors using Cas12f or CasX scaffolds that maintain high activity while fitting in single AAV. Key metric: >30% editing in non-liver tissue in vivo. Or develop non-viral delivery platforms optimized for large mRNA payloads.

NIH Funding

NHGRI funds base/prime editing extensively. SCGE includes editor delivery/efficiency milestones. NHLBI funds in vivo editing for hemoglobin disorders.

Who's Working On It

David Liu lab (Broad, PEmax optimization), Beam Therapeutics (smaller ABE variants), Arbor Biotechnologies (compact Cas12f), Scribe Therapeutics (CasX ~2.8 kb), Prime Medicine