Base Editing Gene Therapy for Precision Single-Nucleotide Correction — Regenerative Therapies
Next-generation CRISPR technology enabling single-nucleotide changes without double-strand DNA breaks. Potentially safer than standard Cas9.
Overview
Base editing is a next-generation gene editing technology developed by David Liu's lab at Harvard/Broad Institute (2016-2017) that enables precise single-nucleotide changes in DNA without creating double-strand breaks (DSBs). Base editors consist of a catalytically impaired Cas9 (nickase or dead Cas9) fused to a deaminase enzyme. Cytosine Base Editors (CBEs) convert C-to-T, while Adenine Base Editors (ABEs) convert A-to-G. Together, CBEs and ABEs can address approximately 60% of known pathogenic point mutations. The lead clinical program is BEAM-101 (Beam Therapeutics) for sickle cell disease. Verve Therapeutics' VERVE-101 uses base editing to knock out PCSK9 for familial hypercholesterolemia. Prime editing (also from David Liu, 2019) represents a further evolution - a search-and-replace editor capable of all 12 point mutation types without DSBs.
Indications
- Sickle cell disease (BEAM-101 - creating HPFH mutation for HbF reactivation)
- Heterozygous familial hypercholesterolemia (VERVE-101 - PCSK9 knockout)
- T-cell acute lymphoblastic leukemia (BEAM-201 - base-edited allogeneic CAR-T)
- Alpha-1 antitrypsin deficiency (preclinical)
- Glycogen storage disease type 1a (preclinical)
- Progeria/Hutchinson-Gilford syndrome (preclinical - ABE corrects C1824T LMNA mutation)
- Stargardt disease (retinal base editing - preclinical)
Mechanism of Action
Nickase Cas9 fused to deaminase paired with guide RNA targeting the specific pathogenic nucleotide. Editing window is typically positions 4-8 of the 20nt target
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| BEAM-101 (ABE-edited Autologous HSCs) | Patient-specific (edited HSCs) | Single infusion (curative intent) | Ex vivo base-edited CD34+ HSCs for SCD (BEAM-101) |
| VERVE-101 (ABE in LNP) | 0.1-0.6 mg/kg | Single infusion | In vivo liver base editing for FH (VERVE-101) |
Evidence Grade
GRADE C
Safety & Contraindications
- No double-strand breaks: reduced risk of translocations and chromothripsis vs standard CRISPR
- Bystander editing: adjacent bases in the editing window may be unintentionally modified
- Off-target RNA editing: deaminase domains may edit RNA transcripts (particularly for CBEs)
- Guide-independent DNA editing: deaminase may cause genome-wide C-to-T transitions at low frequency
- VERVE-101 Phase 1: one patient death (cardiac arrest) - investigation ongoing
- Beam Therapeutics paused BEAM-101 enrollment temporarily in 2023 for manufacturing issues
- Delivery challenges: LNP efficient for liver but limited for other organs
- Immune response to bacterial-origin editing proteins possible
- Very early clinical data - fewer than 50 patients treated globally
- Cost expected to be comparable to Casgevy ($1-3 million per patient)