A grant committee brief: reactivating fetal hemoglobin with an adenine base editor to correct sickle-cell disease without a double-strand break.
Since 2023, Casgevy and Lyfgenia have shown ex vivo genome editing can functionally cure sickle-cell disease — but both depend on a double-strand break and myeloablative conditioning.
The gap · HbF reactivation
The Approach
ABE8e installs a single A>G edit at the HBG1/HBG2 −113 promoter site, recreating a naturally occurring hereditary persistence of fetal hemoglobin (HPFH) variant — no double-strand break, no cutting.
Base-editing schematic · HBG1/HBG2 promoter locus
Editing efficiency achieved in CD34+ HSPCs across three independent donor lots
Sanger + deep sequencing · n=3 donors
Fetal hemoglobin induced per edited allele, above the 20% threshold linked to clinical benefit
HPLC hemoglobin quantification
Off-target editing detected at the top 10 CIRCLE-seq nominated sites
Whole-genome + targeted amplicon sequencing
What's inside
Each aim retires a specific risk before the next begins — the design a study section expects to see.
Both cures that exist today carry real costs: a matched donor, or a permanent double-strand break.
No donor search, no double-strand break, and a conditioning regimen designed to spare marrow reserve.
"The mutation we're installing already exists in nature, in people who never developed sickle-cell symptoms. We're not engineering something new — we're restoring a state biology already proved was safe."
Sickle-cell disease affects roughly 100,000 Americans and an estimated 20 million people worldwide, disproportionately Black and of African, Middle Eastern, and South Asian descent — a population underserved by rare-disease research investment.
The two approved genome-editing therapies proved the concept but priced it near $2.2 million per patient and paired it with a genotoxic conditioning regimen many eligible patients are too sick to tolerate.
A base-editing approach that avoids double-strand breaks addresses the two objections raised most often in FDA and NIH safety reviews of first-generation gene-editing therapies: off-target genotoxicity and large structural variants.
This is the first R01-supported program to target the HBG1/HBG2 promoter directly with a base editor rather than editing BCL11A, the erythroid enhancer targeted by Casgevy.
Because the edit recreates a naturally occurring HPFH allele, the safety argument rests on decades of clinical observation of unaffected carriers, not solely on new animal data.
The proposal is scoped narrowly: four aims, one edit, one delivery method — built to answer a reviewer's first question ("why will this work when others have tried") rather than to promise a platform.
Preclinical data · n=3 independent CD34+ HSPC donor lots · Aim 1 target shown for reference
Total direct costs · 4-year R01 budget
Budget justification, Section 5.3 · figures rounded
Guide RNA and base-editor variant selected; ≥60% editing efficiency confirmed across all three donor genotypes.
16-week xenograft engraftment and off-target sequencing complete; independent safety board reviews go/no-go.
GMP-compatible process transferred; potency assay validated for IND-enabling studies.
Pre-IND meeting held with FDA; Phase 1 protocol and consent documents finalized for submission.
Off-target sites nominated by CIRCLE-seq and computational prediction before any editing begins.
Whole-genome and targeted amplicon sequencing quantify editing at every nominated site per donor lot.
An independent data and safety monitoring board reviews cumulative findings at each aim's go/no-go gate.
High-fidelity editor variants and dose titration substituted wherever off-target signal exceeds 0.1%.
Contribution
From bench validation to a therapy request the committee can fund
Next Question
We are requesting a one-year no-cost extension supplement to fund a natural-history cohort of 30 pediatric and adult sickle-cell patients ahead of first-in-human dosing — a.okonkwo@chop.edu · Division of Hematology.