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categories: ["genetics"]categories: ["genetics"]tags: ["crispr", "genome editing", "gene therapy", "point mutations", "biotechnology"]tags: ["crispr", "genome editing", "gene therapy", "point mutations", "biotechnology"]summary: "A genome editing method that chemically converts one DNA base into another at a targeted site without cutting both strands of the double helix."summary: "A genome editing method that chemically converts one DNA base into another at a targeted site without cutting both strands of the double helix."updated: "2026-07-27"updated: "2026-11-01"humanEvidence: "All human use is early-phase or one-off: base-edited donor T cells were given to a teenager with relapsed leukaemia in 2022, in vivo liver editing has lowered cholesterol in early trials, and a bespoke editor was dosed into one infant."humanEvidence: "All human use is trial-stage or one-off: edited CAR-T cells for one leukaemia patient in 2022, a 35-adult phase 1 liver trial (mean LDL down 62% at the top dose), 31 patients in an ex vivo sickle cell trial, and a bespoke editor given to one infant."access: "No base-editing therapy is approved anywhere as of 2026; the only routes are early-phase clinical trials and one-off bespoke treatments authorised for a single patient."access: "No base-editing therapy is approved anywhere as of November 2026; the only routes are clinical trials and one-off bespoke treatments authorised for a single patient."reversibility: "irreversible"reversibility: "irreversible"issues: ["The Verve and alpha-1 antitrypsin trial results in Current state carry no citations."]------ ```infobox```infobox{{ "caption": "Genome editing platform", "caption": "Genome editing platform", "rows": [ "rows": [ { "label": "Type", "value": "Deaminase–nickase fusion" }, { "label": "Type", "value": "Deaminase-nickase fusion" }, { "label": "First described", "value": "2016 (cytosine), 2017 (adenine)" }, { "label": "First described", "value": "2016 (cytosine), 2017 (adenine)" }, { "label": "Developed by", "value": "David Liu laboratory" }, { "label": "Developed by", "value": "David Liu laboratory" }, { "label": "Edits possible", "value": "4 of 12 substitutions" }, { "label": "Edits possible", "value": "4 of 12 substitutions" }, { "label": "Double-strand break", "value": "No" }, { "label": "Double-strand break", "value": "No" }, { "label": "First human use", "value": "2022, leukaemia CAR-T cells" }, { "label": "First human use", "value": "2022, leukaemia CAR-T cells" }, { "label": "First in vivo use", "value": "2022, PCSK9 in liver" }, { "label": "Readiness", "value": "TRL 7" } { "label": "Readiness", "value": "TRL 7" } ] ]}}lines 62–83 → 62–9031 unchanged lines not shown
The first use in a person came in 2022, when a team at Great Ormond Street Hospital in London treated a teenager with relapsed T-cell acute lymphoblastic leukaemia using donor T cells in which three genes had been disabled by base editing, converting them into a CAR-T product that would not attack itself.[^chiesa2023] The editing was done outside the body, which sidesteps the delivery problem entirely.The first use in a person came in 2022, when a team at Great Ormond Street Hospital in London treated a teenager with relapsed T-cell acute lymphoblastic leukaemia using donor T cells in which three genes had been disabled by base editing, converting them into a CAR-T product that would not attack itself.[^chiesa2023] The editing was done outside the body, which sidesteps the delivery problem entirely. Editing inside the body started the same year. In July 2022 Verve Therapeutics announced it had infused VERVE-101, an adenine editor aimed at the cholesterol-regulating gene *PCSK9* in liver cells, into a patient in New Zealand with heterozygous familial hypercholesterolaemia, which Verve described as the first in vivo base-editing dose in a person.[^gen2022] That trial, Heart-1, paused enrolment in April 2024 after the sixth patient dosed at 0.45 mg/kg developed a grade 3 rise in liver enzymes and grade 3 thrombocytopenia within four days of the infusion. Both resolved within days and neither caused symptoms.[^heart1pause] The company's own investigation, including animal studies using a version of the drug with a guide RNA designed not to edit, concluded that the lipid nanoparticle was likely the primary driver of the abnormalities.[^verveq32024] ## Current state## Current state As of 2026, base editing is in clinical trials rather than approved practice, and the trials divide into two families.As of November 2026, base editing is in clinical trials rather than approved practice, and the trials divide into two families. Ex vivo programmes edit cells outside the body and return them. A sickle cell disease candidate uses an adenine editor to recreate a naturally occurring promoter variant that keeps fetal haemoglobin switched on in adulthood — a different route to the same physiological end as [[casgevy]], which disrupts an erythroid enhancer of the repressor gene *BCL11A* instead. Both approaches share the burden that limits autologous stem cell therapy generally: patients need conditioning chemotherapy to clear marrow space, and that conditioning carries real mortality and infertility risk independent of the edit.Ex vivo programmes edit cells outside the body and return them. Beam Therapeutics' sickle cell candidate, ristoglogene autogetemcel, edits the *HBG1* and *HBG2* promoters in a patient's own blood stem cells so that the repressor BCL11A can no longer bind there, switching production from sickle haemoglobin to fetal haemoglobin. An unplanned interim analysis of the phase 1-2 BEACON trial, published in 2026, covered 31 patients followed for a mean of 6.6 months. Fetal haemoglobin averaged more than 60% of total haemoglobin at six months among the 13 patients assessed then, no investigator-reported severe vaso-occlusive crisis occurred more than 60 days after the last transfusion, 27 of the 31 patients had an adverse event of grade 3 or worse, and one died of idiopathic pneumonia syndrome.[^riscocel] That is a different route to the same physiological end as [[casgevy]], which disrupts an erythroid enhancer of the repressor gene *BCL11A* instead. Both approaches share the burden that limits autologous stem cell therapy generally: patients need conditioning chemotherapy to clear marrow space, and that conditioning carries real mortality and infertility risk independent of the edit. Beam has said it expects to apply for United States approval of the therapy as early as the end of 2026.[^beamq2] In vivo programmes deliver the editor systemically, almost always to the liver, using [[lipid-nanoparticles]]. The first in-human in vivo base editing trial, run by Verve Therapeutics, disabled *PCSK9* in hepatocytes to lower LDL cholesterol permanently; a successor candidate from the same programme reported substantial cholesterol reductions in 2025. A separate liver programme has reported correction — as opposed to disruption — of a disease-causing point mutation in patients with alpha-1 antitrypsin deficiency, which if it holds up would be the first such correction in a person.In vivo programmes deliver the editor systemically, almost always to the liver, using [[lipid-nanoparticles]]. Verve's successor candidate VERVE-102 carries the same adenine editor and *PCSK9* guide RNA as VERVE-101 inside a different particle, one built around a different ionisable lipid and a sugar tag, N-acetylgalactosamine, that lets it enter liver cells through the asialoglycoprotein receptor as well as the LDL receptor.[^heart1pause] Interim results from the phase 1 Heart-2 trial, published in the *New England Journal of Medicine* in 2026, cover 35 adults with heterozygous familial hypercholesterolaemia or premature coronary disease, each given a single infusion at one of six dose levels. Mean blood PCSK9 fell by 51% at the lowest dose and 88% at the highest; mean LDL cholesterol fell by 9% and 62% respectively, an absolute drop of 78 mg/dl at the top dose. The reductions appeared to hold through follow-up, which had reached at least a year in 15 of the 35 participants.[^verve102] Eli Lilly announced the purchase of Verve in June 2025 for about $1.0 billion in cash plus a contingent right to up to $3.00 a share that pays out only if a first patient is dosed in a United States phase 3 trial of VERVE-102 within ten years of closing, and completed it the following month.[^lillyverve][^vervemerger] A randomised, placebo-controlled phase 2 trial with a planned 175 patients and LDL cholesterol at day 90 as its primary endpoint was registered in September 2026 by Verve, now a Lilly subsidiary, and was listed that month as not yet recruiting.[^heart3] One liver programme corrects a disease-causing point mutation rather than disrupting a gene: Beam's BEAM-302, which repairs the single G-to-A change in *SERPINA1* behind the severe PiZZ form of alpha-1 antitrypsin deficiency. At a late-breaking session of the European Respiratory Society congress in September 2026, investigators reported that patients given the 60 mg dose went from blood alpha-1 antitrypsin of about 5 µM at baseline to a steady-state mean near 14 µM, above the 11 µM concentration conventionally treated as protective, with more than 90% of the circulating protein in the corrected form and the mutant form down by 84%. Some patients had been followed to 18 months. Adverse events were mostly mild to moderate infusion reactions and grade 1 liver enzyme rises; one patient had a grade 3 enzyme rise that resolved without treatment while bilirubin stayed normal.[^beam302] Those are sponsor-funded conference data rather than a peer-reviewed paper. A cohort intended to support a potential accelerated approval filing in the United States began dosing in July 2026.[^beamq2] > [!caution] What "one-time" has and has not been shown to mean> Both liver programmes are described as single-dose and permanent, and in the cells that take up an edit that is chemically true. The human record behind the durability claim is short: in the published and presented data for VERVE-102 and BEAM-302, about 18 months at most and a year or more in a minority of dosed patients, and nothing yet on the decades over which a cholesterol drug is supposed to work. An edit also cannot be stopped if it turns out to be the wrong trade against a cheap daily tablet, which is the asymmetry that makes the irreversibility of the method a safety question rather than a selling point. > [!key] The bespoke-therapy case> [!key] The bespoke-therapy case> In 2025 clinicians at the Children's Hospital of Philadelphia treated an infant with a severe urea-cycle disorder using a base editor designed for his specific mutation and delivered by lipid nanoparticle, from diagnosis to dosing in roughly six months.[^musunuru2025] It is the clearest existing demonstration that editing can be personalised, and the clearest illustration that regulatory and manufacturing pathways for one-patient medicines do not yet exist.> In 2025 clinicians at the Children's Hospital of Philadelphia treated an infant with a severe urea-cycle disorder using a base editor designed for his specific mutation and delivered by lipid nanoparticle, from diagnosis to dosing in roughly six months.[^musunuru2025] The case is the clearest existing demonstration that an editor can be designed for one person, and the clearest illustration that regulatory and manufacturing pathways for one-patient medicines do not yet exist. ## Limitations## Limitations The four accessible substitutions are the transitions — C to T, G to A, A to G, T to C. The eight transversions require different chemistry. Glycosylase-based editors that produce C-to-G changes exist but are less efficient and less clean, and for most transversions [[prime-editing]] remains the practical option.The four accessible substitutions are the transitions: C to T, G to A, A to G, T to C. The eight transversions require different chemistry. Glycosylase-based editors that produce C-to-G changes exist but are less efficient and less clean, and for most transversions [[prime-editing]] remains the practical option. Targeting is still constrained by the PAM requirement inherited from Cas9, which limits how the editing window can be positioned over a given base. Cargo size is a problem for viral delivery: a base editor plus guide RNA exceeds the packaging capacity of a single [[aav-vectors|adeno-associated virus]], forcing split-vector designs. And systemic delivery beyond liver and haematopoietic cells remains largely unsolved, which is the same constraint that limits [[targeted-drug-delivery]] generally.Targeting is still constrained by the PAM requirement inherited from Cas9, which limits how the editing window can be positioned over a given base. Cargo size is a problem for viral delivery: a base editor plus guide RNA exceeds the packaging capacity of a single [[aav-vectors|adeno-associated virus]], forcing split-vector designs. And systemic delivery beyond liver and haematopoietic cells remains largely unsolved, which is the same constraint that limits [[targeted-drug-delivery]] generally and that the particles being tested for [[in-vivo-car-t]] are designed to get around. ## Risks## Risks lines 85–95 → 92–1041 unchanged line not shown
Bystander edits raise a subtler issue for [[somatic-gene-therapy]]: a silent bystander change in one cell type may not be silent in another, and the tissue is a mosaic of edit patterns rather than a uniform genotype.Bystander edits raise a subtler issue for [[somatic-gene-therapy]]: a silent bystander change in one cell type may not be silent in another, and the tissue is a mosaic of edit patterns rather than a uniform genotype. In the liver trials so far, the clearest harms have come from the delivery vehicle rather than from the editing chemistry. The laboratory abnormalities that paused Heart-1 were traced to its lipid nanoparticle, and the redesigned particle still produced grade 1 or 2 infusion reactions in about a fifth of Heart-2 patients, along with transient liver enzyme elevations, even though patients were given a steroid the day before dosing and a steroid plus antihistamines on the day. Commenting on the Heart-2 results, Daniel Soffer of the University of Pennsylvania, a lipid specialist and past president of the National Lipid Association, noted that a particle which enters cells through the LDL receptor will reach tissues wherever that receptor is expressed, and that off-target risks will take years to study; Verve's chief medical officer, Scott Vafai, replied that preclinical off-target experiments had found no issues and that further clinical development is meant to establish safety.[^tctmd] For heritable use, the apparent tidiness of base editing has been used as an argument that [[germline-editing]] is now safe enough to attempt. Most of the field rejects that inference. Embryo editing still produces mosaicism, the Cas9-independent off-target mechanism operates during the exact developmental window in question, and no whole-genome assay can certify the absence of scattered point mutations in a single embryo without destroying it. The regulatory posture that followed the [[he-jiankui-affair]] has not shifted, and the frameworks surveyed in [[governance-of-genome-editing]] treat editor chemistry as largely beside the point.For heritable use, the apparent tidiness of base editing has been used as an argument that [[germline-editing]] is now safe enough to attempt. Most of the field rejects that inference. Embryo editing still produces mosaicism, the Cas9-independent off-target mechanism operates during the exact developmental window in question, and no whole-genome assay can certify the absence of scattered point mutations in a single embryo without destroying it. The regulatory posture that followed the [[he-jiankui-affair]] has not shifted, and the frameworks surveyed in [[governance-of-genome-editing]] treat editor chemistry as largely beside the point. ## Outlook## Outlook The near-term question is whether permanent single-dose edits to common risk genes — a lifetime cholesterol reduction from one infusion, for instance — can clear a safety bar set for chronic disease rather than for fatal rare disease. That bar is high, because the comparator is a cheap daily pill and the edit is irreversible. The technical frontier is delivery to tissues other than liver, editors small enough for single-vector packaging, and reliable assays for scattered off-target deamination. The economic frontier, shared with [[gene-therapy-for-aging]] and every other one-time genetic medicine, is whether a treatment designed for one child can ever be paid for, a problem that runs directly into [[access-and-inequality]] and that no current reimbursement system is built to solve.The near-term question is whether permanent single-dose edits to common risk genes, such as a lifetime cholesterol reduction from one infusion, can clear a safety bar set for chronic disease rather than for fatal rare disease. That bar is high, because the comparator is a cheap daily pill and the edit is irreversible. The phase 2 cholesterol trial adds a placebo group, which the Verve and Beam trials reporting so far have not had,[^heart3] and Heart-2 participants are to be followed for up to 15 years.[^tctmd] The technical frontier is delivery to tissues other than liver, editors small enough for single-vector packaging, and reliable assays for scattered off-target deamination. The economic frontier, shared with [[gene-therapy-for-aging]] and every other one-time genetic medicine, is whether a treatment designed for one child can ever be paid for, a problem that runs directly into [[access-and-inequality]] and that no current reimbursement system is built to solve. ## See also## See also lines 110–113 → 119–13314 unchanged lines not shown
[^zuo2019]: `paper` Zuo, E. et al. "Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos." *Science*, 2019. {The method compared edited and unedited cells descended from the same embryo, which is why it detected changes that sequencing predicted sites would miss.}[^zuo2019]: `paper` Zuo, E. et al. "Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos." *Science*, 2019. {The method compared edited and unedited cells descended from the same embryo, which is why it detected changes that sequencing predicted sites would miss.}[^grunewald2019]: `paper` Grünewald, J. et al. "Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors." *Nature*, 2019.[^grunewald2019]: `paper` Grünewald, J. et al. "Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors." *Nature*, 2019.[^musunuru2025]: `paper` Musunuru, K. et al. "Patient-specific in vivo gene editing to treat a rare genetic disease." *New England Journal of Medicine*, 2025. {A report of one infant treated under an individualised protocol, not a trial; it establishes feasibility rather than efficacy.}[^musunuru2025]: `paper` Musunuru, K. et al. "Patient-specific in vivo gene editing to treat a rare genetic disease." *New England Journal of Medicine*, 2025. {A report of one infant treated under an individualised protocol, not a trial; it establishes feasibility rather than efficacy.}[^gen2022]: `news` "Verve Therapeutics doses first patient with in vivo base editing therapy." *Genetic Engineering & Biotechnology News*, 13 July 2022. https://genengnews.com/news/verve-therapeutics-doses-first-patient-with-in-vivo-base-editing-therapy[^heart1pause]: `statement` Verve Therapeutics. Current Report on Form 8-K, 2 April 2024. https://www.sec.gov/Archives/edgar/data/1840574/000119312524084067/d758833d8k.htm {The company's own account of the Heart-1 pause, the laboratory abnormalities behind it, and how VERVE-102's particle differs; it predates the investigation's findings.}[^verve102]: `paper` Vafai, S. B. et al. "In vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia." *New England Journal of Medicine*, 2026;395:648-659. https://doi.org/10.1056/NEJMoa2601283 {A phase 1 interim analysis with no control group and no cardiovascular outcome data; the endpoints are PCSK9 protein and LDL cholesterol.}[^verveq32024]: `statement` Verve Therapeutics. "Verve Therapeutics Announces Pipeline Progress and Reports Third Quarter 2024 Financial Results." Press release filed as Exhibit 99.1 to Form 8-K, 5 November 2024. https://www.sec.gov/Archives/edgar/data/1840574/000095017024121072/verv-ex99_1.htm[^lillyverve]: `statement` Eli Lilly and Company and Verve Therapeutics. "Lilly to acquire Verve Therapeutics to advance one-time treatments for people with high cardiovascular risk." Joint press release, 17 June 2025. https://www.sec.gov/Archives/edgar/data/1840574/000119312525141748/d30505dex991.htm[^vervemerger]: `statement` Verve Therapeutics. Current Report on Form 8-K, 25 July 2025. https://www.sec.gov/Archives/edgar/data/1840574/000119312525165462/d71385d8k.htm {Records completion of the tender offer and merger on 25 July 2025.}[^heart3]: `trial` "A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of VERVE-102, a One-Time Dose Gene Editing Medicine, in Adults With or at High Risk for Atherosclerotic Cardiovascular Disease (ASCVD) Who Require Additional Low-Density Lipoprotein-Cholesterol (LDL-C) Lowering." Sponsor: Verve Therapeutics. ClinicalTrials.gov, NCT07839936. https://clinicaltrials.gov/study/NCT07839936[^riscocel]: `paper` Gupta, A. O. et al. "Base editing of HBG1 and HBG2 promoters for sickle cell disease." *New England Journal of Medicine*, 2026;394:1824-1835. https://doi.org/10.1056/NEJMoa2504835 {An unplanned interim analysis of a single-arm trial; mean follow-up was 6.6 months and the crisis-free endpoint was not yet assessable in most patients.}[^beam302]: `statement` Hurst, J. R. et al. "First-in-human in vivo gene editing for severe alpha-1 antitrypsin deficiency (AATD): initial data from the phase 1/2 study of BEAM-302." European Respiratory Society Congress, 7 September 2026. https://beamtx.com/wp-content/uploads/2026/09/Hurst_ERS_Final_presentation_7Sep26_v2.pdf {A sponsor-funded conference presentation of open-label data to a 24 June 2026 cutoff; lung function and liver outcomes are not reported.}[^beamq2]: `statement` Beam Therapeutics. "Beam Therapeutics reports second quarter 2026 financial results and announces first patient dosed in global pivotal cohort of BEAM-302 trial in alpha-1 antitrypsin deficiency." 4 August 2026. https://www.sec.gov/Archives/edgar/data/1745999/000119312526331522/beam-ex99_1.htm[^tctmd]: `news` Neale, T. "Gene-editing therapy safely lowers PCSK9, LDL cholesterol in phase I: Heart-2." *TCTMD*, 1 June 2026. https://www.tctmd.com/news/gene-editing-therapy-safely-lowers-pcsk9-ldl-cholesterol-phase-i-heart-2 {Carries the independent commentary on infusion premedication and LDL-receptor-mediated uptake, and the planned 15-year follow-up.} removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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