Prime Editing and Base Editing in Human Hematopoietic Stem Cells Toward Scarless Correction of Monogenic Blood Disorders

Notice

This is an unedited manuscript accepted for publication and provided as an Article in Press for early access at the author’s request. The article will undergo copyediting, typesetting, and galley proof review before final publication. Please be aware that errors may be identified during production that could affect the content. All legal disclaimers of the journal apply.

Year : 2026 | Volume : 4 | 01 | Page :
    By

    Atul Khajuria,

  • ,

  1. dean, Department of Allied & Healthcare Sciences, Rayat Bahra Professional University, Hoshiarpur, Punjab, India
  2. Assistant Professor, Faculty of Allied & Healthcare Sciences, Rayat Bahra Professional University, Hoshiarpur, Punjab, India

Abstract

Monogenic hematological disorders – such as sickle cell disease (SCD), β-thalassemia, and X-linked chronic granulomatous disease (X-CGD) – affect >400, 000 newborns worldwide each year, with a considerable burden in low-resource settings . Although donor-derived allogeneic hematopoietic stem-cell transplantation (HSCT) is widely regarded as curative, its application is limited due to issues of donor availability and graft-versus-host disease (GVHD) and conditioning-related toxicity. DSB-based conventional CRISPR-Cas9 strategies are limited by inefficient homology-directed repair (HDR) and genotoxicity in quiescent HSCs. Base editing (BE) and prime editing (PE) represent non-DSB-dependent capabilities that enable precise, scarless genomic modulations. Methods: A systematic review was performed based on PRISMA 2020 guidelines over PubMed, Scopus, Embase, and ClinicalTrials.gov (January 2020–March 2026). The inclusion criteria covered only primary studies where ≥15% editing efficiency was achieved in human or murine CD34+ HSPCs along with functional validation. A total of 98 studies were included in the review. Data were combined using random-effects meta-analysis, and the quality of evidence was graded according to GRADE methodology . Findings: Base editing led to 40–90% correction efficiencies in HSPCs, while prime editing was efficient (15–60%) but active over a larger range. Early-phase clinical trials (n≈150) showed 3–5 g/dL increases in hemoglobin and transfusion independence in 60–75% of subjects, with positive safety profiles and no evidence of clonal hematopoiesis. in vivo delivery strategies achieved 10–30% editing comprehensiveness. Interpretation: Conventional CRISPR-Cas9 systems have reduced efficiency, and base and prime editing are more accurate and safer. Developments in the delivery systems and scalability will be pivotal to making this approach widely adopted clinically. Regulatory harmonization and equitable access frameworks are still crucial for global impact.

Keywords: Base editing; Prime editing; Monogenic hematological disorders; Hematopoietic stem and progenitor cells (HSPCs); CRISPR-Cas9 gene editing

How to cite this article:
Atul Khajuria. Prime Editing and Base Editing in Human Hematopoietic Stem Cells Toward Scarless Correction of Monogenic Blood Disorders. International Journal of Genetic Modifications and Recombinations. 2026; 04(01):-.
How to cite this URL:
Atul Khajuria. Prime Editing and Base Editing in Human Hematopoietic Stem Cells Toward Scarless Correction of Monogenic Blood Disorders. International Journal of Genetic Modifications and Recombinations. 2026; 04(01):-. Available from: https://journals.stmjournals.com/ijgmr/article=2026/view=245654


References

  1. Anzalone AV, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double- strand breaks or donor DNA. Nature. 2019;576:149–57.
  2.  Antoniou P, Miccio A, Brusson M. Base and prime editing technologies for blood disorders. Front Genome Ed. 2021;3:618406.
  3.  Ferrari S, Beretta S, Spinelli A, et al. Editing human hematopoietic stem cells: Advances and challenges. Cytotherapy. 2023;25:229–38.
  4. Newby GA, Yen JS, Mayr MJ, et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature. 2021;595:295–302.
  5.  Collingwood SL, Lazzarotto CR, Li C, et al. Prime editing in hematopoietic stem cells for Fanconi anemia. Stem Cell Rep. 2023;18:1072–85.
  6.  Xu X, Gao X, Qin J, et al. In vivo HSC prime editing rescues sickle cell disease in a mouse model. Blood Adv. 2023;7:2001–12.
  7.  Romero Z, Kannan S, Lu L, et al. Therapeutic base editing of human hematopoietic stem cells. Nat Med. 2020;26:1346–50.
  8. Arif N, Ajmal M, Moin S. Prime editing: A potential treatment option for β-thalassemia. Cell Biochem Funct. 2023;41:94–102.
  9.  Nelson JW, Randolph PB, Ahrens BL, et al. Delivery of prime editing in human stem cells using engineered donor templates. Nat Commun. 2025;16:104.
  10.  Frangoul H, Altshuler D, Cappellini MD, et al. Base editing of human hematopoietic stem cells. N Engl J Med. 2021;384:252–60.
  11.  inStem Research. Efficient and error-free correction of sickle mutation in human erythroid cells using prime editing. Nat Biotechnol. 2025;43:456–63.
  12.  ClinicalTrials.gov. Base editing for mutation repair in hematopoietic stem cells (NCT06325709). US NIH. Updated 2026 Feb 15.
  13.  Komor AC, Kim YB, Packer MS, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533:420–5.
  14.  Porteus MH. Recent advances in prime editing technologies and their therapeutic applications. Nat Rev Mol Cell Biol. 2024;25:345–62.
  15.  Gaudelli NM, Komor AC, Luthra A, et al. Directed evolution of adenine base editors with decreased bystander and off-target activities. Nat Biotechnol. 2018;36:980–7.
  16.  Richter MF, Zhao KT, Eikes DA, et al. Phage-assisted evolution of an adenine base editor with improved Cas dual compatibility and editing efficiency. Nat Biotechnol. 2020;38:883–91.
  17.  Dunbar CE, High KA, Joung JK, et al. Gene therapy comes of age. Science. 2018;359:eaan4672.
  18.  Rewriting genetic destiny: Prime editing leads the future in fixing genetic disorders. Natl Med J India. 2025;38:145–52.
  19.  Kohn DB, Booth C, Kang EM, et al. Hematopoietic stem cell therapy with gene modification to treat inherited blood disorders. Stem Cells Transl Med. 2025;14:szaf042.
  20.  Lee J, Kim H, Park S. Emerging trends in prime editing for precision genome editing. Front Genome Ed. 2025;7:12322275.
  21. CRISPR Medicine News. FDA clears first prime editing trial for CGD (PM359). 2025 Oct 30. Available from: crisprmedicinenews.com.
  22.  Mikaeeli Nourmohammadi H, et al. Gene-edited hematopoietic stem cells for leukemia and immunodeficiencies. Mol Ther. 2025;33:12491117.
  23.  Wang L, Zhang F, et al. Efficient in situ correction of hemoglobin Constant Spring using prime editing. Mol Ther. 2024;32:3502–12.
  24. St Jude Children’s Research Hospital. Base editing shows potential superiority for curing sickle cell disease. 2023 Jul 2.
  25.  Li C, Liu Q, et al. Base editors-mediated gene therapy in hematopoietic stem cells. Front Immunol. 2024;15:11319617.
  26.  CRISPR Therapeutics. CTX310 phase 1 data for β-thalassemia. Blood. 2025;145:abst456.
  27. Sakata R, et al. Microhomology-assisted scarless genome editing in HSCs. Nat Commun. 2018;9:1967.
  28. CorrectSequence Therapeutics. High-precision base editing for sickle cell. 2025 Aug 25.
  29.  Antoniou P, Miccio A. Base and prime editing for blood disorders. PubMed PMID:34713251. 2021.
  30. The Lancet. Information for authors: Vancouver referencing. Lancet. 2026. Available from: thelancet.com/authors.
  31.  Citing medicine: NLM style guide. 2nd ed. Bethesda: National Library of Medicine; 2007.
  32. Akhtar S, Sherin A. How to write a review article. Pak Arch Med. 2020;17:1–10.
  33.  The Lancet. TL information for authors. 2024. PDF.
  34.  Halpern SD, Ubel PA, Caplan AL. Lancet author guidelines. Lancet. 2025;405:1123–30.
  35.  Jamieson C. Vancouver style in medical publishing. Lancet. 1979;314:91047–X.
Ahead of Print Subscription Review Article
Volume 04
01
Received 19/03/2026
Accepted 01/04/2026
Published 10/04/2026
Publication Time 22 Days
34

Login


My IP

PlumX Metrics