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CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review

  • Authors:
    • Maryam Jasem Ruqait Alali
    • Naveen Kumar
    • Malak Essam Fawzy
    • Abdalla Ahmed Eldaw Elamin
    • Vijay Paul Samuel
  • View Affiliations / Copyright

    Affiliations: Ras Al Khaimah College of Medical Sciences, RAK Medical and Health Sciences University, P.O. Box 11172, Ras Al‑Khaimah, United Arab Emirates, Department of Anatomy, Ras Al Khaimah College of Medical Sciences, RAK Medical and Health Sciences University, P.O. Box 11172, Ras Al‑Khaimah, United Arab Emirates
    Copyright: © Ruqait Alali et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 88
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    Published online on: August 26, 2026
       https://doi.org/10.3892/wasj.2026.503
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Abstract

The most common chromosomal aneuploidy compatible with life is Down syndrome (DS or trisomy 21), caused by an extra copy of chromosome 21. Although symptomatic care remains the mainstay of management, new gene‑editing technologies now allow the supernumerary chromosome to be directly silenced or eliminated, providing a critical background for evaluating novel chromosome‑level correction techniques for trisomy 21. The present systematic review synthesized preclinical studies on two genome engineering strategies for correcting trisomy 21: X‑inactive specific transcript (XIST)‑mediated RNA silencing and CRISPR/CRISPR‑associated protein 9 (Cas9)‑mediated chromosome deletion, in cell and animal models. PubMed, Scopus and Web of Science were systematically searched according to the PRISMA 2020 and PRISMA‑S guidelines (inception to March, 2025). Eligible studies applied these interventions to human or murine trisomic cells or in vivo models, and were assessed using the SYRCLE (animal studies) and OHAT‑like (cell‑based studies) risk‑of‑bias domains. In total, six preclinical studies met the inclusion criteria. Of these studies, three used doxycycline‑inducible XIST transgenes to silence one extra chromosome 21 in DS‑induced pluripotent stem cells, achieving >90% silencing while rescuing hematopoietic and neurogenic phenotypes. The other two studies used CRISPR approaches, namely multi‑site chromosomal cleavage or allele‑specific guide RNAs, achieving 10‑30% of disomic derivatives with normalized transcriptomic readouts, while the sixth, an earlier study, used a selection‑based counter‑selection strategy (TKNEO/ganciclovir) that isolated rare disomic clones at markedly lower efficiency (~10‑4). The main limitations were off‑target editing and incomplete/mosaic silencing; no study examined in vivo functional rescue beyond cellular systems. Overall, both XIST silencing and CRISPR‑based editing effectively cleared the extra chromosome 21 in vitro and partially corrected gene‑expression programs and cell‑type functions, paving the way toward chromosome‑level therapy. However, the evidence remains preliminary; further studies are warranted to enhance conversion efficiency, evaluate genomic safety (off‑target and structural variants), and assess durability, safety and functional rescue in animal models in order to establish translational feasibility.
View Figures

Figure 1

PRISMA flow diagram illustrating the
selection, inclusion and exclusion of the studies in the present
systematic review.

Figure 2

Schematic comparison of XIST-mediated
chromosome 21 silencing and CRISPR/Cas9-based chromosome
elimination. The image was created by the authors based on
information from previous studies (5,6,14,15,20,24).
XIST, X-inactive specific transcript; CRISPR, clustered regularly
interspaced short palindromic repeats; Cas9, CRISPR-associated
protein 9; H3K27me3, trimethylation of lysine 27 on histone H3.
View References

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Spandidos Publications style
Ruqait Alali MJ, Kumar N, Fawzy ME, Eldaw Elamin AA and Samuel VP: CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review. World Acad Sci J 8: 88, 2026.
APA
Ruqait Alali, M.J., Kumar, N., Fawzy, M.E., Eldaw Elamin, A.A., & Samuel, V.P. (2026). CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review. World Academy of Sciences Journal, 8, 88. https://doi.org/10.3892/wasj.2026.503
MLA
Ruqait Alali, M. J., Kumar, N., Fawzy, M. E., Eldaw Elamin, A. A., Samuel, V. P."CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review". World Academy of Sciences Journal 8.5 (2026): 88.
Chicago
Ruqait Alali, M. J., Kumar, N., Fawzy, M. E., Eldaw Elamin, A. A., Samuel, V. P."CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review". World Academy of Sciences Journal 8, no. 5 (2026): 88. https://doi.org/10.3892/wasj.2026.503
Copy and paste a formatted citation
x
Spandidos Publications style
Ruqait Alali MJ, Kumar N, Fawzy ME, Eldaw Elamin AA and Samuel VP: CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review. World Acad Sci J 8: 88, 2026.
APA
Ruqait Alali, M.J., Kumar, N., Fawzy, M.E., Eldaw Elamin, A.A., & Samuel, V.P. (2026). CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review. World Academy of Sciences Journal, 8, 88. https://doi.org/10.3892/wasj.2026.503
MLA
Ruqait Alali, M. J., Kumar, N., Fawzy, M. E., Eldaw Elamin, A. A., Samuel, V. P."CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review". World Academy of Sciences Journal 8.5 (2026): 88.
Chicago
Ruqait Alali, M. J., Kumar, N., Fawzy, M. E., Eldaw Elamin, A. A., Samuel, V. P."CRISPR‑mediated chromosome elimination and XIST‑driven silencing in Down syndrome models: A systematic review". World Academy of Sciences Journal 8, no. 5 (2026): 88. https://doi.org/10.3892/wasj.2026.503
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