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Template-independent genome editing and restoration for correcting frameshift disorders

Nature Biomedical Engineering (2026)Cite this article

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Abstract

Frameshift mutations, responsible for >20% of Mendelian inherited diseases, pose substantial therapeutic challenges. Here we developed Template-Independent Genome Editing for Restoration (TIGER), a platform for the efficient and precise correction of frameshift mutations across various models. By identifying reproducible nucleotide-level factors that influence therapeutic efficacy across cells and tissues, we developed a scoring system for guide RNA (gRNA)–Cas9 outcomes. Approximately 75% of deletion and 50% of insertion mutations produced ≥30% in-frame products, sufficient for phenotypic restoration, with 38% and 65% achieving wild-type correction, respectively. To expand the applicability of TIGER across species and genome wide, we retrained the inDelphi algorithm to predict therapeutic gRNAs for single-nucleotide frameshifts. In a mouse model of deafness, delivery of SpCas9 and optimal gRNA via dual adeno-associated virus restored hearing thresholds to wild-type levels, with ~90% of in-frame edits being wild type. TIGER provides a robust and broadly applicable strategy for in vivo correction of inherited frameshift diseases.

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Fig. 1: Homologous predictability on TIGER factors.
Fig. 2: Cross-model evaluation of TIGER-compatible gRNAs.
Fig. 3: NT-resolution prediction of TIGER products.
Fig. 4: Recovered hearing in model mice following TIGER treatment.
Fig. 5: Precise and permanent restoration in TIGER-treated model mice.

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Data availability

All data supporting the findings in this study are available within the Article and its Supplementary Information. All sequencing data have been deposited in the Bio-Med Big Data Center under accession code OEP00006674. All imaging data are available via Figshare at https://doi.org/10.6084/m9.figshare.30487991 (ref. 37). Source data are provided with this paper.

Code availability

Custom scripts used for data analysis are written in Python 2.7 and R 4.3.3, and are available via GitHub at https://github.com/tlz4320/TigerPortal.

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Acknowledgements

We thank L. Zou, Q. Hu, Q. Liu, L. Peng and Q. Hu for conducting the cochlea injectoporation; S. Sun and Z. Zhao for conducting the auditory behaviour tests; G. Zhong for synthesizing dual AAVs; U. Müller for providing Pcdh15-av3j mice; Y. Wang for laboratory management; and J. Ma and all the members of the Xiong laboratory for feedback and discussions. We also thank the Laboratory Animal Resource Center of CIBR for maintenance of model mice, the Animal Care Core of Tsinghua University for generating the Otof-1233delC mouse line, the Imaging Core of CIBR for assistance in imaging, the Flow Cytometry and Genome Center of CIBR for cell sorting and sequencing, the Network and Informatization Office for website construction and the Behavior Analysis Center for providing behaviour equipment. W.X. discloses support for the research described in this study from China Ministry of Science and Technology (grant no. 2021ZD0203304), National Natural Science Foundation of China (grant no. U23A20442), Shenzhen Medical Research Fund (grant no. B2402008) and Beijing Key Laboratory of Brain Science and Brain-Machine Interface. S. Liu discloses support for the research described in this study from the fellowship of China Postdoctoral Science Foundation (grant no. 2021M701920) and National Natural Science Foundation of China (grant no. 32300830). L.L. discloses the support from China Postdoctoral Science Foundation (grant no. GZC20231468) and Shandong Provincial Department of Human Resources and Social Security (grant no. SDBX202302003). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Shiwei Qiu, Lian Liu, Bin Xiang.

Authors and Affiliations

  1. School of Life Sciences, Tsinghua University, Beijing, China

    Shiwei Qiu, Dong Li, Hanqing Hou, Kuan Li, Shang Li, Shuang Liu, Chunlai Chen, Xin Liang & Qianwen Sun

  2. Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Shiwei Qiu, Bin Xiang, Ziqin Jin, Yahong Li, Dong Li, Kuan Li, Gege Wei, Jiangping Xie, Shuang Liu & Wei Xiong

  3. Chinese Institute for Brain Research, Beijing (CIBR), Beijing, China

    Shiwei Qiu, Bin Xiang, Ziqin Jin, Yahong Li, Dong Li, Kuan Li, Gege Wei, Jiangping Xie, Shuang Liu & Wei Xiong

  4. IDG/McGovern Institute for Brain Research at Tsinghua University, Tsinghua University, Beijing, China

    Shiwei Qiu, Dong Li, Hanqing Hou, Shuang Liu & Xin Liang

  5. Tsinghua–Peking Center for Life Sciences, Tsinghua University, Beijing, China

    Shiwei Qiu, Kuan Li & Qianwen Sun

  6. School of Life Sciences, Shandong University, Qingdao, China

    Lian Liu

  7. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Bin Xiang

  8. State Key Laboratory of Complex, Severe, and Rare Diseases, Tsinghua University, Beijing, China

    Dong Li & Xin Liang

  9. SimpGen Therapeutics Co., Ltd., Suzhou, China

    Dong Li

  10. State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China

    Shang Li & Chunlai Chen

  11. Beijing Key Laboratory of Brain Science and Brain-Machine Interface, Beijing, China

    Wei Xiong

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Contributions

Molecular cloning by Z.J., Y.L., D.L. and S. Li. Cell culture, transfection and sequencing by S.Q., L.L., Z.J. and Y.L. Mutant cell line generation and PE by Z.J. and Y.L. Cochlear tissue culture and electroporation by L.L., G.W. and S. Liu. Cochlear cell collection and sequencing by S.Q. and L.L. Bioinformatic screen and analysis by B.X. and K.L. Mouse design by L.L. Mouse surgery and viral injection by S.Q and H.H. Mouse breeding and auditory behaviour by L.L., S.Q., H.H. and J.X. Cochlea tissue immunostaining and biochemistry by S.Q. Supervision by L.L., X.L., C.C., Q.S. and W.X. Paper writing by S.Q, L.L., B.X. and W.X. Experiment design and oversight by W.X.

Corresponding author

Correspondence to Wei Xiong.

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Competing interests

W.X. is a cofounder of SimpGen Therapeutics. This relationship did not influence this study. The other authors declare no competing interests.

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Nature Biomedical Engineering thanks Yilai Shu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Comparable InDel frequency and spectrum between the WT and av3j alleles.

a–c, Histograms showing mirrored in-frame/InDel profiles between av3j mutation-gRNA combinations (upper panels) and corresponding WT combinations (lower panels) from mouse cochleae. All three combination pairs exhibit symmetric frequencies of products across various InDel types distinguished by changed numbers of nucleotide (NT) or amino acid (AA). Green bars represent in-frame products. d, Histogram of in-frame/InDel profiles for wm-3j-gRNA4 from av3j cochleae. (a–d) Each biological replicate represents an amplicon from independently collected, transfected cochlear cells. Number of replicates are shown in panels. e–g, Bar graphs showing comparable positions of the top three in-frame products between av3j-gRNA1~3 combinations and the corresponding WT combinations. h, Bar graph showing the position of the length-restoring products of the av3j-gRNA4 combination.

Source data

Extended Data Fig. 2 Symmetric InDel patterns between I-C strand pairs.

a, Schematic of InDel profiling for gRNA pairs in HEK293T cells. Editing profiles are plotted by mirror correlation across 132 pairs, with 92 pairs (69.7%) exhibiting a Pearson correlation coefficient (R) > 0.6. Read counts for each combination are shown as dark blue side bars. b, Averaged InDel patterns for I-strands and C-strands. c, Examples of mirrored patterns for pairs with different R values: #1, R = 0.99 pair with dominant Ins1 events; #2, R = 0.99 pair with dominant Del1 events; and #3, R = 0.6 pair with both Ins1 and Del1 events.

Source data

Extended Data Fig. 3 Partial prediction of cochlear InDel patterns by cell profiles and algorithms.

a, InDel profiles of 118 deafness mutation-gRNA combinations from mouse cochlea tissue (left) and mouse N2a cells (right), sorted by the Pearson correlation coefficient (R, red square). Read counts for each combination are shown as dark blue side bars. b, InDel profiles predicted by the inDelphi algorithm. Note that inDelphi does not output NT information for changes larger than +1. c, InDel profiles predicted by the FORECasT algorithm. d, Averaged InDel patterns for I-strands and C-strands. e–g, Examples of mirrored patterns between cochlea and N2a cell profiles, with the N2a profiles showing certain large NT number change events.

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Extended Data Fig. 4 Partial prediction of cochlear in-frame outcomes by cell profiles.

a, b, In-frame profiles of 87 Del1-gRNA combinations (a) and 31 Ins1-gRNA combinations (b) from mouse cochlea tissue (left) and mouse N2a cells (right), sorted by in-frame ratio (orange side bars). Person correlation coefficient (R, red square) and length-restoring ratio (blue side bars) for each combination are shown respectively. c, d, Averaged in-frame patterns for cochlear and N2a cells for Del1 mutations (c) and Ins1 mutations (d).

Source data

Extended Data Fig. 5 Overview of the TIGER portal.

a, Schematic of re-training the inDelphi algorithm with 264 gRNA edits from HEK293T and 118 gRNA edits from cochleae. Ins1 prediction was upgraded from 1 NT on both sides of cut site to 2 NT on the left and 1 NT at the right. Del1 prediction was updated from a 50:50 ratio to a 2NT on both side prediction. b, Plots showing identity changed NT values for gRNAs targeting the 40 deafness and top 100 prevalent pathogenic Del1 and Ins1 mutations from ClinVar, as predicted by the TIGER portal. c, Workflow illustrating applications of the TIGER portal. d, Workflow showing operations of the TIGER portal website.

Source data

Extended Data Fig. 6 In-frame products of OTOF-1236C-gRNA1.

a, Predicted in-frame products for human OTOF-1236delC-gRNA1 from the TIGER portal. b, Sequenced 3n + 1 products for mouse Otof-1233C-gRNA1 from the cochlea dataset. c, Protein-level in-frame products for mouse Otof-1233delC-gRNA1 derived from b.

Extended Data Fig. 7 Generation and characterization of Otof-1233delC mouse line.

a, Four-color chromatogram showing the genotypes of WT, Otof1233delC/+, and Otof1233delC/1233delC mice. b, Western blot analysis of Otoferlin protein in cochleae using an Otoferlin antibody from control and Otof1233delC/1233delC mice, with GAPDH serving as an internal control. c, Whole mount immunostaining of WT (c) and of Otof1233delC/1233delC (d) cochleae. Otoferlin (red), Myo7a (green), and DAPI (blue) signals are shown. Lower panels highlight magnified regions (white frame) from the upper panels. White frames in lower panels highlight Otoferlin-positive IHCs in WT cochleae (c) and Otoferlin-negative IHCs in Otof1233delC/1233delC cochleae (d). Scale bars: 100 μm (upper panels), 20 μm (lower panels). e, Click ABR waveforms from WT (left) and Otof1233delC/1233delC (right) mice. f, Quantification of click and pure-tone ABR thresholds for WT (gray) and Otof1233delC/1233delC (purple) mice.

Source data

Extended Data Fig. 8 AAV9 dosage effect on IHCs in mice.

a, Whole mount immunostaining of WT cochleae demonstrating 400 nl AAV9-CAG-mCherry (1×1013 GC/ml) induces mCherry expression in 100% of IHCs. mCherry (red), Myo7a (yellow), and DAPI (blue) signals are shown. Right panels highlight magnified regions (white frames) from the left panels. Scale bars: 200 μm (left), 20μm (right). Multiple mice were tested to validate this observation. b, Whole mount immunostaining of Otof1233delC/1233delC cochleae revealing dual AAV9(SpCas9 + gRNA1) dosage-dependent Otoferlin expression in IHCs. Otoferlin (green), Myo7a (red), and DAPI (blue) signals are shown. The injected dual AAV9 volume was from 400, 600, 800, 1000, to 1500 nl, as indicated on the top of panels. Scale bars: 100 μm. c, Quantification of Otoferlin expressing IHC in uninjected and dual AAV9 injected Otof1233delC/1233delC mice. d, Quantification of click and pure-tone ABR thresholds from graded volume of dual AAV9 treated Otof1233delC/1233delC mice (green), in comparison with WT mice (gray) and untreated Otof1233delC/1233delC mice (purple).

Source data

Extended Data Fig. 9 Safety of 1000 nl AAV9 injection in wild-type mice.

a, Whole mount immunostaining of WT cochleae after 1000 nl 1×1013 dual AAV9-(SpCas9 + gRNA1) injection. Myo7a (red), Otoferlin (green), and DAPI (blue) signals are shown. Right panels displayed magnified regions (white frames) from left panels. Scale bars: 200 μm (left), 20μm (right). b, Quantification of click and pure-tone ABR thresholds for uninjected (gray) and injected (green) mice. c, H&E staining of major organs (brain, heart, kidney, liver, and lung) from AAV9-injected mice. Scale bars: 200 μm.

Source data

Extended Data Fig. 10 Long-term hearing evaluation in Otof1233delC/1233delC mice.

a, b, Wave I amplitude (a) and latency (b) from 80 dB SPL click ABR recorded in WT, Otof1233delC/1233delC, and treated Otof1233delC/1233delC mice over time. c–f, Pure-tone ABR threshold at 3 month (c), 5 months (d), 7 months (e), and 9 months (f).

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Qiu, S., Liu, L., Xiang, B. et al. Template-independent genome editing and restoration for correcting frameshift disorders. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01635-5

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