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Human germline nuclear transfer to overcome mitochondrial disease and failed fertilization after ICSI

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Providing additional insights on the efficacy of human nuclear transfer (NT). Here, and earlier, NT has been applied to minimize transmission risk of mitochondrial DNA (mtDNA) diseases. NT has also been proposed for treating infertility, but it is still unclear which infertility indications would benefit. In this work, we therefore additionally assess the applicability of NT to overcome failed fertilization.

Methods

Patient 1 carries a homoplasmic mtDNA mutation (m.11778G > A). Seventeen metaphase II (MII) oocytes underwent pre-implantation genetic testing (PGT), while five MII oocytes were used for spindle transfer (ST), and one in vitro matured (IVM) metaphase I oocyte underwent early pronuclear transfer (ePNT). Patients 2–3 experienced multiple failed intracytoplasmic sperm injection (ICSI) and ICSI-assisted oocyte activation (AOA) cycles. For these patients, the obtained MII oocytes underwent an additional ICSI-AOA cycle, while the IVM oocytes were subjected to ST.

Results

For patient 1, PGT-M confirmed mutation loads close to 100%. All ST-reconstructed oocytes fertilized and cleaved, of which one progressed to the blastocyst stage. The reconstructed ePNT-zygote reached the morula stage. These samples showed an average mtDNA carry-over rate of 2.9% ± 0.8%, confirming the feasibility of NT to reduce mtDNA transmission. For patient 2–3 displaying fertilization failure, ST resulted in, respectively, 4/5 and 6/6 fertilized oocytes, providing evidence, for the first time, that NT can enable successful fertilization in this patient population.

Conclusion

Our study showcases the repertoire of disorders for which NT can be beneficial, to overcome either mitochondrial disease transmission or failed fertilization after ICSI-AOA.

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Data Availability

Data is available upon request.

Code availability

Not applicable.

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Acknowledgements

We thank the IVF lab team of the Department for Reproductive Medicine, Ghent University Hospital, for the collection of human oocytes.

Funding

This study was supported by grants from the China Scholarship Council (CSC) awarded to M.T. (Grant no. 201506160059) and Special Research Fund from Ghent University (Bijzonder Onderzoeksfonds, BOF) awarded to M.T. (Grant no. 01SC2916 and no. 01SC9518), the unrestricted educational grant of Ferring Pharmaceuticals (Aalst, Belgium), and multiple funds from FWO-Vlaanderen (Flemish fund for scientific research, Grant no. G051017N, G051516N and G1507816N). B.B. and A.C. are supported by FWO-Vlaanderen (Flemish fund for scientific research, Grant no. 11C2821N and 1S80222N, respectively).

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Authors and Affiliations

  1. Ghent-Fertility and Stem Cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium

    Maoxing Tang, Annekatrien Boel, Noemi Castelluccio, Arantxa Cardona Barberán, Antonia Christodoulaki, Bieke Bekaert, Mina Popovic, Frauke Vanden Meerschaut, Petra De Sutter, Dominic Stoop & Björn Heindryckx

  2. Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium

    Björn Menten, Sofie Symoens & Paul J. Coucke

  3. Division of Paediatric Neurology and Metabolic Diseases, Department of Paediatrics, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium

    Arnaud V. Vanlander

Authors
  1. Maoxing Tang
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  2. Annekatrien Boel
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  3. Noemi Castelluccio
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  4. Arantxa Cardona Barberán
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  8. Frauke Vanden Meerschaut
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  15. Björn Heindryckx
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Contributions

M.T., B.H., and A.B. designed and performed the experiments, collected and analyzed data, and wrote the manuscript. A.C.B., N.C., A.C., M.P., B.B., and F.V.M performed data acquisition and analysis. P.D.S., B.M., S.S., R.V.C., D.S., and P.C. conceived, designed, and supervised the experiments. All authors contributed to the interpretation of the results and revised the manuscript.

Corresponding author

Correspondence to Annekatrien Boel.

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Ethics approval

The use of human oocytes/embryos was approved by the Ghent University Hospital Ethical Committee (EC 2016/0872) and the Belgian Federal Commission for medical and scientific research on embryos in vitro (FCE-ADV_071_UZ Gent).

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Informed consent was obtained from all individual participants included in the study.

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Patients signed informed consent regarding publishing their data.

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The authors declare no competing interests.

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Maoxing Tang and Annekatrien Boel are shared first authors.

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Tang, M., Boel, A., Castelluccio, N. et al. Human germline nuclear transfer to overcome mitochondrial disease and failed fertilization after ICSI. J Assist Reprod Genet 39, 609–618 (2022). https://doi.org/10.1007/s10815-022-02401-7

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