Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Mar;39(3):609-618.
doi: 10.1007/s10815-022-02401-7. Epub 2022 Jan 22.

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

Maoxing Tang  1 , Annekatrien Boel  2 , Noemi Castelluccio  1 , Arantxa Cardona Barberán  1 , Antonia Christodoulaki  1 , Bieke Bekaert  1 , Mina Popovic  1 , Frauke Vanden Meerschaut  1 , Petra De Sutter  1 , Björn Menten  3 , Sofie Symoens  3 , Arnaud V Vanlander  4 , Dominic Stoop  1 , Paul J Coucke  3 , Björn Heindryckx  1
Affiliations

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

Maoxing Tang et al. J Assist Reprod Genet. 2022 Mar.

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.

Keywords: Female infertility; Fertilization failure; Mitochondrial DNA disease; Pronuclear transfer; Spindle transfer.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

References

    1. Craven L, Tang MX, Gorman GS, De Sutter P, Heindryckx B. Novel reproductive technologies to prevent mitochondrial disease. Hum Reprod Update. 2017;23(5):501–519. doi: 10.1093/humupd/dmx018. - DOI - PubMed
    1. Zhang J, Liu H, Luo S, Lu Z, Chavez-Badiola A, Liu Z, et al. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod Biomed Online. 2017;34(4):361–368. doi: 10.1016/j.rbmo.2017.01.013. - DOI - PubMed
    1. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases Nat Rev Dis Primers. 2016;2:16080. doi: 10.1038/nrdp.2016.80. - DOI - PubMed
    1. White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999;65(2):474–482. doi: 10.1086/302488. - DOI - PMC - PubMed
    1. de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA. Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation. J Inherit Metab Dis. 2012;35(6):1059–69. doi: 10.1007/s10545-012-9465-2. - DOI - PMC - PubMed

Substances