Oocyte spindle transfer for prevention of mitochodrial disease: the question of membrane fusion technique

Abstract

I read with interest the report on the live birth after oocyte spindle transfer recently published in RBMOnline (Zhang et al, 2017Zhang J. Liu H. Luo S. Lu Z. Chávez-Badiola A. Liu Z. Yang M. Merhi Z. Silber S.J. Munné S. Konstantinidis M. Wells D. Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod. Biomed. Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). I wish to congratulate the authors on this important breakthrough in the prevention of the transmission of mitochondrial disease. As presented, however, the article has a number of weaknesses and limitations in a number of areas, as also pointed out in the accompanying Editorial (Alikani et al, 2017Alikani M. Fauser B.C.J. García-Valesco J.A. Simpson J.L. Johnson M.H. First birth following spindle transfer for mitochondrial replacement thrapy.Reprod. Biomed. Online. 2017; 34: 333-336Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). This letter is focused on one of them – the method of membrane fusion used for spindle transfer. Zhang et al, 2017Zhang J. Liu H. Luo S. Lu Z. Chávez-Badiola A. Liu Z. Yang M. Merhi Z. Silber S.J. Munné S. Konstantinidis M. Wells D. Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod. Biomed. Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar used electrofusion, a technique known to produce premature activation of human oocytes (Cohen et al, 1998Cohen J. Scott R. Alikani M. Schimmel T. Munné S. Levron J. Wu L. Brenner C. Warner C. Willadsen S. Ooplasmic transfer in mature human oocytes.Mol. Hum. Reprod. 1998; 4: 269-280Crossref PubMed Scopus (280) Google Scholar), a condition suspected to be at the origin of embryo aneuploidy (Paull et al, 2013Paull D. Emmanuele V. Weiss K.A. Treff N. Stewart L. Hua H. Zimmer M. Kahler D.J. Goland R.S. Noggle S.A. Prosser R. Hirano M. Sauer M.V. Egli D. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants.Nature. 2013; 493: 632-637Crossref PubMed Scopus (185) Google Scholar). In fact, three out of four blastocysts obtained from reconstituted oocytes in the report by Zhang et al, 2017Zhang J. Liu H. Luo S. Lu Z. Chávez-Badiola A. Liu Z. Yang M. Merhi Z. Silber S.J. Munné S. Konstantinidis M. Wells D. Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod. Biomed. Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar were aneuploid. In the first scientifically documented experimental work on spindle transfer between mature human oocytes (Tesarik et al, 2000Tesarik J. Nagy Z.P. Mendoza C. Greco E. Chemically and mechanically induced membrane fusion: non-activating methods for nuclear transfer in mature human oocytes.Hum. Reprod. 2000; 15: 1149-1154Crossref PubMed Scopus (37) Google Scholar), which was not cited in the paper by Zhang et al, 2017Zhang J. Liu H. Luo S. Lu Z. Chávez-Badiola A. Liu Z. Yang M. Merhi Z. Silber S.J. Munné S. Konstantinidis M. Wells D. Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod. Biomed. Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, two methods that avoided premature oocyte activation were used. Fusion between a karyoplast and an enucleated oocyte was achieved either chemically, with polyethylene glycol, or by mechanical manipulation. Both methods resulted in a low degree of spontaneous oocyte activation and a high capacity of the reconstructed oocytes to undergo subsequent calcium-induced activation (Tesarik et al, 2000Tesarik J. Nagy Z.P. Mendoza C. Greco E. Chemically and mechanically induced membrane fusion: non-activating methods for nuclear transfer in mature human oocytes.Hum. Reprod. 2000; 15: 1149-1154Crossref PubMed Scopus (37) Google Scholar). It is evident that the optimal methodology of spindle transfer for mitochondrial replacement therapy is far from being established, and future research is urgently needed.