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Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations (2016)

Chapter: Appendix B: Summary of MRT Research

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Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

Appendix B

Summary of MRT Research

The following tables are a compilation of selected maternal spindle transfer (MST) (see Table B-1) and pronuclear transfer (PNT) (see Table B-2) studies. Study endpoints, materials and methods, and results are highlighted. The data are listed as presented in the respective publications, with no further calculation or interpretation by the committee.

Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

TABLE B-1 Summary of MST Research

Study/Model Materials and Methods
Wang et al. (2001)


Mouse (Kunming and C57BL/6J)
  • Enucleation in 3 percent sucrose
  • Transfer of C57BL/6J spindle-chromosome complexes to Kunming enucleated oocytes
  • 142 oocyte-karyoplast reconstructed pairs fused by 1-3 rounds of electrofusion
  • 11 fused oocytes used in IVF
  • Transfer of eight 1-4 cell stage embryos into two foster mothers

Tachibana et al. (2009)
(Oregon Health & Science University [OHSU] Group)


Nonhuman primate
(rhesus macaques)

  • 15 MST embryos transferred into 9 females: 6 with 1-2 blastocysts, 3 with 2 cleavage stage (4-8 cell) embryos
Lee et al. (20 12)
(OHSU Group)


Nonhuman primate
(rhesus macaques)
  • mtDNA copy number in karyoplasts and cytoplasts
  • 102 MST oocytes generated by MST
  • Transfer of preselected female embryos; recovery of fetuses preterm (135 days post-embryo transfer)





Tachibana et al. (20 13)
(OHSU Group)


Nonhuman primate
(rhesus macaques)
Cryo-thaw MST oocytes:
  • Transfer of fresh spindle to vitrified cytoplast and vice versa
  • Implantation of four blastocysts derived by transfer of vitrified spindles into fresh oocyte cytoplasts
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Endpoints Results
  • Enucleation
  • Fertilization (2 pronuclei and extrusion of sec ond polar body)
  • Embryonic and developmental potential
  • Nuclear-cytoplasmic relationship
  • 100 percent enucleation
  • 25 pairs (17.6 percent) successfully fused
  • 9 fused oocytes (82 percent) successfully fertilized
  • One foster mother (50 percent) delivered two “transfer” pups (C57BL/6J nucleus, Kunming cytoplasm/cellular or ganelles)
  • Body weight of transfer offspring was in range for Kunming (oocyte donor) mice
  • Visualization and isolation of intact MII spindle-chromosomal complexes
  • Karyoplast fusion
  • Developmental potential of embryos
  • F1 health, mtDNA carryover
  • Karyoplasts isolated by polarized microscopy contained approximately 1.5 percent of the volume of cytoplasts
  • Fusion of karyoplast with SeV prevented premature activation of oocytes
  • Live birth of four offspring (one set of twins, Mito and Tracker; two singletons, Spindler and Spindy)
  • ND mtDNA carryover (using as says sensitive to detect >3 percent heteroplasmy)
  • mtDNA carry over into karyoplasts
  • Embryonic developmental potential
  • Heteroplasmy in somatic tissues of preterm fetus and fetus oocytes, 135 days post-embryo transfer
  • 0.6 percent carry over of mtDNA into karyoplast
  • 62 percent of MST oocytes developed to blastocysts after fertilization
  • Female MST embryos selected by TE biopsy; two female singlet on pregnancies generated from selected blastocysts
  • mtDNA carry over (ND) or <0.5 percent (cerebrum, heart, and blood in fetus #2) in fetal somatic organs and tissues
  • 11/12 oocytes in each fetus displayed low (< 5.5 percent) or ND levels of mtDNA heteroplasmy; one oocyte from each fetus contained substantial mtDNA carry over (16.2 percent and 14. 1 percent)
  • Effect of cryo-thaw on fertilization, embryo development, and live birth following MST in oocytes

Cryo-thaw MST oocytes:

  • Fresh spindle to vitrified cytoplast: impaired fertilization (50 percent) and blastocyst development (0 percent), compared with 91 percent and 57 percent in controls, respectively
  • Vitrified spindle to fresh cytoplast: 88 percent fertilization and 68 percent blastocyst rate, similar to control (91 percent and 57 percent, respectively)
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Study/Model Materials and Methods

2009 rhesus offspring:

  • Measurement of body weight, bloodwork, and mitochondrial function (birth-3 years)

Tachibana et al. (20 13)
(OHSU Group)


Human oocyte



  • 106 donated oocytes: 65 underwent MST, 33 controls
  • Reciprocal MST followed by ICSI

Paull et al. (2013)
(New York Stem Cell Foundation [NYSCF] Group)

Human oocyte

  • 18 synchronized donated oocytes underwent reciprocal MST
  • Fusion of spindle-chromosomal complex by SeV or electrical pulse
  • Parthenogenetically activated



Neupane et al. (2014)

Mouse
(NZB/OlaHsd and B6D2/F1)
  • MST and PNT: transfer of MII-SCC or pronuclei, respectively, from NZB/OlaHsd to B6D2/F1 oocytes and zygotes, respectively
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Endpoints Results
  • Overall health and postnatal development of rhesus macaque offspring from 2009 study
  • Live birth of a female offspring (Crysta)

 2009 rhesus offspring:

  • Normal de velopment
  • No change in het eroplasmy in blood and skin samples
  • Developmental potential
  • Establishment and pluripotency of embryonic stem cell (ESC) lines
  • mtDNA carry over in oocytes and ESCs
  • Cytogenetic analyses
  • Efficacy of MST in cryopreserved oocytes
  • Significant proportion of MST oocytes (52 percent) showed abnormal fertilization compared with controls (13 percent)
  • Normally fertilized MST oocytes had statistically significant level of blastocyst development (62 percent) similar to that of controls (76 percent)
  • Mean mtDNA carry over in MST embryos 0.5 percent
  • Mean carry over in derived ESC lines 0.6 percent
  • No structural or numerical chromosomal abnormalities in ESC lines
  • Developmental potential of MST embryos
  • mtDNA copy number and volume in karyoplasts
  • mtDNA carry over in preimplantation embryos
  • Efficient development to blastocyst stage (39 percent), statistically similar to controls (33 percent)
  • mtDNA copy number in karyoplasts was 0.36 percent of total mtDNA in MII oocytes; corresponded to volume of karyoplasts (0.89 percent of intact MII oocytes)
  • Mean mtDNA carry over 0.31 percent in preimplantation embryos
  • Depolimerization via cooling or cryo-thaw prevents premature oocyte activation following fusion by electrical pulse
  • mtDNA carry over
  • Embryonic developmental competence
  • Parthenogenesis: NS difference in fusion, reconstruction, two-cell and blastocyst formation rate between activated MII and control groups; blastocyst quality similar to that of controls
  • ICSI: NS difference in ICSI survival, 8-16 cell embryo formation between fertilized MII and control groups; no blastocyst formation in either group
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Study/Model Materials and Methods









Wang et al. (2014)


Mouse



  • Developmental potential (in vitro and in vivo)
  • mtDNA carryover (F1 and F2 generations)

Newcastle group (unpublished)a


Human oocyte

[In progress]

a Human Fertilisation and Embryology Authority (HFEA). 2014. Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update.




NOTE: ESC = embryonic stem cell; F1 = first generation; F2 = second generation; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; MII = metaphase II; MST = maternal spindle transfer; mtDNA = mitochondrial DNA; ND = non-detectable; NS = non-significant; PNT = pronuclear transfer; SeV = Sendai virus; TE = trophoectoderm.

Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Endpoints Results

MST versus PNT

  • NS difference in successful fusion, cleavage rate, and blastocyst formation rate between MST (parthenogenetic) and PNT
  • NS difference in mean mtDNA carryover:
    • MST oocytes: 0.29 percent (ND in 17/21, <2.15 percent in 4/21)
    • PNT zygotes: 0.29 percent (ND in 21/25, <2.6 percent in 4/25)
  • 27 metaphase II spindle-chromosomal complexes (MII-SCCs) transferred
  • 18 MST embryos transferred to pseudopregnant females
  • mtDNA carryover: tail tip/brain tissue and internal organs (F1) and toe tips (F2)
  • 85.7 percent developed to blastocyst
  • 44.4 percent live, healthy births
  • 5.5 percent mtDNA carryover (F1 tail tip/brain)
  • ND-6.88 percent mtDNA carryover (F1 internal organs)
  • ND-7.1 percent mtDNA carryover (F2 tail tip)
[In progress] [In progress]
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

TABLE B-2 Summary of PNT Research

Study/Model Materials and Methods

McGrath and Solter (1983)


Mouse

  • C3H/HeJ
  • C57BL/6J
  • (ICR)
  • Transfer of male and female pronuclei in karyoplast from zygote to enucleated zygote of genetically distinct substrain
  • Development of reconstructed zygote in vitro to day 5 morula of blastocyst
  • Transfer of reconstructed (64) and control (34) zygotes to pseudopregnant females




Sato et al. (2005)



Mito-mouse (ΔmtDNA): C57BL/6J (B6) with 4696-bp deletion

Normal control: C57BL/6J (B6)

  • Transplantation of both pronuclei in karyoplast from mito-mouse zygote to enucleated normal zygotes
  • Avg. ΔmtDNA levels in zygotes estimated by second polar body biopsy
  • 39 PNT zygotes, ΔmtDNA/total mtDNA estimated to be 17-53 percent (average 25 percent), transferred into two pseudo-pregnant females
  • 34 non-PNT zygotes (est. 11-47 percent ΔmtDNA; avg. 32 percent) implanted in two pseudo pregnant females




Craven et al. (2010)
(Newcastle Group)



Human zygotes (abnormally fertilized [unipronuclear/tripronuclear])

  • 1 or 2 pronuclei transferred from abnormally fertilized zygote to enucleated recipient zygote
  • Monitored 6-8 days in vitro for embryonic developmental potential
  • Optimized procedure to minimize cytoplasm carried in karyoplast
  • mtDNA carryover measured in blastomeres
  • Total mtDNA copy number in oocytes
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Endpoints Results
  • Embryonic development
  • Live birth of offspring
  • Overall efficacy of enucleation and fusion of the pronuclei to enucleated zygote: 91 percent
  • 96 percent of PNT zygotes developed to morula or blastocyst at day 5 (versus 100 percent in nonmanipulated controls)
  • Live birth of 10 PNT offspring (16 percent) compared with 5 control offspring (15 percent); 7/10 PNT offspring survived to adulthood compared with 3/5 control offspring
  • Coat color phenotype of PNT offspring was that of the nuclear donor
  • 5/7 PNT offspring surviving to adulthood were fertile (no control value given)
  • Rescue from disease phenotype
  • mtDNA carryover
  • Change in ΔmtDNA levels during embryogenesis, postnatal development and aging
  • 11 mice born following transfer of PNT embryos (compared to 9 in controls)
  • Avg. carryover of ΔmtDNA in PNT mice: 11 percent at weaning (range 6-21 percent), increased to 33 percent +300 days from weaning (range 5-44 percent); estimated to be 43 percent at 800 days
  • Avg. ΔmtDNA levels in non-PNT mice: 66 percent at weaning (range 51-73 percent), 80 percent at +170 days
  • PNT offspring rescued from disease phenotypes: all (11) PNT mice survived >300 days after birth; comparable weight gain, no observed renal abnormalities, steady blood lactate and urea levels compared with normal controls
  • Non-PNT mice died at 218-277 days; exhibited renal abnormalities, elevated blood lactate and urea levels, decreased weight gain compared with normal control mice
  • mtDNA carryover
  • Embryonic developmental potential
  • 22.7 percent and 22.2 percent of 1- and 2-pronuclei transfer PNT zygotes, respectively, developed past 8-cell stage; 8.3 percent to blastocyst stage (50 percent of nonmanipulated, abnormally fertilized controls)
  • Optimized PNT to reduce cytoplasm volume: mtDNA carryover ND in 4 of 9 embryos; remaining five embryos: average <2 percent mtDNA carryover (range in blastomeres: ND-11.4 percent)
  • Range of mtDNA copy number in oocytes: approx. 100,000-850,000
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Study/Model Materials and Methods

Neupane et al. (2014)


Mouse (NZB/OlaHsd & B6D2/F1)





  • MST and PNT: transfer of MII-SCC and pronuclei, respectively, from NZB/OlaHsd to B6D2/F1 oocytes and zygotes, respectively
Wang et al. (2014)


Mouse
  • 38 PNT zygotes reconstructed
  • 13 PNT embryos transferred to pseudopregnant females
  • mtDNA carryover: examined in tail tip/brain tissue and internal organs (F1) and toe tips (F2)


Newcastle group, (unpublished)a

[Unavailable]

aHuman Fertilisation and Embryology Authority (HFEA). 2014. Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update.

NOTE: ΔmtDNA = mitochondrial DNA deletion; F1 = first generation; F2 = second generation; MII-SCC = metaphase II-spindle chromosome complex; MST = maternal spindle transfer; mtDNA = mitochondrial DNA; ND = non-detectable; NS = non-significant; PNT = pronuclear transfer.

Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Endpoints Results
  • mtDNA carry over
  • Embryonic developmental competence
  • Blastocyst quality similar to that of controls
  • 1/8 blastomeres from cleavage stage embryos presented with 4.9 percent mtDNA carryover (7/8 ND); sensitivity of assay not disclosed

MST versus PNT

  • NS difference in successful fusion, cleavage rate, and blastocyst formation rate between MST (parthenogenetic) and PNT
  • NS difference in mean mtDNA carryover:
    • MST oocytes: 0.29 percent (ND in 17/21, <2.15 percent in 4/21)
    • PNT zygotes: 0.29 percent (ND in 21/25, <2.6 percent in 4/25)
  • Developmental potential
  • mtDNA carryover (F1 and F2 generations)
  • 81.3 percent developed to blastocyst
  • 53.8 percent live, healthy births
  • 23.7 percent mtDNA carryover (F1 tail tip/brain)
  • 5.5-39.8 percent mtDNA carryover (F1 internal organs)
  • 22.1 percent mtDNA carryover (F2 toe tip)
  • mtDNA carryover
  • Chromosomal makeup
  • High rates of development to blastocyst stage
  • Subtle differences in embryo development
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×

REFERENCES

Craven, L., H. A. Tuppen, G. D. Greggains, S. J. Harbottle, J. L. Murphy, L. M. Cree, A. P. Murdoch, P. F. Chinnery, R. W. Taylor, R. N. Lightowlers, M. Herbert, and D. M. Turnbull. 2010. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465(7294):82-85.

HFEA (Human Fertilisation and Embryology Authority). 2014. Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update. London, UK: HFEA.

Lee, H. S., H. Ma, Rita C. Juanes, M. Tachibana, M. Sparman, J. Woodward, C. Ramsey, J. Xu, E.-J. Kang, P. Amato, G. Mair, R. Steinborn, and S. Mitalipov. 2012. Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Reports 1(5):506-515.

McGrath, J., and D. Solter. 1983. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 220(4603):1300-1302.

Neupane, J., M. Vandewoestyne, S. Ghimire, Y. Lu, C. Qian, R. Van Coster, J. Gerris, T. Deroo, D. Deforce, P. De Sutter, and B. Heindryckx. 2014. Assessment of nuclear transfer techniques to prevent the transmission of heritable mitochondrial disorders without compromising embryonic development competence in mice. Mitochondrion 18:27-33.

Paull, D., V. Emmanuele, K. A. Weiss, N. Treff, L. Stewart, H. Hua, M. Zimmer, D. J. Kahler, R. S. Goland, S. A. Noggle, R. Prosser, M. Hirano, M. V. Sauer, and D. Egli. 2013. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493(7434):632-637.

Sato, A., T. Kono, K. Nakada, K. Ishikawa, S.-I. Inoue, H. Yonekawa, and J.-I. Hayashi. 2005. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proceedings of the National Academy of Sciences of the United States of America 102(46):16765-16770.

Tachibana, M., M. Sparman, H. Sritanaudomchai, H. Ma, L. Clepper, J. Woodward, Y. Li, C. Ramsey, O. Kolotushkina, and S. Mitalipov. 2009. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461(7262):367-372.

Tachibana, M., P. Amato, M. Sparman, J. Woodward, D. M. Sanchis, H. Ma, N. M. Gutierrez, R. Tippner-Hedges, E. Kang, H.-S. Lee, C. Ramsey, K. Masterson, D. Battaglia, D. Lee, D. Wu, J. Jensen, P. Patton, S. Gokhale, R. Stouffer, and S. Mitalipov. 2013. Towards germline gene therapy of inherited mitochondrial diseases. Nature 493(7434):627-631.

Wang, M. K., D. Y. Chen, J. L. Liu, G. P. Li, and Q. Y. Sun. 2001. In vitro fertilisation of mouse oocytes reconstructed by transfer of metaphase II chromosomes results in live births. Zygote 9(1):9-14.

Wang, T., H. Sha, D. Ji, Helen L. Zhang, D. Chen, Y. Cao, and J. Zhu. 2014. Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases. Cell 157(7):1591-1604.

Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 165
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 166
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 167
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 168
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 169
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 170
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 171
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 172
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 173
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 174
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 175
Suggested Citation:"Appendix B: Summary of MRT Research." National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
×
Page 176
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Mitochondrial replacement techniques (MRTs) are designed to prevent the transmission of mitochondrial DNA (mtDNA) diseases from mother to child. While MRTs, if effective, could satisfy a desire of women seeking to have a genetically related child without the risk of passing on mtDNA disease, the technique raises significant ethical and social issues. It would create offspring who have genetic material from two women, something never sanctioned in humans, and would create mitochondrial changes that could be heritable (in female offspring), and therefore passed on in perpetuity. The manipulation would be performed on eggs or embryos, would affect every cell of the resulting individual, and once carried out this genetic manipulation is not reversible.

Mitochondrial Replacement Techniques considers the implications of manipulating mitochondrial content both in children born to women as a result of participating in these studies and in descendants of any female offspring. This study examines the ethical and social issues related to MRTs, outlines principles that would provide a framework and foundation for oversight of MRTs, and develops recommendations to inform the Food and Drug Administration’s consideration of investigational new drug applications.

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