CRISPR/CAS9 and mitochondrial gene replacement therapy: Promising techniques and ethical considerations

American Journal of Stem Cells

Volumn 5, Issue 2, 2016, Pages 39-52

  Fogleman, Sarah ^a   Santana, Casey ^a   Bishop, Casey ^a   Miller, Alyssa ^a   Capco, David G ^b  

^a GEORGETOWN UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b ARIZONA STATE UNIVERSITY   (United States)

Author keywords

Assisted human reproduction; CRISPR Cas systems; Ethics; Gene editing; Mitochondrial diseases; Mitochondrial replacement therapy; Nuclear transfer

Indexed keywords

MITOCHONDRIAL DNA;

CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; DISEASE SEVERITY; DISEASE TRANSMISSION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA SEQUENCE; GENE MUTATION; GENE REPLACEMENT THERAPY; GENE SEQUENCE; HUMAN; MITOCHONDRIAL GENE; MUSCULAR DYSTROPHY; NONHUMAN; REVIEW; RISK BENEFIT ANALYSIS;

EID: 85015139831     PISSN: None     EISSN: 21604150     Source Type: Journal    
DOI: None     Document Type: Review

References (48)

1. Richardson J, Irving L, Hyslop LA, Choudhary M, Murdoch A, Turnbull DM and Herbert M. Concise reviews: Assisted reproductive technologies to prevent transmission of mitochondrial DNA disease. Stem Cells 2015; 33: 639-645.
2. Hellebrekers DM, Wolfe R, Hendrickx AT, de Coo IF, de Die CE, Geraedts JP, Chinnery PF and Smeets HJ. PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring. Hum Reprod Update 2012; 18: 341-349.
3. Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M and Turnbull DM. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010; 465: 82-85.
4. Schon EA, DiMauro S and Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 2012; 13: 878-890.
5. Lieber DS, Calvo SE, Shanahan K, Slate NG, Liu S, Hershman SG, Gold NB, Chapman BA, Thorburn DR, Berry GT, Schmahmann JD, Borowsky ML, Mueller DM, Sims KB and Mootha VK. Targeted exome sequencing of suspected mitochondrial disorders. Neurology 2013; 80: 1762-1770.
6. Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF and Turnbull DM. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008; 63: 35-39.
7. Arpa J, Cruz-Martinez A, Campos Y, Gutierrez-Molina M, Garcia-Rio F, Perez-Conde C, Martin MA, Rubio JC, Del Hoyo P, Arpa-Fernandez A and Arenas J. Prevalence and progression of mitochondrial diseases: a study of 50 patients. Muscle Nerve 2003; 28: 690-695.
8. Hammans SR, Sweeney MG, Brockington M, Lennox GG, Lawton NF, Kennedy CR, Morgan-Hughes JA and Harding AE. The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 1993; 116: 617-632.
9. Pitceathly RD, Taanman JW, Rahman S, Meunier B, Sadowski M, Cirak S, Hargreaves I, Land JM, Nanji T, Polke JM, Woodward CE, Sweeney MG, Solanki S, Foley AR, Hurles ME, Stalker J, Blake J, Holton JL, Phadke R, Muntoni F, Reilly MM, Hanna MG and Consortium UK. COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. JAMA Neurol 2013; 70: 1556-1561.
10. Chinnery PF, Andrews RM, Turnbull DM and Howell NN. Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet 2001; 98: 235-243.
11. Chinnery PF, Howell N, Lightowlers RN and Turnbull DM. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 1998; 121: 1889-1894.
12. Richardson J, Irving L, Hyslop LA, Choudhary M, Murdoch A, Turnbull DM and Herbert M. Concise reviews: assisted reproductive technologies to prevent transmission of mitochondrial DNA disease. Stem Cells 2015; 33: 639-645.
13. Doudna J. Jennifer Doudna: We can now edit our DNA, but let’s do it wisely. Ted Talk 2015 [video file]. Retrieved from .
14. Gorman GS, Grady JP, Ng Y, Schaefer AM, McNally RJ, Chinnery PF, Yu-Wai-Man P, Herbert M, Taylor RW, McFarland R and Turnbull DM. Mitochondrial donation--how many women could benefit? N Engl J Med 2015; 372: 885-887.
15. Rebolledo-Jaramillo B, Su MS, Stoler N, McElhoe JA, Dickins B, Blankenberg D, Korneliussen TS, Chiaromonte F, Nielsen R, Holland MM, Paul IM, Nekrutenko A, Makova KD. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 2014; 111: 15474-79.
16. Tachibana M, Amato P, Sparman M, Woodward J, Sanchis DM, Ma H, Gutierrez NM, Tippner-Hedges R, Kang E, Lee HS, Ramsey C, Masterson K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer R and Mitalipov S. Towards germline gene therapy of inherited mitochondrial diseases. Nature 2013; 493: 627-631.
17. Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O and Mitalipov S. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009; 461: 367-372.
18. Battaglia DE, Goodwin P, Klein NA and Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 1996; 11: 2217-2222.
19. Zhang J. Revisiting germinal vesicle transfer as a treatment for aneuploidy in infertile women with diminished ovarian reserve. J Assist Reprod Genet 2015; 32: 313-317.
20. Neupane J, Vandewoestyne M, Ghimire S, Lu Y, Qian C, Van Coster R, Gerris J, Deroo T, Deforce D, De Sutter P and Heindryckx B. Assessment of nuclear transfer techniques to prevent the transmission of heritable mitochondrial disorders without compromising embryonic development competence in mice. Mitochondrion 2014; 18: 27-33.
21. Samuels DC, Wonnapinij P and Chinnery PF. Preventing the transmission of pathogenic mitochondrial DNA mutations: can we achieve long-term benefits from germ-line gene transfer? Hum Reprod 2013; 28: 554-559.
22. Wang T, Sha H, Ji D, Zhang HL, Chen D, Cao Y and Zhu J. Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases. Cell 2014; 157: 1591-1604.
23. Amato P, Tachibana M, Sparman M and Mitalipov S. Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases. Fertil Steril 2014; 101: 31-35.
24. Yin H, Xue W, Chen S, Bogorad R, Benedetti E, Grompe M, Koteliansky V, Sharp PA, Jacks T and Anderson DG. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol 2014; 32: 551-553.
25. Regalado A. CRISPR gene editing to be tested on people by 2017, says Editas. MIT Technology Review 2015; [Epub ahead of print].
26. Han A. Look for CRISPR/Cas9 to treat eye diseases first, scientists say. Genome Web 2016; [Epub ahead of print].
27. Feenberg A. On being a human subject: interest and obligation in the experimental treatment of incurable disease. Philos Forum 1992; 23.
28. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C and Huang J. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 2015; 6: 363-372.
29. Cohen J and Alikani M. The biological basis for defining bi-parental or tri-parental origin of offspring from cytoplasmic and spindle transfer. Reprod Biomed Online 2013; 26: 535-537.
30. Mitalipov S and Wolf DP. Clinical and ethical implications of mitochondrial gene transfer. Trends Endocrinol Metab 2014; 25: 5-7.
31. Ishii T. Potential impact of human mitochondrial replacement on global policy regarding germline gene modification. Reprod Biomed Online 2014; 29: 150-155.
32. Nuffield Council on Bioethics. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. London: Nuffield Council on Bioethics 2012.
33. Demma A. Legal Information. Parents via egg donation (n.d.). Retrieved from .
34. Baylis F. The ethics of creating children with three genetic parents. Reprod Biomed Online 2013; 26: 531-534.
35. Bredenoord AL and Braude P. Ethics of mitochondrial gene replacement: from bench to bedside. BMJ 2010; 341: c6021.
36. Lode E. Slippery slope arguments and legal reasoning. Calif Law Rev 1999; 87.
37. Darnovsky M. A slippery slope to human germline modification. Nature 2013; 499: 127.
38. Gericke CA, Riesberg A and Busse R. Ethical issues in funding orphan drug research and development. J Med Ethics 2005; 31: 164-168.
39. Klitzman R, Toynbee M and Sauer MV. Controversies concerning mitochondrial replacement therapy. Fertil Steril 2015; 103: 344-346.
40. Cyranoski D. Ethics of embryo editing divides scientists. Nature 2015; 519: 272.
41. Vogel G. Embryo engineering alarm. Science 2015; 347: 1301.
42. Lander ES. Brave new genome. N Engl J Med 2015; 373: 5-8.
43. National Academies of Sciences, Engineering, and Medicine. International summit on human gene editing: a global discussion. Washington, D.C.: The National Academies Press 2016.
44. Lanphier E, Urnov F, Haecker SE, Werner M and Smolenski J. Don’t edit the human germ line. Nature 2015; 519: 410-411.
45. American Medical Association. Code of me-dical ethics: opinions on patient-physician relationships. Chicago: American Medical Association 2016.
46. Public Health Directorate/Health Science and Bioethics Division. Draft regulations to permit the use of new treatment techniques to prevent the transmission of a serious mitochondrial disease from mother to child. Department of Health, U.K. 2014.
47. Gallagher J. UK approves three-person babies. BBC 2015; [Epub ahead of print].
48. Cellular, tissue, and gene therapies advisory committee. Oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility. FDA 2014.