Using CRISPR-Cas9 In Human Fetuses to Prevent Trisomy 16 and Trisomy 22 Induced Miscarriages

Authors

  • Emily Qin Newark Academy
  • Nicole Guilz Columbia University

DOI:

https://doi.org/10.47611/jsrhs.v11i4.3859

Keywords:

aneuploidy, Trisomy 16, Trisomy 22, CRISPR-Cas9, gene editing, in utero

Abstract

About 50% of abortions have been found to be caused by aneuploidy, roughly 60% of which are trisomy. The most common trisomy occurs on chromosome 16, 21, and 22. However, trisomy 21 (also called Down Syndrome) is viable in about 57% of cases, while trisomy 16 and 22 result in miscarriage in nearly every pregnancy. Thus, additional therapies and treatments must be explored, especially through quickly advancing techniques such as gene editing. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) combined with the cleaving endonuclease CRISPR-associated protein (Cas9) harbors potential for targeted chromosome deletion, possibly increasing the chance of survival in fetuses with trisomy 16 or 22. However, the risks and safety benefits during genetic diagnosing and potential treatment of the fetus should also be considered. Successfully demonstrated approaches of editing or eliminating extraneous chromosomes in studies of both animal models and lab-cultured human embryos will be discussed. In particular, this paper will examine possible gene editing approaches such as elimination of entire chromosomes, large-scale deletions, and chromosomal truncations to target trisomy. In order to determine the efficacy of these approaches in trisomy, the use of CRISPR-Cas9 to specifically treat trisomy via autosomal deletion and counter-selection markers will be deliberated. Delivery methods for the in-utero therapy includes viral techniques such as retroviruses and adeno-associated vectors (AAVs) as well as non-viral techniques like electroporation and nanoparticles. This paper will propose hypothetical treatments for CRISPR-Cas9 in human embryos to target trisomy 16 and 22 while also examining the bioethical implications of doing so.

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References or Bibliography

Čulić, V., Lozic, B., Kuzmić-Prusac, I., Mijaljica, G., & Pavelić, J. (2011). Full trisomy 5 in a sample of spontaneous abortion and Arias Stella reaction. Medical science monitor : international medical journal of experimental and clinical research, 17(10), CS116–CS119. https://doi.org/10.12659/msm.881969

Littman, E., Phan, V., Harris, D., Severino, M., & La, A. (2014). The most frequent aneuploidies in human embryo are similar to those observed in the early pregnancy loss. Fertility And Sterility, 102(3), e344. doi: 10.1016/j.fertnstert.2014.07.1162

Morris, J. K., Wald, N. J., & Watt, H. C. (1999). Fetal loss in Down syndrome pregnancies. Prenatal diagnosis, 19(2), 142–145.

Jia, C. W., Wang, L., Lan, Y. L., Song, R., Zhou, L. Y., Yu, L., Yang, Y., Liang, Y., Li, Y., Ma, Y. M., & Wang, S. Y. (2015). Aneuploidy in Early Miscarriage and its Related Factors. Chinese medical journal, 128(20), 2772–2776. https://doi.org/10.4103/0366-6999.167352

O'Connor, C. (2008) Chromosomal abnormalities: Aneuploidies. Nature Education 1(1):172

Hassold, T., & Hunt, P. (2001). To err (meiotically) is human: the genesis of human aneuploidy. Nature reviews. Genetics, 2(4), 280–291. https://doi.org/10.1038/35066065

Chen, C. P., Huang, M. C., Chern, S. R., Wu, P. S., Chen, S. W., Chuang, T. Y., Town, D. D., & Wang, W. (2019). Mosaic trisomy 22 at amniocentesis: Prenatal diagnosis and literature review. Taiwanese journal of obstetrics & gynecology, 58(5), 692–697. https://doi.org/10.1016/j.tjog.2019.07.020

Bergman, M.T. (2019). Harvard researchers share views on future, ethics of gene editing. Retrieved 1 September 2022, from https://news.harvard.edu/gazette/story/2019/01/perspectives-on-gene-editing/

NHS. (2017). Chorionic villus sampling - What happens . Retrieved 16 August 2022, from https://www.nhs.uk/conditions/chorionic-villus-sampling-cvs/what-happens/

Hopkins Medicine. (2019). Chorionic Villus Sampling (CVS). Retrieved 14 September 2022, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/chorionic-villus-sampling-cvs#:~:text=CVS%20is%20usually%20done%20between,defects%2C%20such%20as%20spina%20bifida.

Amniocentesis - Mayo Clinic. (2022). Retrieved 16 August 2022, from https://www.mayoclinic.org/tests-procedures/amniocentesis/about/pac-20392914

Salomon, L. J., Sotiriadis, A., Wulff, C. B., Odibo, A., & Akolekar, R. (2019). Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 54(4), 442–451. https://doi.org/10.1002/uog.20353

Papas, R. S., & Kutteh, W. H. (2021). Genetic Testing for Aneuploidy in Patients Who Have Had Multiple Miscarriages: A Review of Current Literature. The application of clinical genetics, 14, 321–329. https://doi.org/10.2147/TACG.S320778

Techniques of fetal intervention. UCSF BCH Fetal Treatment Center - Techniques of Fetal Intervention. (n.d.). Retrieved August 3, 2022, from https://fetus.ucsf.edu/techniques-fetal-intervention/

Doudna, J. A., & Charpentier, E. (2014). Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science (New York, N.Y.), 346(6213), 1258096. https://doi.org/10.1126/science.1258096

Bulcha, J. T., Wang, Y., Ma, H., Tai, P., & Gao, G. (2021). Viral vector platforms within the gene therapy landscape. Signal transduction and targeted therapy, 6(1), 53. https://doi.org/10.1038/s41392-021-00487-6

Vargas, J. E., Chicaybam, L., Stein, R. T., Tanuri, A., Delgado-Cañedo, A., & Bonamino, M. H. (2016). Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives. Journal of translational medicine, 14(1), 288. https://doi.org/10.1186/s12967-016-1047-x

Goswami, R., Subramanian, G., Silayeva, L., Newkirk, I., Doctor, D., Chawla, K., Chattopadhyay, S., Chandra, D., Chilukuri, N., & Betapudi, V. (2019). Gene Therapy Leaves a Vicious Cycle. Frontiers in oncology, 9, 297. https://doi.org/10.3389/fonc.2019.00297

Palanki, R., Peranteau, W. H., & Mitchell, M. J. (2021). Delivery technologies for in utero gene therapy. Advanced drug delivery reviews, 169, 51–62. https://doi.org/10.1016/j.addr.2020.11.002

Murthy SK. Nanoparticles in modern medicine: state of the art and future challenges. Int J Nanomedicine. 2007;2(2):129-41. PMID: 17722542; PMCID: PMC2673971.

Zuccaro, M. V., Xu, J., Mitchell, C., Marin, D., Zimmerman, R., Rana, B., Weinstein, E., King, R. T., Palmerola, K. L., Smith, M. E., Tsang, S. H., Goland, R., Jasin, M., Lobo, R., Treff, N., & Egli, D. (2020). Allele-Specific Chromosome Removal after Cas9 Cleavage in Human Embryos. Cell, 183(6), 1650–1664.e15. https://doi.org/10.1016/j.cell.2020.10.025

Muraki, K., Nyhan, K., Han, L., & Murnane, J. P. (2012). Mechanisms of telomere loss and their consequences for chromosome instability. Frontiers in oncology, 2, 135. https://doi.org/10.3389/fonc.2012.00135

Qin, Y., Wong, B., Zhong, L., Geng, F., Parada, L. F., & Wen, D. (2021). Generation of Sex-Reversed Female Clonal Mice via CRISPR-Cas9-Mediated Y Chromosome Deletion in Male Embryonic Stem Cells. The CRISPR journal, 4(1), 147–154. https://doi.org/10.1089/crispr.2020.0074

Martin, J., Han, C., Gordon, L. A., Terry, A., Prabhakar, S., She, X., Xie, G., Hellsten, U., Chan, Y. M., Altherr, M., Couronne, O., Aerts, A., Bajorek, E., Black, S., Blumer, H., Branscomb, E., Brown, N. C., Bruno, W. J., Buckingham, J. M., Callen, D. F., … Pennacchio, L. A. (2004). The sequence and analysis of duplication-rich human chromosome 16. Nature, 432(7020), 988–994. https://doi.org/10.1038/nature03187

Dunham, I., Shimizu, N., Roe, B. A., Chissoe, S., Hunt, A. R., Collins, J. E., Bruskiewich, R., Beare, D. M., Clamp, M., Smink, L. J., Ainscough, R., Almeida, J. P., Babbage, A., Bagguley, C., Bailey, J., Barlow, K., Bates, K. N., Beasley, O., Bird, C. P., Blakey, S., … O'Brien, K. P. (1999). The DNA sequence of human chromosome 22. Nature, 402(6761), 489–495. https://doi.org/10.1038/990031

Eleveld, T. F., Bakali, C., Eijk, P. P., Stathi, P., Vriend, L. E., Poddighe, P. J., & Ylstra, B. (2021). Engineering large-scale chromosomal deletions by CRISPR-Cas9. Nucleic acids research, 49(21), 12007–12016. https://doi.org/10.1093/nar/gkab557 (chromosome deletion)

Li, L. B., Chang, K. H., Wang, P. R., Hirata, R. K., Papayannopoulou, T., & Russell, D. W. (2012). Trisomy correction in Down syndrome induced pluripotent stem cells. Cell stem cell, 11(5), 615–619. https://doi.org/10.1016/j.stem.2012.08.004

Chamberlain, J. R., Schwarze, U., Wang, P. R., Hirata, R. K., Hankenson, K. D., Pace, J. M., Underwood, R. A., Song, K. M., Sussman, M., Byers, P. H., & Russell, D. W. (2004). Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science (New York, N.Y.), 303(5661), 1198–1201. https://doi.org/10.1126/science.1088757

Khan, I. F., Hirata, R. K., Wang, P. R., Li, Y., Kho, J., Nelson, A., Huo, Y., Zavaljevski, M., Ware, C., & Russell, D. W. (2010). Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Molecular therapy : the journal of the American Society of Gene Therapy, 18(6), 1192–1199. https://doi.org/10.1038/mt.2010.55

Farr, C., Fantes, J., Goodfellow, P., & Cooke, H. (1991). Functional reintroduction of human telomeres into mammalian cells. Proceedings of the National Academy of Sciences of the United States of America, 88(16), 7006–7010. https://doi.org/10.1073/pnas.88.16.7006

Rossidis, A. C., Stratigis, J. D., Chadwick, A. C., Hartman, H. A., Ahn, N. J., Li, H., Singh, K., Coons, B. E., Li, L., Lv, W., Zoltick, P. W., Alapati, D., Zacharias, W., Jain, R., Morrisey, E. E., Musunuru, K., & Peranteau, W. H. (2018). In utero CRISPR-mediated therapeutic editing of metabolic genes. Nature medicine, 24(10), 1513–1518. https://doi.org/10.1038/s41591-018-0184-6

Alapati, D., Zacharias, W. J., Hartman, H. A., Rossidis, A. C., Stratigis, J. D., Ahn, N. J., Coons, B., Zhou, S., Li, H., Singh, K., Katzen, J., Tomer, Y., Chadwick, A. C., Musunuru, K., Beers, M. F., Morrisey, E. E., & Peranteau, W. H. (2019). In utero gene editing for monogenic lung disease. Science translational medicine, 11(488), eaav8375. https://doi.org/10.1126/scitranslmed.aav8375

Zuo, E., Huo, X., Yao, X., Hu, X., Sun, Y., Yin, J., He, B., Wang, X., Shi, L., Ping, J., Wei, Y., Ying, W., Wei, W., Liu, W., Tang, C., Li, Y., Hu, J., & Yang, H. (2017). CRISPR/Cas9-mediated targeted chromosome elimination. Genome biology, 18(1), 224. https://doi.org/10.1186/s13059-017-1354-4

Abe, T., Suzuki, Y., Ikeya, T., & Hirota, K. (2021). Targeting chromosome trisomy for chromosome editing. Scientific reports, 11(1), 18054. https://doi.org/10.1038/s41598-021-97580-1

Tran, N. D., Porada, C. D., Almeida-Porada, G., Glimp, H. A., Anderson, W. F., & Zanjani, E. D. (2001). Induction of stable prenatal tolerance to beta-galactosidase by in utero gene transfer into preimmune sheep fetuses. Blood, 97(11), 3417–3423. https://doi.org/10.1182/blood.v97.11.3417

Shangaris, P., Loukogeorgakis, S.P., Subramaniam, S. et al. In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Sci Rep 9, 11592 (2019). https://doi.org/10.1038/s41598-019-48078-4

Davey, M. G., Riley, J. S., Andrews, A., Tyminski, A., Limberis, M., Pogoriler, J. E., Partridge, E., Olive, A., Hedrick, H. L., Flake, A. W., & Peranteau, W. H. (2017). Induction of Immune Tolerance to Foreign Protein via Adeno-Associated Viral Vector Gene Transfer in Mid-Gestation Fetal Sheep. PloS one, 12(1), e0171132. https://doi.org/10.1371/journal.pone.0171132 (AAVs)

Lino, C. A., Harper, J. C., Carney, J. P., & Timlin, J. A. (2018). Delivering CRISPR: a review of the challenges and approaches. Drug delivery, 25(1), 1234–1257. https://doi.org/10.1080/10717544.2018.1474964

Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., & Jaenisch, R. (2013). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4), 910–918. https://doi.org/10.1016/j.cell.2013.04.025

Pritchard, N., Kaitu'u-Lino, T., Harris, L., Tong, S., & Hannan, N. (2021). Nanoparticles in pregnancy: the next frontier in reproductive therapeutics. Human reproduction update, 27(2), 280–304. https://doi.org/10.1093/humupd/dmaa049

Ricciardi, A. S., Bahal, R., Farrelly, J. S., Quijano, E., Bianchi, A. H., Luks, V. L., Putman, R., López-Giráldez, F., Coşkun, S., Song, E., Liu, Y., Hsieh, W. C., Ly, D. H., Stitelman, D. H., Glazer, P. M., & Saltzman, W. M. (2018). In utero nanoparticle delivery for site-specific genome editing. Nature communications, 9(1), 2481. https://doi.org/10.1038/s41467-018-04894-2

Riley, R. S., Kashyap, M. V., Billingsley, M. M., White, B., Alameh, M. G., Bose, S. K., Zoltick, P. W., Li, H., Zhang, R., Cheng, A. Y., Weissman, D., Peranteau, W. H., & Mitchell, M. J. (2021). Ionizable lipid nanoparticles for in utero mRNA delivery. Science advances, 7(3), eaba1028. https://doi.org/10.1126/sciadv.aba1028 (lipid-based nanoparticles)

Rothschild J. (2020). Ethical considerations of gene editing and genetic selection. Journal of general and family medicine, 21(3), 37–47. https://doi.org/10.1002/jgf2.321

Human Genetic Engineering - AP-NORC. (2022). Retrieved 1 September 2022, from https://apnorc.org/projects/human-genetic-engineering/

Uddin, F., Rudin, C. M., & Sen, T. (2020). CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Frontiers in oncology, 10, 1387. https://doi.org/10.3389/fonc.2020.01387

Ma, H., Marti-Gutierrez, N., Park, S. W., Wu, J., Lee, Y., Suzuki, K., Koski, A., Ji, D., Hayama, T., Ahmed, R., Darby, H., Van Dyken, C., Li, Y., Kang, E., Park, A. R., Kim, D., Kim, S. T., Gong, J., Gu, Y., Xu, X., … Mitalipov, S. (2017). Correction of a pathogenic gene mutation in human embryos. Nature, 548(7668), 413–419. https://doi.org/10.1038/nature23305

Schwartz, M. (2018). CRISPR is a gene-editing tool that's revolutionary, though not without risk. Retrieved 1 September 2022, from https://stanmed.stanford.edu/2018winter/CRISPR-for-gene-editing-is-revolutionary-but-it-comes-with-risks.html

Kim, M. (2022). With CRISPR gene editing, unique treatments begin to take off for rare diseases. The Washington Post. Retrieved September 1, 2022, from https://www.washingtonpost.com/health/2022/02/05/crispr-rare-diseases/

Werner, E. F., Han, C. S., Burd, I., Lipkind, H. S., Copel, J. A., Bahtiyar, M. O., & Thung, S. F. (2012). Evaluating the cost-effectiveness of prenatal surgery for myelomeningocele: a decision analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 40(2), 158–164. https://doi.org/10.1002/uog.11176

Leary, A. (2019, April 23). Why finding cures for genetic disabilities shouldn't be our main goal. Rooted in Rights. Retrieved September 1, 2022, from https://rootedinrights.org/why-finding-cures-for-genetic-disabilities-shouldnt-be-our-main-goal/

Published

11-30-2022

How to Cite

Qin, E., & Guilz, N. (2022). Using CRISPR-Cas9 In Human Fetuses to Prevent Trisomy 16 and Trisomy 22 Induced Miscarriages. Journal of Student Research, 11(4). https://doi.org/10.47611/jsrhs.v11i4.3859

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Section

HS Review Articles