Fatal genetic d isorders No cure 1 in 3 infant deaths are from genetic disorders Stevenson David A and John C Carey 2004 180523 infant deaths University of Utah 19981998 Maternal Age Carrier for unwanted gene ID: 927222
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Slide1
Humangermlinemodification
Slide2Fatal genetic disorders No cure
Slide31 in 3 infant deaths are from genetic disorders
Stevenson, David A, and John C Carey (2004).
180/523 infant deaths
University of Utah
(1998-1998)
Slide4Maternal Age Carrier for unwanted gene?Down Syndrome
Allen, Emily Graves et al ( 2008).
Slide5What can we do about this?
Slide6Genetic Modification at Embryonic Stage
Slide7Preimplantation Genetic Diagnosis(PGD)
Slide8Ovarian stimulation & oocyte retrieval(GnRH agonist)
Slide9Co-incubation of sperm + egg in petri dish
~70% success rate
Brezina
, Paul R et al (2013).
Slide102) Embryo Biopsy
Slide113 – 5 days post fertilization, biopsy occurs
Slide123) FISHScreen for genetic abnormalities
Slide13SelectNormalEmbryo
&
Discard
Abnormal
Slide14Embryonic transfer & pregnancy
Slide15Mitochondrial Replacement Therapy(MRT)
Legal in UK
Since 2015
Slide16Slide17Slide18Slide19CRISPR/Cas9Clustered Regularly Interspaced Palindromic Repeats
2
components
Slide201) Guide RNA
2) Cas9
Redman, Melody et al (2016).
Slide21HDR vs. NHEJ
Slide22Microinjection into Cytoplasm/Nucleus
Liu,
Chengyu
et al (2013).
Slide23Microinjection
Lino, Christopher A et al (2018).
Near 100% accuracy
Most efficient at yielding normal embryos
Low rate of off-target effects
Slide24Electroporation of zygote“Nucleofection”
Lino, Christopher A et al (2018).
Slide25Limitations to Germline Modification
Slide26CRISPR/Cas9:
not 100% accurate
Heritable changes
off target effects - BAD
Lino, Christopher A et al (2018).
Slide27PGD/IVF/MRT
Moral status of early embryo
destruction of fertilized embryos
IVF procedure:
stressful on woman limited chance of success
Slide28Proposed Regulation of Human Germline Modification
Refine gene-editing techniques on
Tripronuclear
zygotes
Reduce off-target mutations - guide RNA
Improve IVF techniques to increase rate of normal embryosLegalize MRT – UK already has!
Liang,
Puping
et al (2015).
Slide29Tripronuclear (3n) Zygotes
Liang,
Puping
et al (2015).
Product of IVF, usually discarded
HDR editing ~ 25% success
NHEJ ~ 20-60% success
Practice template for CRISPR/Cas9
Lino, Christopher A et al (2018).
Slide30