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editing methodologies. It is 
possible that continuing research may yield new methodologies that rapidly 
supersede the safety and efficacy of current editing approaches. 
Non-Heritable Genome Editing: 
The Use of Genome Editing in Somatic Cells
One potential alternative to HHGE for the treatment of genetic dis-
eases is somatic genome editing. This section discusses some of the relative 
 advantages and disadvantages of somatic editing in comparison with HHGE.
The initial applications of genome editing in humans occurred in 
 somatic cells, the cells that make up all of the cells of the body except 
sperm, eggs, and their precursor cells. The effects of genome editing carried 
4 It has also been proposed that genome editing could be used as an alternative to MRT to 
prevent the transmission of mitochondrial DNA (mtDNA) disease (Reddy et al., 2015). This 
study used mito chondrial targeted restriction endonucleases or TALENS and showed they 
could be used to potentially lower mutation load. However, this procedure led to net depletion 
of mtDNA and thus was not suitable for oocytes with a very high level of heteroplasmic or 
homoplasmic mtDNA mutations. A recent paper reports the use of base editing on mtDNA 
(Mok et al., 2020) and may represent a new approach to addressing mitochondrial disease. A 
detailed analysis of mtDNA editing requires a separate study, in the context of existing treat-
ments for mitochondrial diseases and options such as MRT.
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out in somatic cells are generally limited to the individual treated and would 
not be transmissible to that person’s offspring. (The special circumstance 
of editing somatic cells that are located in an individual’s reproductive 
system, such as editing in the testes to treat infertility, is discussed later in 
this chapter.) Despite the cost that would be associated with any clinical 
use of HHGE and the complex social, ethical, and scientific issues that 
heritable genome editing raises, the potential limitations associated with 
somatic edit ing, discussed below, represent one reason that HHGE has 
been proposed as a theoretical alternative for parents wishing to have a 
genetically-related child who does not have the disease-causing genotype.
Somatic genome editing is an option for treating patients with monogenic 
disorders, but it remains in early stages of clinical use, and much more expe-
rience will be needed to assess its safety and efficacy. The first clinical trial, 
initiated in 2009, tested the safety of using ZFNs to prevent the progression 
to AIDS in people infected by HIV (Tebas et al., 2014); and multiple trials 
using ZFNs, TALENs, and CRISPR systems are currently in progress.5 With 
significant funding across multiple companies, somatic genome editing is 
likely to lead to numerous human trials in the coming decade. 
The simplest targets for somatic editing are ones in which cells can be 
removed from a patient, treated outside the body, and returned (ex vivo 
genome editing) (Li et al., 2020). At present, the primary conditions that 
can be approached in this way are diseases resulting from mutations in 
HSCs. For example, promising results have been reported for patients af-
fected with SCD and beta-thalassemia who were treated with CRISPR-Cas 
reagents to induce expression of fetal hemoglobin,6 although long-term 
follow-up will be needed before conclusions can be drawn regarding its 
successes and limitations. Trials are also under way using genome editing 
to enhance the activity of CAR T cells for cancer immunotherapy (Bailey 
and Maus, 2019; Stadtmauer et al., 2020).
For many other envisioned somatic therapies, the genome editing re-
agents will need to be delivered directly to a patient’s cells and tissues (in 
vivo genome editing). When a disease affects multiple organs, the challenge 
of delivery is magnified. Only in a few cases is the target tissue readily 
 accessible. One favorable example is the eye, where direct injection of a 
viral vector carrying CRISPR-Cas reagents is feasible and is being applied 
for a rare retinal blindness condition.7 The liver is also relatively accessible, 
and ZFNs are being employed to enhance a gene addi tion therapy in trials 
targeting hemophilia and metabolic disease.8 
5 See clinicaltrials.gov.
6 See, for example, clinical trial numbers NCT03745287 and NCT03655678.
7 See clinical trial NCT03872479.
8 See clinical trial numbers NCT02695160, NCT03041324, and NCT02702115.
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One feature of many of the above cases is that they rely on disruption 
of genome sequences by NHEJ. As noted above, this pathway is more active 
in most cells after a double-strand break is introduced than HDR. Treat-
ments relying on HDR are in development, but attaining therapeutically 
relevant efficiencies remains challenging. For quite a number of genetic 
conditions, a non-disease-causing allele could be created via base editing 
and such approaches are being pursued actively.
While somatic genome editing avoids some of the challenging issues 
raised by HHGE—because somatic editing involves treating existing 
 patients who can typically consent and because the resulting genetic 
changes would not be passed on to subsequent generations—somatic 
editing has some disadvantages. First, because editing does not alter 
the germline, a patient receiving somatic therapy for a genetic disease 
could still transmit the disease-causing mutation to future children. 
Additionally, because only a fraction of targeted cells might be edited, 
eliminating cells with the disease genotype or positive selection for the 
edited cells might be needed to increase the fraction of stems cells that 
have been edited. For example, protocols for somatic editing of hemato-
poietic stem cells (HSCs) commonly include cytotoxic chemotherapy to 
eliminate native HSCs before infusion of edited cells. These treatments 
confer risk of harm. Somatic genome editing therapies are also likely 
to be very expensive, although costs are unknown and likely to vary 
(Rockoff, 2019). 
Heritable Genome Editing: The Use of Genome Editing in Zygotes
At present, the primary approach that could be used for undertaking 
HHGE would involve genome editing in zygotes. Because edits introduced 
would be present in every cell in the body, and the resulting genetic modifi-
cations could be passed on to subsequent generations, it would be critically 
important to obtain the desired genetic change at the target site and ensure 
an absence of editing-induced changes elsewhere in the genome. There are 
unique challenges in characterizing the editing events in zygotes and early 
embryos, as well as important gaps in understanding how to precisely con-
trol genome editing in these cells.9
9 Genome editing technologies have also been adapted to affect the epigenetic state of 
somatic cells by altering DNA methylation (Kang et al., 2019) and histone modifications 
( Pulecio et al., 2017). Extensive epigenetic remodeling occurs during early development, and it 
is not clear whether epigenome editing would be heritable or how it would operate in zygotes 
and early embryos. Much more research on epigenome editing in embryos would need to be 
under taken before it could be considered as an intervention for congenital imprinting disorders 
(Eggermann et al., 2015).
Heritable Human Genome Editing
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A zygote—the single, fertilized cell that results from the combination 
of parental gametes (the egg and sperm)—is the earliest stage of embryonic 
 development. At first the maternal and paternal chromosomes remain in 
two distinct pronuclei in


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