Sangamo Announces Nature Biotechnology Publication of New Strategies for Optimizing the Specificity of Gene Editing Nucleases
July 29 2019 - 11:00AM
Business Wire
Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine
company, announced today the publication in Nature Biotechnology of
a manuscript by Jeffrey Miller, Ph.D., and colleagues at Sangamo,
describing two new strategies for optimizing the specificity of
genome editing using zinc finger nucleases (ZFNs). The ability to
engineer highly specific gene editing nucleases with little or no
detectable activity at unintended genomic sequences is a key safety
factor for therapeutic applications. The strategies entail
engineering the two key functional regions within the ZFN
structure, namely adjusting the binding affinity of the zinc finger
array which recognizes DNA, and slowing the catalytic rate of the
Fok1 cleavage domain. The two approaches, which are complementary,
may be combined to enable near 100% on-target modification with no
detectable off-targets. The manuscript, titled “Enhancing gene
editing specificity by attenuating DNA cleavage kinetics,” was
published online on July 29 and will appear in the August issue of
Nature Biotechnology.
“When attempting to improve the specificity of genome editing
tools, on-target editing efficiency is often sacrificed,” said
Edward Rebar, Ph.D., Chief Technology Officer, Sangamo. “With these
new strategies, the high efficiency we have observed previously
with ZFN-mediated genome editing was completely preserved, while
off-target activity was reduced by approximately 1000-fold, to
below the level of detectability. These results are important as we
believe the capabilities they demonstrate will help ensure the
safety of our genome editing tools when used in the clinic.”
In order to adjust the binding affinity of the zinc finger
recognition domain, the authors substituted a discrete, positively
charged residue in the zinc finger framework to eliminate a
nonspecific contact with the negatively charged phosphate backbone
of the DNA. By varying the number of fingers bearing this
substitution, the authors showed in cellular studies that they
could effectively tune ZFN affinity into an optimally specific
range, with no loss of on-target efficiency.
In a related series of cellular studies, the authors screened
single-amino acid substitutions in the Fok1 nuclease domain in
order to identify those able to improve specificity by slowing down
catalysis. The goal of the study was to observe whether mutations
would provide more time for the ZFNs to selectively dissociate from
off-target sites prior to a cleavage event, which would improve
global specificity. These studies yielded single-residue
substitutions that could increase specificity by more than
1000-fold.
In a final study detailed in the manuscript, Sangamo scientists
applied these two strategies in a therapeutically relevant setting
by designing ZFNs that targeted the endogenous TCR-alpha gene in
T-cells. Treatment of these T-cells with optimized ZFNs resulted in
a greater than 98% on-target knockout efficiency of the TCR-alpha
gene with undetectable off-target activity at a median assay
background level of 0.01%. Sangamo believes these engineered
improvements to the specificity of its ZFN genome editing platform
have the potential to enable the routine generation of designed
nucleases capable of high efficiency editing with minimal or no
detectable off-target activity.
These results add to Sangamo’s body of research demonstrating
the high degree of precision, efficiency, and specificity of ZFNs
for genome editing. In March 2019, Nature Communications published
data demonstrating new ZFN architectures enabling high-precision
genome editing. These new architectures yielded a 64-fold increase
in the diversity of ZFNs available for targeting any DNA
segment.
About Sangamo Therapeutics, Inc.
Sangamo Therapeutics is committed to translating ground-breaking
science into genomic medicines with the potential to transform
patients’ lives using gene therapy, ex vivo gene-edited cell
therapy, and in vivo genome editing and gene regulation. For more
information about Sangamo, visit www.sangamo.com
Forward-Looking Statements
This press release contains forward-looking statements based on
Sangamo's current expectations. These forward-looking statements
include, without limitation, statements relating to the ability to
engineer the ZFN structure to enable on-target modification, the
effects of these strategies on Sangamo’s genome editing tools, the
safety attributes associated with these strategies and their
ability to help ensure the safety of Sangamo’s gene editing tools
in the clinic, whether or not these effects may be replicated in
the clinic, the potential for these engineered improvements to
improve specificity on designed nucleases, and other statements
that are not historical fact. These statements are not guarantees
of future performance and are subject to certain risks,
uncertainties and assumptions that are difficult to predict.
Factors that could cause actual results to differ include, but are
not limited to, risks and uncertainties related to: early
preclinical data, including the risk that the early preclinical
data may not warrant regulatory approvals to conduct any human
clinical trials, and may not be representative of the results of
any such human clinical trials; whether Sangamo’s gene editing
tools and strategies will produce any beneficial therapeutic effect
in humans; Sangamo's ability to develop commercially viable
products; and the potential for technological developments by
Sangamo's competitors that will obviate Sangamo's ZFN technology.
These risks and uncertainties are described more fully in Sangamo's
Quarterly Report on Form 10-Q for the quarter ended March 31, 2019
as filed with the Securities and Exchange Commission.
Forward-looking statements contained in this press release are made
as of this date, and Sangamo undertakes no duty to update such
information except as required under applicable law.
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Investor Relations – United States
McDavid Stilwell 510-970-6000, x219 mstilwell@sangamo.com
Media Inquiries – United States Aron
Feingold 510-970-6000, x421 afeingold@sangamo.com Investor Relations and Media Inquiries – European
Union Caroline Courme 33 4 97 21 27 27
ccourme@sangamo.com
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