Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine
company, today announced the publication of a manuscript describing
the activity of allele-selective zinc finger protein
transcription-factors (ZFP-TFs) in preclinical models of
Huntington’s disease (HD). The data were published online on July 1
and will appear in the July 2019 issue of Nature Medicine.
The publication describes research by Sangamo and collaborators
at the CHDI Foundation, in which ZFP-TFs were engineered to
selectively target the mutant form of the huntingtin gene (HTT) and
repress its transcription, selectively lowering production of the
mutant Huntingtin protein (mHTT). Preclinical data from HD
patient-derived fibroblasts and neurons demonstrated that a single
administration of ZFP-TFs resulted in the selective repression of
over 99% of HD-causing HTT disease alleles over a wide dose range,
while preserving the expression of at least 86% of healthy
wild-type HTT alleles.
Huntington’s disease is a progressive, fatal, neurodegenerative
disorder caused by a dominant mutation involving the expansion of a
CAG trinucleotide repeat in exon 1 of the HTT gene. Fully penetrant
disease alleles of mutant HTT have more than 39 CAG repeats, but
most HD patients have one healthy wild-type copy of HTT with less
than 22 CAG repeats. Led by first author Bryan Zeitler, PhD,
Sangamo scientists engineered ZFP-TFs capable of preferentially
binding longer CAG repeat arrays on the disease allele while
avoiding the shorter repeat array on the healthy allele. These
ZFP-TFs exhibited disease-allele selectivity and also demonstrated
a high level of specificity for the mutant HTT repeat as compared
to other CAG-containing genes in the human genome.
“Ever since the mutation that causes Huntington’s Disease was
identified in 1993, the ultimate goal for HD research has been to
develop a therapy that could directly target the mutant CAG repeat
while avoiding the wild-type form given its important role in many
cellular functions,” said Gillian Bates, PhD, Professor of
Molecular Neuroscience, Queen Square Institute of Neurology, UCL,
London, who played a key role in the international effort to clone
the HTT gene and disease causing mutation and is not involved in
the study. “Sangamo’s ZFP-TF approach is particularly compelling
because it represents a potentially universal allele-selective
treatment that could possibly require a one-time administration. If
successfully translated into the clinic, this could be
transformative for patients and their families.”
Data from preclinical in vivo studies using different HD mouse
models demonstrated improvements in a range of molecular,
histopathological, electrophysiological, and other functional
endpoints following treatment with Sangamo’s ZFP-TFs. In neurons
cultured from the zQ175 mouse model (~188 CAG repeats) of HD,
recombinant AAV delivery of ZFP-TFs to primary neurons resulted in
reduction of mutant HTT mRNA and HTT protein by more than 98% with
no reduction of wild-type HTT. In vivo, toxic aggregates of the
mutant HTT protein were reduced by greater than 99%. Moreover, the
well-characterized zQ175 electrophysiological deficits in the brain
were fully reversed following ZFP treatment. Functional restoration
of neuronal biomarkers was also demonstrated by several measures,
including the use of PET imaging ligands in living mice. This
outcome has the potential to be translated for use as an efficacy
marker in clinical trials. The results were confirmed and extended
in an additional mouse model of HD, in which treatment with ZFP-TFs
led to the repression of mutant HTT protein and significant
improvement in motor function.
Finally, extensive in vivo tolerability assessments showed no
evidence of a neuroinflammatory response or changes in behavior or
locomotor function in mice treated with ZFP-TFs out to 15 months of
age. This suggests that the long-term striatal expression of
ZFP-TFs is generally well-tolerated in mice.
“These studies present the first direct demonstration of disease
allele-selective transcriptional repression at the mutated
Huntingtin gene locus. While several HTT-lowering therapies are
advancing into the clinic, they all rely on indirect approaches
that do not directly target the mutation. Moreover, these
strategies either lower both mutant and normal HTT or employ
allele-targeting that is limited to a subgroup of patients, in some
cases requiring multiple intrathecal injections over a patient’s
lifetime,” said Adrian Woolfson, M.D., Ph.D., Sangamo’s Executive
Vice President of Research and Development. “Sangamo’s engineered
ZFP-TFs demonstrated a combination of high selectivity, genome-wide
specificity, and long-term tolerability that we believe establishes
a new benchmark for engineered transcription factors. Overall,
these data provide compelling preclinical evidence for the
potential viability of Sangamo’s ZFP-TF gene regulation platform as
a novel disease modifying therapeutic approach for the treatment of
Huntington’s disease.”
About Huntington’s Disease
Huntington’s disease (HD) is an inherited neurodegenerative
disease that typically presents in adults aged between 30 and 50.
HD is caused by a mutation in one of the alleles of the huntingtin
gene (HTT), leaving only one functional or healthy copy of HTT in
the cell. The mutated HTT produces the mutant HTT protein, leading
to profound neuronal loss and progressive deterioration of motor,
psychiatric, and cognitive abilities. There are currently no
disease-modifying therapies available for HD.
About Sangamo’s Gene Regulation Platform
Sangamo's zinc finger protein transcription factor (ZFP-TF) gene
regulation technology is designed to either selectively repress
(down-regulate) or activate (up-regulate) the expression of a
specific gene or gene allele following a single administration.
This technology enables targeting of a broad range of diseases
requiring regulation of endogenous gene expression and differs from
other approaches such as gene therapy or zinc finger
nuclease-mediated (ZFN) genome editing, which are designed to
replace or correct a missing or mutated gene or DNA sequence.
Sangamo is developing ZFP-TFs as a novel therapeutic approach
for diseases of the central nervous system (CNS). Sangamo has a
collaboration with Pfizer, deploying the ZFP-TF gene regulation
approach to repress the expression of the mutated C9ORF72 gene
allele linked to genetic forms of amyotrophic lateral sclerosis
(ALS) and frontotemporal dementia (FTD). Sangamo is also developing
ZFP-TFs to down-regulate the expression of tau, a protein
associated with Alzheimer's disease and other tauopathies.
Takeda Pharmaceutical Company Limited is working with Sangamo on
further engineered ZFP-TFs designed to selectively target the
mutant HTT gene and repress its transcription. Takeda intends to
evaluate this potential clinical candidate for the treatment of HD
in potential preclinical Investigational New Drug (IND)-enabling
studies.
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, 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 therapeutic
potential of Sangamo's ZFP-TF gene regulation platform for the
treatment of CNS diseases, including the potential of Sangamo’s
ZFP-TF gene regulation platform as a novel disease modifying
therapeutic approach for the treatment of HD; the potential for
Sangamo's ZFP-TF approach to represent an allele-selective
treatment that could possibly require a one-time administration;
the potential for HD mouse model preclinical data to translate into
the clinic; the potential for preclinical studies to be
IND-enabling; 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 ZFP-TFs will
produce any beneficial therapeutic effect in humans; Sangamo's
reliance on Takeda, its other partners and other third-parties to
further develop its technology; Sangamo's ability to develop
commercially viable products; and the potential for technological
developments by Sangamo's competitors that will obviate Sangamo's
ZFP-TF 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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