RICHMOND, Calif., April 4,
2018 /PRNewswire/ -- Sangamo Therapeutics, Inc.
(NASDAQ: SGMO) announced today the publication of preclinical
murine study data from the company's in vivo genome editing
program for Mucopolysaccharidosis Type II (MPS II) in the
April 2018 issue of Molecular
Therapy. In the study, in a mouse model of MPS II, zinc
finger nuclease (ZFN)-mediated genome editing of cells in the liver
resulted in expression of therapeutic levels of iduronate
2-sulfatase (IDS), an enzyme MPS II patients lack, and in the
prevention of metabolic and neurological disease symptoms. The work
was conducted in collaboration with the University of Minnesota's Center for Genome
Engineering.
The preclinical study provided proof of concept for development
of SB-913, an in vivo genome editing product candidate
Sangamo is currently evaluating in the CHAMPIONS Study, a Phase 1/2
clinical trial assessing the potential safety and efficacy of
SB-913 in up to nine adult males with attenuated MPS II. SB-913
uses Sangamo's ZFN genome editing technology delivered
intravenously via AAV6 vectors and is a single-treatment strategy
intended to provide stable, continuous production of the IDS
enzyme.
About the Preclinical Study
Male MPS II model mice
between six and nine weeks of age were injected with one of three
increasing dose levels of a genome editing treatment consisting of
AAV2/8 vectors encoding a pair of ZFNs and a corrective human
IDS (hIDS) gene. The treatment was designed to
integrate the hIDS gene in a precise location within the
albumin gene in liver cells.
Treated mice, at both one and four-months after injection,
exhibited dose-dependent expression of IDS enzyme in blood and
peripheral tissues, including the spleen, kidney, lung, heart, and
skeletal muscle. Enzyme expression in liver cells reached levels
greater than 200-fold higher than in wild-type mice. In all tested
peripheral organs, treatment at the highest dose resulted in
greater than 95% reduction in glycosaminoglycan (GAG) substrate
levels. Importantly, treatment with Sangamo's genome editing
therapy at the highest dose level also prevented the development of
neurocognitive deficit in the young MPS II model mice, as measured
by the Barnes Maze test.
"The continuous supply of enzyme produced by the genome-edited
liver cells in these young mice not only protected organs and
tissue from damage, but importantly also promoted passage across
the blood brain barrier to exert neuroprotective effects. If we see
similar effects in clinical trials in humans, ZFN-mediated genome
editing would represent a transformative treatment for children
with MPS II," said Chester Whitley,
Ph.D., M.D., director of the Gene Therapy Center at the
University of Minnesota Medical School
and a senior author on the manuscript.
Citation: Laoharawee et al., Dose-Dependent Prevention of
Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated
In Vivo Genome Editing, Molecular Therapy (2018),
https://doi.org/10.1016/j.ymthe.2018.03.002
About MPS II (Hunter's syndrome)
Mucopolysaccharidosis
Type II (MPS II, Hunter's syndrome) is an X-linked recessive
lysosomal storage disorder that occurs almost exclusively in males.
MPS II is caused by mutations in the gene encoding iduronate
2-sulfatase (IDS), resulting in a deficiency of IDS, a metabolic
enzyme required for the degradation of the glycosaminoglycans
(GAGs) heparan and dermatan sulfate within the lysosomes of cells.
The absence of IDS enzyme, results in lysosomal GAG accumulation,
leading to skeletal abnormalities, cardiac and respiratory
obstructions, organomegaly, and in severe cases of the disease
neurological impairment and death when patients reach adolescence.
According to the National MPS Society, one in 100,000 to one in
every 150,000 male births will result in MPS II. Current
standard of care treatment for MPS II consists of chronic enzyme
replacement therapy (ERT) with human IDS enzyme (hIDS). However,
ERT requires life-long, weekly infusions because the hIDS is often
cleared from circulation in the body within hours of treatment due
to its short half-life and has not been shown to address the
neurological symptoms of the disease.
Sangamo's In Vivo Genome Editing Approach
With
SB-913, Sangamo aims to treat MPS II by using its proprietary ZFN
genome editing technology to insert a corrective IDS gene into a
precise location in the DNA of liver cells with the goal of
enabling a patient's liver to produce a lifelong and stable supply
of the human IDS enzyme.
To restrict editing to liver cells, the ZFNs and the corrective
gene are delivered in a single intravenous infusion using AAV6
vectors that target the liver. The ZFNs enter the cells as inactive
DNA instructions in a format designed only for liver cells to
unlock. Once "unlocked", the ZFNs then identify, bind to and cut
the DNA in a specific location within the albumin gene. Using the
cells' natural DNA repair processes, liver cells can then insert
the corrective gene for IDS at that precise location. The genome
editing therapy is intended to ultimately target a population that
includes pediatric patients, and it will be important in this
population to be able to produce stable levels of therapeutic
enzyme for the lifetime of the patient.
The ability to permanently and precisely integrate the
therapeutic IDS gene into the DNA differentiates Sangamo's in
vivo genome editing approach from conventional AAV cDNA gene
therapy and from lenti- or retroviral-based gene therapies that
insert genes randomly into the genome.
SB-913 has received several regulatory designations, including
Orphan Drug, Fast Track and Rare Pediatric Disease designations
from the FDA as well as Orphan Medicinal Product designation from
the European Medicines Agency (EMA).
About Sangamo Therapeutics
Sangamo
Therapeutics, Inc. is focused on translating ground-breaking
science into genomic therapies that transform patients' lives using
the company's industry leading platform technologies in genome
editing, gene therapy, gene regulation and cell therapy. The
Company is conducting Phase 1/2 clinical trials in Hemophilia A and
Hemophilia B, and lysosomal storage disorders MPS I and MPS II.
Sangamo has exclusive, global collaboration and license agreements
with Kite, a Gilead Sciences company, to develop next-generation
autologous and allogeneic engineered cell therapies for the
treatment of cancer using zinc finger nuclease genome editing
technology; with Pfizer Inc. for gene therapy programs for
Hemophilia A; with Bioverativ Inc. for hemoglobinopathies,
including beta thalassemia and sickle cell disease; and with Shire
International GmbH to develop therapeutics for Huntington's
disease. For more information about Sangamo, visit the Company's
website at www.sangamo.com.
Forward-Looking Statements
This press release contains forward-looking statements regarding
Sangamo's current expectations. These forward looking statements
include, without limitation, references to Sangamo's aims to treat
MPS II by using its proprietary ZFN genome editing technology to
insert a corrective IDS gene into a precise location in the DNA of
liver cells with the goal of enabling a patient's liver to produce
a lifelong and stable supply of the human IDS enzyme and the
potential for the clinical trial to have results similar to those
observed in the preclinical mouse study. 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, the dependence on the success of the clinical
trials of lead programs, the lengthy and uncertain regulatory
approval process, uncertainties related to the initiation and
completion of clinical trials, whether clinical trial results will
validate and support the safety and efficacy of Sangamo's product
candidates, and the reliance on partners and other third-parties to
meet their obligations. Actual results may differ from those
projected in forward-looking statements due to risks and
uncertainties that exist in Sangamo's operations and business
environments. These risks and uncertainties are described more
fully in Sangamo's Annual Report on Form 10-K and Quarterly Reports
on Form 10-Q as filed with the Securities and Exchange Commission.
Forward-looking statements contained in this announcement 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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