Sangamo Announces Publication In Molecular Therapy Of Preclinical Study Data From MPS II In Vivo Genome Editing Program

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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