Study Results Provide Proof of Concept for Development of MPS II Drug

Preclinical murine study data from Sangamo Therapeutics’ in vivo genome editing program for Mucopolysaccharidosis Type II (MPS II) provided proof of concept for development of its product candidate SB-913.

The work was conducted in collaboration with the University of Minnesota’s Center for Genome Engineering, and results from the study were published in the April 2018 issue of the journal Molecular Therapy. The data showed that the zinc finger nuclease (ZFN)-mediated genome editing of cells in the liver of a mouse model of MPS II resulted in the expression of therapeutic levels of iduronate 2-sulfatase (IDS), and in the prevention of metabolic and neurological disease symptoms. The IDS enzyme is lacked by patients with MPS II.

ZFN genome editing technology is used via SB-913 to insert a corrective IDS gene into an exact location in the DNA of liver cells, with the intention of permitting a patient’s liver to produce a lifelong and stable supply of the enzyme. The drug has already received an array of regulatory labels from the U.S. Food and Drug Administration (FDA), including Orphan Drug, Fast Track, and Rare Pediatric Drug Designations.

The study, titled “Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing,” was led by Kanut Laoharawee of the Center for Genome Engineering, Department of Genetics Cell Biology and Development at the University of Minnesota and colleagues. Male MPS II model mice between 6 and 9 weeks were injected with 1 of 3 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.

At both 1 and 4 months after injection, treated mice displayed 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 a reduction greater than 95% in glycosaminoglycan (GAG) substrate levels.

"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 in a press release.

MPS II, which leads to cardiac and respiratory obstructions and symptoms that are primarily cognitive in nature, is currently treated with chronic enzyme replacement therapy (ERT) with hIDS. Because of the frequency required for ERTs to be effective, and its lack of ability to address neurological symptoms of the disease, the most important finding from the study could be that SB-913 — at the highest dose level – prevented the development of neurocognitive deficit in the young MPS II model mice, as measured by the Barnes Maze test.

“Our results demonstrate that systemic administration of AAV2/8 vectors encoding a pair of ZFNs and the hIDS-donor-targeting insertion into the intron 1 of the mouse albumin locus results in high-level expression of hIDS activity in the liver with subsequent secretion into the bloodstream and widespread IDS enzyme distribution,” the study concluded.

“Based on the results described here and additional pre-clinical data, a phase 1 clinical study has been approved by the FDA (NCT03041324), and the first patient was recently infused, the first human application of in vivo genome editing.”

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