CHAMPIONS: A phase 1/2 clinical trial with dose escalation of SB-913 ZFN-mediated in vivo human genome editing for treatment of MPS II (Hunter syndrome)

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Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, progressive, X-linked genetic disorder that is caused by mutations in the human IDS gene and is characterized by deficient activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). Without functional IDS activity, the glycosaminoglycans (GAG), dermatan sulfate and heparan sulfate, accumulate in the body and lead to widespread tissue and organ damage. Patients with MPS II develop progressive respiratory and cardiac disease, skeletal abnormalities and in the severe form, cognitive decline and early death, despite treatment with enzyme replacement therapy. SB-913 is a new type of investigational treatment for MPS II. SB-913 uses zinc finger nuclease (ZFN)-mediated in vivo genome editing to insert a normal copy of the IDS transgene into liver cells, delivered via AAV2/6 vectors. The precision and specificity of SB-913 allows for integration at a targeted genomic location and is intended to reduce GAG accumulation with lifelong continuous endogenous production of IDS. CHAMPIONS is an ongoing Phase 1/2 clinical trial to determine if dose escalation of SB-913 is safe and tolerable in patients with MPS II, and is the first trial to attempt in vivo genome editing in humans. CHAMPIONS is a multicenter, open-label, dose escalation study with one-time peripheral intravenous infusion of SB-913, followed by three years of observation. Six adult subjects with attenuated MPS II have received SB-913, with two subjects in each of three dose cohorts (5e12 vg/kg, 1e13 vg/kg, and 5e13 vg/kg). The infusions were generally well-tolerated and no serious adverse events related to the study drug were reported at any dose with up to 10 months of exposure. No persistent transaminitis was observed. Additional analysis of the trial data is ongoing and will be presented as available. These results support further development of SB-913 for the treatment of MPS II.

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