Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II

A Phase I / 2, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-913, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis II (MPS II)

The purpose of the study is to evaluate the safety, tolerability and effect on leukocyte and plasma Iduronate 2-Sulfatase (IDS) enzyme activity of ascending doses of SB-913. SB-913 is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the IDS gene into the Albumin locus in hepatocytes with the goal of lifelong therapeutic production of the IDS enzyme.

The objectives of the study are to provide long term expression of IDS and improve the current clinical outcome of enzyme replacement therapy (ERT) in subjects with MPS II, a recessive lysosomal storage disorder that results from mutations in the gene encoding IDS. SB-913 is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-913 is intended to function by placement of the corrective copy of IDS transgene into the genome of the subject's own hepatocytes, under the control of the highly expressed endogenous albumin locus, and is expected to provide permanent, liver-specific expression of Iduronate 2-Sulfatase for the lifetime of an MPS II patient.

Inclusion Criteria:

• Male or female 5 years to 65 years of age.
• Clinical diagnosis of MPS II (based on evidence of hepatosplenomegaly, dysostosis multiplex by X-ray, valvular heart disease, or obstructive airway disease) IDS deficiency confirmed by gene sequencing.

Exclusion Criteria:

• Known to be unresponsive to ERT
• Neutralizing antibodies to AAV 2/6
• Serious intercurrent illness or clinically significant organic disease (unless secondary to MPS II)
• Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2
• Lack of tolerance to idursulfase treatment with significant IARs or occurrence of anaphylaxis
• Markers of hepatic dysfunction
• Creatinine ≥ 1.5 mg/dL
• Contraindication to the use of corticosteroids for immunosuppression
• Current treatment with systemic (IV or oral) immunomodulatory agent or steroid use (topical treatment allowed)
• Participation in prior investigational drug or medical device study within the previous 3 months
• Prior treatment with a gene therapy product
• Elevated or abnormal circulating α-fetoprotein (AFP)
• Weight < 20 kg at Screening Visit