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

Phase 1

Terminated

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg	SB-913	A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.
Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg	SB-913	A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.
Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg	SB-913	A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.

Primary Outcome Measures

Name	Time	Method
Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion	Up to 36 months after the SB-913 infusion	Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in subjects who receive SB-913 as assessed by Common Terminology Criteria for Adverse Events (CTCAE)

Secondary Outcome Measures

Name	Time	Method
Effect of SB-913 on IDS Activity	Baseline and Month 33 after the SB-913 infusion	Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.
Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels	Baseline and 36 months after the SB-913 infusion	Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 36
Annualized Frequency of Idursulfase (or Equivalent ERT) Administration.	Up to 36 months after the SB-913 infusion	Change from baseline in annualized frequency of idursulfase (or equivalent ERT)
AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen	Up to 36 months after the SB-913 infusion	Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24. All the subjects had AAV2/6 clearance in all the samples assessed (i.e., plasma, saliva, urine, stool, and semen) by week 24. Subjects were only tested until Week 24 because, by that time, they all had 3 consecutive negative tests in all body fluids.

Locations (5): UCSF Benioff Children's Hospital Oakland
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Oakland, California, United States
NYU School of Medicine, Neurogenetics Division
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New York, New York, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
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Chicago, Illinois, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
University of North Carolina
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Chapel Hill, North Carolina, United States