Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I

Phase 1

Terminated

Brief Summary: The purpose of the study is to evaluate the safety, tolerability of ascending doses of SB-318. SB-318 is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the α-L-iduronidase (IDUA) gene into the Albumin locus in hepatocytes with the goal of lifelong therapeutic production of the IDUA enzyme.

Detailed Description: The objectives of the study are to provide long term expression of IDUA and improve the current clinical outcome of enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT) therapy in subjects with attenuated MPS I, a recessive lysosomal storage disorder that results from mutations in the gene encoding IDUA. SB-318 is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-318 is intended to function by placement of the corrective copy of the IDUA 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 iduronidase for the lifetime of an MPS I patient.

Recruitment & Eligibility

Inclusion Criteria

Male or female ≥ 5 years of age
Clinical diagnosis of attenuated MPS I deficiency (Hurler-Scheie, Scheie, or Hurlers status post-HSCT)

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 I)
Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2
Lack of tolerance to laronidase 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-318 at Next Ascending Dose 5.00E+13 vg/kg	SB-318	A single dose of each of the three components of SB-318 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.
Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg	SB-318	A single dose of each of the three components of SB-318 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.
Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg	SB-318	A single dose of each of the three components of SB-318 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events	Up to 36 months after the SB-318 infusion	Number of Participants with Treatment-Emergent Adverse Events

Secondary Outcome Measures

Name	Time	Method
Effect of SB-318 on IDUA Activity	Baseline and Month 36 after the SB-318 infusion	Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.
Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels	Baseline and 24 months after the SB-318 infusion	Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24
AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen	Up to 24 months after the SB-318 infusion	Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24.