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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I / 2, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-318, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis I (MPS I)

Conditions
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MPS I

Intervention / Treatment
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* Biological: SB-318


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg<br>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. | Biological: SB-318<br>* 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.<br>|
| Experimental: Cohort 2: SB-318 at Next Ascending Dose 5.00E+13 vg/kg<br>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. | Biological: SB-318<br>* 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.<br>|
| Experimental: Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg<br>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. | Biological: SB-318<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events | Number of Participants with Treatment-Emergent Adverse Events | Up to 36 months after the SB-318 infusion | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis I, MPS I, Hurler-Scheie syndrome, Gene Therapy, Gene Editing, Zinc Finger, SB-318, Rare, Genetic, DNA, Sangamo, Genome editing, Empowers, ZFN, Hurler, Gene Specific Targeted Insertion