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

Sangamo Therapeutics

Status and phase: Terminated; Phase 2; Phase 1

Conditions: MPS I

Treatments: Biological: SB-318

Study type: Interventional

Funder types: Industry

Identifiers

NCT02702115

SB-318-1502

Details and patient eligibility

About

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.

Full 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.

Enrollment: 3 patients

Sex: All

Ages: 5+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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3 participants in 3 patient groups

Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg

Experimental group

Description:

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.

Treatment:

Biological: SB-318

Cohort 2: SB-318 at Next Ascending Dose 5.00E+13 vg/kg

Experimental group

Description:

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.

Treatment:

Biological: SB-318

Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg

Experimental group

Description:

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.

Treatment:

Biological: SB-318