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

Phase 2TerminatedNCT02702115

Sangamo Therapeutics3 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

MPS I

Interventions

SB-318BIOLOGICAL

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.

Eligibility

Sex: ALLMin age: 5 Years

Medical Language ↔ Plain English

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

Locations (1)

UCSF Benioff Children's Hospital Oakland

Oakland, California, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment-Emergent Adverse Events

Number of Participants with Treatment-Emergent Adverse Events

Time frame: Up to 36 months after the SB-318 infusion

Secondary Outcomes

Effect of SB-318 on IDUA Activity

Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.

Time frame: 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

Time frame: 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.

Time frame: Up to 24 months after the SB-318 infusion

Data from ClinicalTrials.gov

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