Clinical trial NCT02702115: Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: MPS I
Keywords: 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
Lead sponsor: Sangamo Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-03-08
Enrollment: 3
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events
timeFrame: Up to 36 months after the SB-318 infusion
Secondary outcomes:
measure: Effect of SB-318 on IDUA Activity
timeFrame: Baseline and Month 36 after the SB-318 infusion
measure: Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels
timeFrame: Baseline and 24 months after the SB-318 infusion
measure: AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen
timeFrame: Up to 24 months after the SB-318 infusion
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
Study officials:
affiliation: Sangamo Therapeutics
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Ou L, Przybilla MJ, Ahlat O, Kim S, Overn P, Jarnes J, O'Sullivan MG, Whitley CB. A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I. Mol Ther. 2020 Jun 3;28(6):1442-1454. doi: 10.1016/j.ymthe.2020.03.018. Epub 2020 Apr 8.