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

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.

Inclusion Criteria:

- Male or female >18 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)