RGX-111 Gene Therapy in Patients With MPS I

Mucopolysaccharidosis type I (MPS I) is a rare recessive genetic disease caused by a
deficiency of α-L-iduronidase (IDUA) leading to an accumulation of glycosaminoglycans (GAGs)
in tissues of patients with MPS I. While currently available therapies, enzyme replacement
therapy (ERT) and hematopoietic stem cell transplantation (HSCT), provide clinical benefit
over untreated disease progression, they still possess significant limitations. ERT does not
cross the blood-brain barrier and, therefore, does not treat the central nervous system (CNS)
effects of the disease, and HSCT has clinically relevant morbidity and mortality and is not
able to completely treat the CNS effects. RGX-111 is designed to deliver a functioning gene
enabling the production of IDUA in the brain. This is a Phase I, first-in-human, multicenter,
open-label, dose escalation study of RGX-111. Two, one time doses of RGX-111 will be studied
in approximately 5 subjects who have MPS I. Safety will be the primary focus for the initial
24 weeks after treatment (primary study period) whereupon, subjects will continue to be
assessed (safety and efficacy) for up to a total of 104 weeks following treatment with
RGX-111.

Inclusion Criteria:

- Must meet any of the following criteria:

- Has documented evidence of early- stage neurocognitive deficit due to MPS I,
defined as either of the following:

1. A score of ≥ 1 standard deviation below mean on IQ testing or in 1 domain of
neuropsychological function ( verbal comprehension, attention, or perceptual
reasoning).

2. A decline of >1 standard deviation on sequential testing

- Patient or Patient's legal guardian must be willing and able to provide written,
signed informed consent.

Exclusion Criteria:

- Has contraindications for intracisternal injection or lumbar puncture

- Has contraindications for immunosuppressive therapy

- Has neurocognitive deficit not attributable to MPS I or diagnosis of a
neuropsychiatric condition

- Received intrathecal (IT) laronidase at any time and experienced a significant AE
considered related to IT administration

- Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper
limit of normal (ULN) or total bilirubin >1.5 × ULN at screening, unless the subject
has a previously known history of Gilbert's syndrome and a fractionated bilirubin that
shows conjugated bilirubin <35% of total bilirubin.