A Study of Intrathecal Enzyme Therapy for Cognitive Decline in MPS I

This study is a 24-month open label, prospective, randomized trial in 16 MPS I patients age
six years or older who have documented evidence of cognitive decline. The study will test
the safety and efficacy of intrathecal recombinant human alpha-L iduronidase (rhIDU) to
reduce or stabilize cognitive decline by assessing the subjects at baseline with
neuropsychological, clinical, radiological, and biochemical evaluations and then monitoring
the change in these parameters during a regimen of first monthly, then quarterly,
intrathecal treatments with rhIDU. The clinical safety of the regimen will be assessed by
monitoring of adverse events, cerebrospinal fluid (CSF) laboratory assessments, and clinical
evaluations.

Subjects will be randomized to a treatment or a control group for 12 months, following which
all subjects will receive 12 months of active treatment. During the first 12 months, the
control group will receive similar study assessments but will be unblinded with no placebo
administered. Subjects will have extensive baseline screening evaluations, after which
subjects who were randomized to the treatment group will receive their first dose of
intrathecal rhIDU. The enzyme will be administered via intrathecal injection at 1-3 month
intervals throughout the 24-month study period. There will be a mid-study analysis after 12
months comparing changes in IQ and memory tests between controls and the treatment group. If
pre-established criteria of improvement are met, the study will terminate at the 12 month
point. If shown to be effective, intrathecal enzyme replacement therapy (ERT) would be the
only treatment for cognitive decline in patients who do not qualify for and/or are unable to
have hematopoietic stem cell transplantation.

Inclusion Criteria:

- The presence of MPS I disease as documented by low α-L-iduronidase activity

- Age six years or older.

- The presence of acquired cognitive deficits as demonstrated by:

1. A score of one standard deviation below mean on IQ testing or in one domain of
neuropsychological function (language, memory, or non-verbal ability), OR

2. Documented historical evidence of a decline of greater than one standard
deviation on sequential testing, OR

3. A score between 0.75 and 1 standard deviation below the mean, AND the cognitive
deficit affects daily performance.

- The decline in function is not explainable by other neurological or psychiatric
factors.

- Subject and/or guardian willing and able to provide written informed consent.

- Negative urine pregnancy test at screening (non-sterile females of child-bearing
potential only)

- Currently using two acceptable methods of birth control as determined by the
investigator and willing to continue to use acceptable birth control during their
participation in the study (non-sterile females of child-bearing potential who are
sexually active only)

- Willing and able to comply with study procedures. For example, the subjects must be
able to complete written and computer-based testing. The subjects must be able to lie
still in the MRI scanner for at least 40 minutes without sedation.

Exclusion Criteria:

- The subject has undergone hematopoietic stem cell transplantation

- Recent initiation of intravenous Aldurazyme® therapy with less than 6 months of
therapy. Subjects who have been receiving Aldurazyme® therapy for more than 6 months,
and those who have never received Aldurazyme® therapy, will be allowed to enroll

- Pregnant or lactating, or considering pregnancy

- Receipt of an investigational drug or procedure within 30 days of enrollment

- A condition, medical or other, that prevents participation in the study, including
severe auditory or visual impairment, significant lumbar pathology, lumbar catheter,
or recent major surgery within 6 weeks that would preclude their ability to
participate.

- Infusion reactions to intravenous Aldurazyme® therapy that require ongoing medical
intervention, special prophylaxis or altered rate or dose of enzyme administration

- The subject has a programmable VP shunt that is incompatible with the 3 Tesla MRI
magnet and is unable or unwilling to undergo shunt revision to a MRI compatible
device.

- The subject has another contraindication for MRI, such as nonremovable metal in the
body.

- The subject has severely impaired spinal CSF flow, demonstrated by failure of
appearance of 99mTechnetium-DTPA in the basal cisterns by 4 hours after intra-lumbar
administration.