Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

The objective for the study is to establish chimerism following reduced intensity
conditioning with no grade III/IV GVHD. The primary endpoint we will follow is production of
the missing enzyme at ≥ 10% of the normal level at day 180 post-transplant in > 90% of
patients.

Inclusion criteria:

1. Patients must have a confirmed diagnosis of inherited metabolic disorder / inborn
error of metabolism. Diagnosis should be confirmed by appropriate test(s) (enzyme
and/or mutation analysis) before study entry. Patients must not be eligible for
myeloablative chemotherapy as a preparative regimen for transplant due to age,
co-morbidities or organ dysfunction.

Inborn errors of metabolism / Inherited Metabolic Disorders (IMD) eligible for this
study include the following:

- Hurler Syndrome (MPS I)

- Hurler-Scheie Syndrome with early neurologic involvement and/or sensitization to
ERT

- Hunter Syndrome (MPS II)

- Sanfilippo Syndrome (MPS III)

- Krabbe Disease (Globoid Leukodystrophy)

- Metachromatic Leukodystrophy (MLD)

- Adrenoleukodystrophy (ALD and AMN)

- Sandhoff Disease

- Tay Sachs Disease

- Pelizaeus Merzbacher (PMD)

- Niemann-Pick Disease

- Alpha-mannosidosis

2. Patients must have adequate function of other organ systems as measured by:

- Creatinine less than or equal to 2.0 mg/dl and creatinine clearance ≥60
cc/min/1.73m2. Newborns must have a creatinine clearance ≥ 25 cc/min. For babies
less than or equal to 3 months of age, the raw value on glomerular filtration
rate (GFR) must be ≥ 1 cc/kg/min.

- Hepatic transaminases (ALT/AST) 2.5 x normal, bilirubin <2.0mg/dl

- Normal cardiac function by echocardiogram or radionuclide scan (ejection fraction
or shortening fraction >80% of normal value for age)

- Pulmonary function tests (PFTs) demonstrating forced expiratory volume at one
second (FEV1) of ≥50% of predicted for age. If child is too young or unable to
perform PFTs, crying vital capacity result of >50% of normal value for age or
resting pulse oximeter >92% on room air or clearance by pulmonologist will be
required.

3. Patient must have a related donor (identical or mismatched for 1, 2 or 3 Human
Leukocyte Antigen (HLA)-A, -B or -DR loci).

4. Patient, and parent, or legal guardian must have given written informed consent
according to FDA guidelines.

5. Patients must have a minimum life expectancy of at least 6 months.

6. Female patients of childbearing potential cannot be pregnant or
lactating/breast-feeding and must be either surgically sterile, postmenopausal (no
menses for the previous 12 months), or must be practicing an effective method of birth
control as determined by the investigator (e.g., oral contraceptives, double barrier
methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner
with vasectomy).

7. There is no upper or lower age limit for this study.

Exclusion Criteria

1. Patients with uncontrolled seizures, apnea, evidence of recurrent or uncontrolled
aspiration, or need for chronic mechanical ventilation.

2. Patients with allogeneic stem cell transplant with cytoreductive therapy in the past 6
months.

3. Subjects must not have had previous radiation therapy that would preclude total body
irradiation (TBI) (as determined by radiation therapist)

4. Uncontrolled infection or severe concomitant diseases, which in the judgment of the
Principal Investigator, could not tolerate reduced intensity transplantation.

5. Subjects with a positive human immunodeficiency virus (HIV) antibody test result

6. Subjects who are pregnant, as indicated by a positive serum human chorionic
gonadotropin (HCG) test

7. Subjects whose only donor is pregnant at the time of intended transplant

8. Subjects of childbearing potential who are not practicing adequate contraception as
defined by the investigator at the site

9. Jehovah's witnesses being unwilling to be transfused

10. Patients that have any comorbid condition which, in the view of the Principal
Investigators, renders the patient at too high a risk from treatment complications and
regimen related morbidity/mortality.

11. Lack of related donors