UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
The primary objective of the study is to determine the safety and feasibility of intrathecal
 administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of
 metabolism who have evidence of early demyelinating disease in the central nervous system
 (CNS) who are undergoing standard treatment with unrelated umbilical cord blood
 transplantation (UCBT). The secondary objective of the study is to describe the efficacy of
 UCBT with intrathecal administration of DUOC-01 in these patients.
The inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, most
 of which involve a single gene mutation resulting in an enzyme defect. In the majority of
 cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or
 interfere with normal cellular function. Often times, patients may appear normal at birth but
 during infancy begin to exhibit disease manifestations, frequently including progressive
 neurological deterioration due to absent or abnormal brain myelination. The ultimate result
 is death in later infancy or childhood.

 Currently, the only effective therapy to halt the neurologic progression of disease is
 allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of
 permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed
 engraftment of donor cells in the CNS when administered through the intravenous route, which
 is associated with ongoing disease progression over 2-4 months before stabilization. The
 engraftment of donor cells in a patient with an IMD provides a constant source of enzyme
 replacement, thereby slowing or halting the progression of disease.

 This study will evaluate the safety of a potential new treatment for patients with certain
 IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention,
 intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01) will serve as
 an adjunctive therapy to a standard UCB transplant. The goal of this therapy is to accelerate
 delivery of donor cells to the CNS thereby bridging the gap between systemic transplant and
 engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and
 cells used for HSCT will be derived from the same UCB donor unit.
Inclusion Criteria:

 1. Patients must be age ≥1 week to <21 years.

 2. Patients must have one of the following inherited metabolic diseases detected by
 enzyme or mutation analysis, and confirmed by repeat testing on a separately obtained
 sample:

 Adrenoleukodystrophy (ALD) Batten Disease Hunter Syndrome (MPS II) Krabbe disease
 (Globoid Leukodystrophy) Metachromatic Leukodystrophy (MLD) Niemann Pick disease type
 A or B Pelizaeus-Merzbacher disease (PMD) Sandhoff disease Tay Sachs disease. Alpha
 Mannosidosis Sanfilippo (MPS III)

 3. Patients must have neurologic evidence of their disease, either clinically or via
 neuroimaging or neurophysiological testing. Examples of evidence of neurologic
 involvement include, but are not limited to the following:

 -  Abnormal EEG, Brainstem Auditory Evoked Response (BAER), and/or Visual Evoked
 Potentials (VEP).

 -  Abnormal brain MRI, ie. increased Loes score (measure of white matter damage,
 demyelination, and brain atrophy) and/or abnormal corticospinal tracts as
 assessed by MRI with diffusion tensor imaging (DTI).

 -  Three or more of the early clinical markers: problems sleeping, increased
 activity, behavior difficulties, seizure-like activity, chewing behavior,
 inappropriate bladder training, inappropriate bowel training.

 4. Patients must have adequate organ function as measured by:

 -  Renal: Serum creatinine < 2.0 mg/dl

 -  Hepatic: Hepatic transaminases (ALT/AST) < 5 x normal, bilirubin < 2.0 mg/dl
 (except in patients with Gilbert's disease or newborns with physiological or
 breast milk associated jaundice).

 -  Cardiac: Normal cardiac function by echocardiogram or radionuclide scan
 (shortening fraction or ejection fraction

 -  80% of normal value for age). Patients with acquired or congenital
 cardiomyopathy may receive melphalan as a substitute for cyclophosphamide.

 -  Pulmonary: Pulmonary function tests demonstrating FVC, FEV1, and DLCO ≥ 60% of
 predicted in patients who can complete the testing. If patient cannot perform
 PFT's, an O2 sat must be >90% on room air.

 5. Patients must not have a suitable fully matched, non-carrier sibling or related bone
 marrow donor.

 6. Patients must have an available, suitably matched, banked UCB unit in a
 two-compartment configuration (see graft selection criteria in section 5.2).

 7. Patients must have a performance status as follows: Lansky ≥ 40%, or Karnofsky ≥ 40%.

 8. Patients must have a life expectancy of ≥ 6 months.

 Exclusion Criteria:

 1. Prior organ, tissue, or stem cell transplant within 3 years of study entry.

 2. Prior participation in any gene or regenerative cell therapy study.

 3. Inability to have an MRI scan or lumbar puncture.

 4. Intractable seizures.

 5. Chronic aspiration.

 6. Bleeding disorder.

 7. Evidence of HIV infection or HIV positive serology.

 8. Uncontrolled bacterial, viral, or fungal infection at the time of pre-UCBT
 cytoreduction.

 9. Inability to obtain patient's, parent's or legal guardian's consent.

 10. Requirement of ventilatory support.

 11. Pregnant or breastfeeding.

 12. Active concurrent malignancy, or receiving concurrent radiotherapy, immunosuppressive
 medications, or cytotoxic chemotherapy