UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

The inherited metabolic disorders (IMD) are a 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 buildup of substances 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 symptoms, 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 slow or halt this neurologic decline is allogeneic hematopoietic stem cell transplantation (HSCT). 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. However, one barrier to the success of HSCT is the slower engraftment of donor cells in the central nervous system (CNS), which is associated with ongoing disease progression over 2-4 months before stabilization.

This study will evaluate the safety of an additional cell therapy for patients who are receiving HSCT using umbilical cord blood (UCB) cells from an allogeneic (non-self) donor for treatment of an IMD that is known to benefit from HSCT. The additional cell therapy, UCB-derived oligodendrocyte-like cells (DUOC-01), will serve as a supplementary therapy to a standard UCB transplant. DUOC-01 is administered intrathecally (injected into the spinal fluid) after transplant. The goal of this therapy is to accelerate delivery of donor cells to the CNS, thereby bridging the gap between the time from UCB transplant to engraftment of the UCB cells in the CNS, with the goal of preventing disease progression.

This study is only performed at Duke University Medical Center and only patients who are medically eligible for a UCB transplant will be enrolled.

Inclusion criteria

• Patients must be age ≥1 week to ≤21 years.
• 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)

• 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.
• 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.
• Patients must have an available, suitably matched, banked UCB unit for transplant.
• Patients must have a performance status as follows: Lansky ≥ 40%, or Karnofsky ≥ 40%
• Patients must have a life expectancy of ≥ 6 months.

Exclusion criteria

• Prior organ, tissue, or stem cell transplant within 3 years of study entry.
• Prior participation in any gene or regenerative cell therapy study.
• Inability to have an MRI scan or lumbar puncture.
• Intractable seizures.
• Chronic aspiration.
• Bleeding disorder.
• Evidence of HIV infection or HIV positive serology.
• Uncontrolled bacterial, viral, or fungal infection at the time of pre-UCBT cytoreduction.
• Inability to obtain patient's, parent's or legal guardian's consent.
• Requirement of ventilatory support.
• Pregnant or breastfeeding.
• Active concurrent malignancy, or receiving concurrent radiotherapy, immunosuppressive medications, or cytotoxic chemotherapy