Brief Summary
The primary objective of the study is to determine the safety and feasibility of intrathecal
<br /> administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of
<br /> metabolism who have evidence of early demyelinating disease in the central nervous system
<br /> (CNS) who are undergoing standard treatment with unrelated umbilical cord blood
<br /> transplantation (UCBT). The secondary objective of the study is to describe the efficacy of
<br /> UCBT with intrathecal administration of DUOC-01 in these patients.
Detailed Description
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.
Study Criteria
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
