Treatment of Early Infantile-Onset Lysosomal Storage Diseases With Fetal Umbilical Cord Blood (UCB) Transplantation

The purpose of this study is to determine the safety of first trimester fetal stem cell therapy using unrelated donor partially HLA-matched stem and progenitor cells derived from human umbilical cord blood for the treatment of selected lysosomal storage diseases that are known to cause severe and irreversible neurological disability in early infancy and which are lethal in childhood.

This study is designed as a prospective phase I open-label single center trial. It is designed to asses the safety and feasibility of administration of ALD-601 UCB cells to first trimester fetuses known to be affected with a lethal lysosomal storage disease. The sample size is 12 patients enrolled in cohorts of size 3. Safety measures will be monitored by an independent DSMC in each of the 4 cohorts prior to proceeding to the next cohort.

Biological parents being considered for therapy will have HLA testing, mutation analysis for disease status, and psychological counseling. Mothers will have ultrasounds for gestational age and chorion villus testing for mutation analysis for Krabbe, MLD, Tay Sachs, Sandhoff, or PMD (whichever appropriate). A crown-rump length will be determined the day before the scheduled transfer. The fetal weight will be calculated from formula: Y (kg) = (2.9026 x 10-1) (X 2.6528). The estimated fetal weight at that gestational age would be about 0.5 ounces or 14 grams. A suitably matched unrelated umbilical cord blood will be identified and the 20% portion will be manipulated for the isolation of ALD-601 cells. ALD-601 (ALDHbr) cells are isolated by high speed flow sorting on the FACSAria (BD Biosciences). Upon completion of the sort, ALD-601 UCB cells are counted, viability is determined, and the cellular composition of the sample is measured by analytical flow cytometry using fluorescence antibodies to lineage marker for T-cells, granulocytes, monocytes, and erythrocytes. The content of ALDHbr cells is also confirmed by analytical flow cytometry. A dose of 1 x 105 - 2 x 106 cells/kg of estimated fetal weight is suspended in 300 microliters of Cellgenix Stem Cell Medium (CellGenix, Inc.). Release criteria will allow a maximum of 5 x 104 T cells/kg. If the sorted sample contains greater than 5 x 104 T cells/kg it is re-sorted using the FACSAria and re-evaluated for cell number, viability, and cellular content. Sterility testing will include Bac-T/ALERT cultures, endotoxin measurement (LAL), and gram stain. After meeting criteria for product release, ALD-601 is transported at 2-8 degree C in a validated cooler to Duke and released to the Stem Cell Laboratory. Duke personnel will transport the cooler containing the ALD-601 product to the ultrasound suite, where the medical team will allow the ALD-601 to warm briefly to room temperature prior to injection. Under continuous ultrasound guidance, a 22-gauge X 5 inch procedure needle will be used to puncture the fetal peritoneal cavity. 100 microliters of sterile saline will be instilled to confirm intraperitoneal placement. The stem cell infusion will then be injected through the needle followed by the injection of 200 microliters (dead space of the needle: 60 microliters) to displace all cells from the dead space of the needle. An ultrasound will be performed 24 hours later to confirm fetal viability. A subsequent ultrasound will be undertaken at 18 weeks gestation to confirm viability, assess detailed fetal anatomy and adequate serial fetal growth.