Lentivirus-mediated gene therapy for Fabry disease.

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Cryopreserved mobilized autologous blood progenitors stored for more than 2 years successfully support blood count recovery after high-dose chemotherapy.

BACKGROUND AIMS: The ability of hematopoietic progenitor cells-apheresis (HPC-A) that have been stored for many years after cryopreservation to reconstitute hematopoiesis following high-dose chemo/radiotherapy has not been well-documented. METHODS: In this retrospective study, eight Canadian centers contributed data from 53 autologous stem cell transplants (ASCT) performed using HPC-A that had undergone long-term storage (>2 years, range 2-7 years) and 120 ASCT using HPC-A stored for <6 months (short-term storage). RESULTS: The doses of nucleated and CD34(+) cells per kilogram recipient weight were similar between the short- (mean ± SD, 4.7 ± 4.9 × 10(8) and 6.8 ± 4.3 × 10(6), respectively) and long- (4.0 ± 4.9 × 10(8) and 6.1 ± 3.4 × 10(6), respectively) term storage groups. The median days to neutrophils (absolute neutrophil count; ANC) >0.5 × 10(9)/L (median 11 days for both short- and long-term storage) and platelets >20 × 10(9)/L (median 12 and 11 for short- and long-term storage, respectively) post-ASCT were not significantly different between the two groups. When ASCT performed with <5 × 10(6)/kg CD34(+) cells was compared there was also no difference in ANC or platelet recovery (median 12 days for both after short-term storage, and 12 and 11 days, respectively, after long-term storage). Fourteen HPC-A products stored for >5 years also showed similar count recoveries as the entire long-term storage group (median 11 days for both ANC and platelets). CONCLUSIONS: Cryopreserved HPC-A can be stored for at least 5 years with no apparent loss in their ability to support hematopoietic reconstitution after high-dose chemotherapy.

Autologous peripheral blood progenitor cells are a potential source of parvovirus B19 infection.

BACKGROUND: Parvovirus B19 is a cause of delayed red blood cell (RBC) engraftment after marrow transplantation (BMT). The diagnosis of parvovirus infection requires serologic and DNA testing in the context of clinical disease and characteristic marrow morphologic findings; however, the source of infection is often difficult to determine. STUDY DESIGN AND METHODS: Investigation of a case of delayed RBC engraftment and pure RBC aplasia (PRCA) occurring 3 months after autologous peripheral blood progenitor cell (PBPC) transplantation in a patient with high-risk diffuse large B-cell lymphoma. DNA testing of serum and of a sample of cryopreserved PBPCs was performed. RESULTS: Marrow morphology showed a maturational arrest of erythroid cells with giant proerythroblasts. Polymerase chain reaction and nucleic acid hybridization confirmed the presence of parvovirus DNA in the serum and in a sample of sequestered PBPCs saved at the time of PBPC harvest. PRCA resolved after the administration of intravenous immune globulin. CONCLUSION: Autologous PBPCs are a potential source of parvovirus infection, which may cause significant disease after autologous BMT.