title: Stem cell collection and gene transfer in Fanconi anemia.
abstract: Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34(+) stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34(+) cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34(+) cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials.
authors.affiliation: Fanconi Anemia Comprehensive Care Center, Divisions of Experimental Hematology and Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Kelly
authors.forename: Susan
authors.initials: S
authors.lastname: Radtke
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Brenden
authors.initials: B
authors.lastname: Balcik
authors.forename: Kimberley
authors.initials: K
authors.lastname: Bohn
authors.forename: Robin
authors.initials: R
authors.lastname: Mueller
authors.forename: Todd
authors.initials: T
authors.lastname: Schuesler
authors.forename: Moira
authors.initials: M
authors.lastname: Haren
authors.forename: Lilith
authors.initials: L
authors.lastname: Reeves
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Thomas
authors.initials: T
authors.lastname: Leemhuis
authors.forename: Richard
authors.initials: R
authors.lastname: Harris
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
authors.forename: Franklin O
authors.initials: FO
authors.lastname: Smith
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002469:Cell Separation / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D007223:Infant; D013234:Stem Cells / Q000166:cytology; D019076:Transgenes / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D018076:DNA, Complementary; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein