Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.
Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
Ott
Marion G
MG
Department of Hematology/Oncology, University Hospital, German Cancer Research Center, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Schmidt
Manfred
M
Schwarzwaelder
Kerstin
K
Stein
Stefan
S
Siler
Ulrich
U
Koehl
Ulrike
U
Glimm
Hanno
H
Kühlcke
Klaus
K
Schilz
Andrea
A
Kunkel
Hana
H
Naundorf
Sonja
S
Brinkmann
Andrea
A
Deichmann
Annette
A
Fischer
Marlene
M
Ball
Claudia
C
Pilz
Ingo
I
Dunbar
Cynthia
C
Du
Yang
Y
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Lüthi
Ursula
U
Hassan
Moustapha
M
Thrasher
Adrian J
AJ
Hoelzer
Dieter
D
von Kalle
Christof
C
Seger
Reinhard
R
Grez
Manuel
M
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D041321:Chromosomes, Human, X; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000235:genetics*; D018014:Gene Transfer Techniques; D008040:Genetic Linkage; D005819:Genetic Markers; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics*; D009504:Neutrophils / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C416371:PRDM16 protein, human; D012333:RNA, Messenger; C425066:SETBP1 protein, human; D014157:Transcription Factors