Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome
Journal
Blood
ISSN
0006-4971
1528-0020
Date Issued
2023
Author(s)
Roxane Labrosse
Julia I. Chu
Myriam A. Armant
John K. Everett
Danilo Pellin
Niharika Kareddy
Andrew L. Frelinger
Lauren A. Henderson
Amy E. O’Connell
Amlan Biswas
Jet Coenen-van der Spek
Alexandra Miggelbrink
Claudia Fiorini
Hriju Adhikari
Charles C. Berry
Vito Adrian Cantu
Johnson Fong
Jason Jaroslavsky
Derin F. Karadeniz
Quan-Zhen Li
Shantan Reddy
Aoife M. Roche
Chengsong Zhu
Jennifer S. Whangbo
Colleen Dansereau
Brenda Mackinnon
Emily Morris
Stephanie M. Koo
Wendy B. London
Safa Baris
Ahmet Ozen
Elif Karakoc-Aydiner
Jenny M. Despotovic
Lisa R. Forbes Satter
Akihiko Saitoh
Yuta Aizawa
Mai Anh Thi Nguyen
Vy Do Uyen Vu
Scott B. Snapper
Anne Galy
Luigi D. Notarangelo
Frederic D. Bushman
David A. Williams
Sung-Yun Pai
Type
Resource Types::text::journal::journal article
Abstract
<jats:title>Abstract</jats:title>
<jats:p>Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein–expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10–producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.</jats:p>
<jats:p>Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein–expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10–producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.</jats:p>
Subjects
eczema
;
genetic therapy
;
hematopoietic stem cell transplantation
;
hematopoietic stem cells
;
humans
;
wiskott-aldrich syndrome
;
wiskott-aldrich syndrome protein
;
antibiotic agent
;
busulfan
;
complementary dna
;
corticosteroid
;
dactinomycin
;
fludarabine
;
immunoglobulin
;
interleukin 10
;
lentivirus vector
;
pneumococcus vaccine
;
rituximab
;
romiplostim
;
steroid
;
vincristine
;
wiskott aldrich syndrome protein
;
wiskott aldrich syndrome protein
;
article
;
autoimmune disease
;
autoimmunity
;
bleeding tendency
;
bone marrow cell
;
cancer combination chemotherapy
;
cancer radiotherapy
;
cellular immunity
;
child
;
clinical article
;
controlled study
;
cytoskeleton
;
disease exacerbation
;
drug safety
;
eczema
;
epstein barr virus infection
;
feasibility study
;
follow up
;
gene dosage
;
gene therapy
;
genetic transduction
;
genotoxicity
;
gingiva bleeding
;
graft versus host reaction
;
hematopoietic stem cell transplantation
;
human
;
human cell
;
humoral immunity
;
laboratory test
;
male
;
medical history
;
myeloablative conditioning
;
nonhuman
;
open study
;
orchiectomy
;
phase 1 clinical trial
;
phase 2 clinical trial
;
pilot study
;
platelet count
;
pneumococcal infection
;
pre b lymphocyte
;
preschool child
;
promoter region
;
prophylaxis
;
protein expression
;
radical resection
;
rectum hemorrhage
;
recurrent disease
;
regulatory b lymphocyte
;
regulatory t lymphocyte
;
rhabdomyosarcoma
;
school child
;
superinfection
;
testis cancer
;
thrombocyte transfusion
;
viral gene delivery system
;
viral gene therapy
;
viremia
;
wiskott aldrich syndrome
;
eczema
;
gene therapy
;
genetics
;
hematopoietic stem cell
;
metabolism
;
procedures
;
wiskott aldrich syndrome