Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency

Shaw, Kit L.; Garabedian, Elizabeth; Mishra, Suparna; Barman, Provaboti; Davila, Alejandra; Carbonaro, Denise A.; Shupien, Sally; Silvin, Christopher; Geiger, Sabine; Nowicki, B; Smogorzewska, E; Brown, Berkley; Wang, Xiaoyan; Oliveira, Satiro N. De; Choi, Yeong; Ikeda, Alan K.; Terrazas, Dayna; Fu, Pei Yu; Yu, Allen Chi Shing; Fernandez, Beatriz Campo; Cooper, Aaron; Engel, Barbara C.; Podsakoff, Greg M.; Balamurugan, Arumugam; Anderson, Stacie M.; Muul, Linda; Jagadeesh, G. Jayashree; Kapoor, Neena; Tse, Justin R.; Moore, Theodore B.; Purdy, Ken; Rishi, Radha; Mohan, Kathleen M.; Skoda-Smith, Suzanne; Buchbinder, David; Abraham, Roshini S.; Scharenberg, Andrew M.; Yang, Otto O.; Cornetta, Kenneth; Gjertson, David W.; Hershfield, Michael S.; Sokolic, Robert A.; Candotti, Fabio; Kohn, Donald B.

doi:10.1172/jci90367

Cited by 76 publications

(66 citation statements)

References 34 publications

(44 reference statements)

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“…At least 20 genes have been associated with SCID [1]. Currently, curative treatments such as hematopoietic stem cell transplantation (HSCT) [2][3][4] and gene therapy [5][6][7] can improve a patient's outcome if the treatment can be initiated before severe infections occur. Previously, a significant number of children with SCID would die before a diagnosis was made [8] or before a curative treatment could be administered [2,9,10].…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

Chien

Lee

et al. 2017

IJNS

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A study of newborn screening for severe combined immunodeficiency (SCID) by detecting the T-cell receptor excision circle (TRECs) copy number in dried blood spots (DBSs) collected from newborns 3 days of age began in 2010 in Taiwan, and SCID screening was subsequently implemented country-wide in 2012. A total of 920,398 newborns were screened during a period of 78 months. Of these, 175 newborns (0.02%) were requested to undergo an immune function survey, and 136 cases (1 in 6768 newborns) were ultimately diagnosed as having T cell lymphopenia. The screening detected seven cases of typical SCID, with an incidence of 1 in 131,485 newborns (95% confidence interval, 1/63,693~1/271,434). Hematopoietic stem cell transplantation was performed in six patients before overt infection occurred, and the survival rate was 100%. The screening also detected eight cases of SCID variants and 20 cases of 22q11.2 deletion syndrome. Other etiologies of T lymphopenia were identified, and those newborns were evaluated and managed according to their immunological status. Owing to the introduction of newborn screening by measuring the TREC copy number, early administration of treatments became possible for newborns with conditions that put them at risk of primary or secondary immunodeficiency.

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Section: Introductionmentioning

confidence: 99%

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

Chien

Lee

et al. 2017

IJNS

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“…Rapid identification of ADA deficiency allows prompt initiation of enzyme replacement therapy and consideration for gene therapy [34][35][36] . Gene therapy may also be offered as a treatment option for X-linked SCID [37][38] . Finally, having a molecular diagnosis allows for risk stratification with regard to late effects following transplantation.…”

Section: Genetic Counselingmentioning

confidence: 99%

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

Heimall¹

2018

J Pediatrics & Pediatr Med

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Severe combined immunodeficiency (SCID) is a group of the most severe of primary immunodeficiencies and is typically fatal in the first year of life without hematopoietic cell transplantation (HCT). Improved transplantation techniques and supportive care measures have resulted in improved survival following HCT. Furthermore, patients are being diagnosed earlier since the widespread implementation of SCID newborn screening in the United States and moving on to transplantation before 3.5 months of age. As such, most SCID patients are now expected to live well into adulthood following successful HCT. Many centers are using conditioning with alkylating agents, including busulfan and melphalan, pre-transplantation to achieve full T and B cell immune reconstitution; however, significant concerns remain regarding the attendant risks of using chemotherapeutic agents in early infancy. Several long-term follow-up studies have demonstrated high rates of non-immunologic late effects depending on the conditioning regimen employed and SCID genotype. The full risk of conditioning in this patient population remains incompletely characterized, and further research on post-HCT outcomes is needed. It is imperative that all providers caring for SCID survivors both in childhood and adulthood be aware of the risk of late effects. Guidelines for long-term follow-up were recently published, and the recommendations are briefly summarized here.

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“…5 The remaining 10 patients were treated on a new trial using only the MND-ADA vector (the "400 series": 401-410), which has performed better in the laboratory and in patients than vectors more closely related to murine leukemia virus. 5,8,35 Molecular methods were designed to detect both vectors with equal efficiency, and except where noted, integrations of the 2 vectors are reported together. Cumulatively across all patients and samples, we sequenced 91 680 integration sites with 49 612 692 sequence reads.…”

Section: Integration Preferences and Common Insertion Sites (Ciss) Ofmentioning

confidence: 99%

“…Notably, the 3 patients with the highest diversity (404, 408, and 410) are the only ones with sufficient B-cell reconstitution to permit discontinuation of gammaglobulin replacement. 8 …”

Section: Clonal Diversity Varies Widely Between Patientsmentioning

confidence: 99%

“…[2][3][4][5][6][7][8] In contrast to the patients in the trial reported herein and despite the similarity between the retroviral vector backbones used, the majority of patients in a clinical trial for Wiskott-Aldrich syndrome (WAS) developed leukemias after treatment. 9,10 Other retroviral trials for SCID-X1 and chronic granulomatous disease (CGD) using vectors based on murine leukemia virus or spleen focus forming virus have also observed vector-related leukemias and dysplastic events.…”

Section: Introductionmentioning

confidence: 96%

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Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients

Cooper

Lill²,

Shaw³

et al. 2017

Blood

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Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency

Abstract: Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.

Cited by 76 publications

References 34 publications

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients

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