Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

Cavazzana, Marina; Six, Emmanuelle; Lagresle-Peyrou, Chantal; André-Schmutz, Isabelle; Hacein‐Bey‐Abina, Salima

doi:10.1089/hum.2015.137

Cited by 97 publications

(52 citation statements)

References 81 publications

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“…Ex vivo HSC gene therapy clinical trials involving SCID-X1 patients are demonstrating clear clinical benefits (reviewed by Cavazzana et al 45 ) but require elaborate protocols, sophisticated facilities, and gentotoxic conditioning. Here, we propose a simpler, safer, and more versatile gene therapy approach to SCID-X1 that involves the direct IV injection of FV vectors with no prior conditioning regimen.…”

Section: Discussionmentioning

confidence: 99%

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

et al. 2018

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“…In addition, Southern blot analysis of human genomic DNA failed to demonstrate any significant homology with Moloney virus. Also, unlike X-SCID [6]—which is a single inherited gene disorder (mutation of γ c -encoding gene) occurring in infants/young children where retroviral vectors were used for the integration of the functional copy of γ c gene into the genome of CD34+ hematopoietic stem/progenitor cells [30]—the Chiron gene therapy products were used in adults for the treatment of HIV, cancer, or hemophilia (11 studies). Furthermore, the gene therapies were either injected directly into the tumor, administered as intramuscular or intravenous injections, or used to transfect PBMCs that were non-stem cell in origin.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Safety Follow-Up of Subjects Previously Treated with Non-Replicating Retroviral Vector-Based Gene Therapies

et al. 2016

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ObjectiveOur objective was to evaluate the life-long safety profile of gene therapy using retroviral (non-replicating) vectors (nRCR), or cell products in 127 subjects with hemophilia, human immunodeficiency virus (HIV), or cancer, previously treated with such gene therapy.MethodsWe assessed the occurrence of serious adverse events (SAEs), deaths and presence of replication competent retrovirus (RCR).ResultsA total of 23 subjects remained until the data cut-off date of 31 July 2013 and provided safety information of up to 18 years. Of the 104 subjects who discontinued, the primary reason was loss to follow-up (47.2 %; n = 60). The follow-up period for the 60 subjects lost to follow-up was 7–10 years. A total of 41 subjects experienced at least one SAE, and 15 subjects died. We reviewed SAEs and cause of death (none related to the active therapy), but no evidence was found for safety signals related to new malignancy or neurologic, rheumatological, autoimmune, or hematologic disorder. RCR results were negative, indicating no evidence for in vivo vector persistence.ConclusionDespite the loss of follow-up, which is the limiting factor in this long-term safety trial, the findings from this long-term follow-up study are encouraging.

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“…Constitutive activation of the transgene 7 , the choice of vectors 8 and specific details of the gene therapy procedure have all been proposed as factors contributing to the risk of leukemia and myelodysplastic syndrome that occurred in several trials for primary immunodeficiency disorders (PIDs) including SCID-X1 9, 10 , chronic granulomatous disease (CGD) 11, 12 and Wiskott-Aldrich Syndrome (WAS) 13 . With 2 nd generation self-inactivating (SIN) vectors, multiple SCID-X1 patients have successfully reconstituted T-cell immunity in the absence of early leukemic events 14,15,16 with a follow up of up to 7 years. However, the follow-up of these therapies remains too short to assess the long-term genotoxicity risk of the newer generation vectors, as transformation of T-4 cells growth can take more than 10 years to manifest (Six, E., et al, Abstract #753, ASGCT Meeting, 2017).One strategy to convert the semi-random delivery and integration of a corrective IL2RG cDNA into the genome is through a genome editing (GE) approach.…”

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confidence: 99%

Gene Correction for SCID-X1 in Long-Term Hematopoietic Stem Cells

Pavel-Dinu

Wiebking

Dejene

et al. 2018

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Gene correction in human long-term hematopoietic stem cells (LT-HSCs(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/397463 doi: bioRxiv preprint first posted online Aug. 22, 2018; 2 evidence of abnormal hematopoiesis following transplantation, a functional measure of the lack of genotoxicity. Deep analysis of potential off-target activity detected two sites with low frequency (<0.3%) of off-target mutations. The level of off-target mutations was reduced to below the limit of detection using a high fidelity Cas9.Moreover, karyotype evaluation identified no genomic instability events. We achieved high levels of genome targeting frequencies (median 45%) in CD34 + HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect of patient derived cells both in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.X-linked severe combined immunodeficiency (SCID-X1) is a rare, primary immune deficiency (PID) caused by mutations in the IL2RG gene on the X-chromosome.The gene encodes a shared subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Without early treatment, affected male infants die in the first year of life from infections. Although allogeneic hematopoietic cell transplant (allo-HCT) is considered the standard of care for SCID-X1, it holds significant risks due to potential incomplete immune reconstitution, graft versus host disease (GvHD) and a decreased survival rate in the absence of an HLA-matched sibling donor 1 . Importantly, because of the selective advantage of lymphoid progenitors expressing normal IL2RG, only a small number of genetically corrected hematopoietic stem and progenitor cells (HSPCs) are needed to reconstitute T-cell immunity. The selective advantage has been demonstrated both by allo-HCT and by rare experiments of nature, in which a spontaneous reversion in a hematopoietic progenitor gives rise to a functional T-cell repertoire in a SCID-X1 patient 2,3 . The rare patients with reversion mutations and patients who received allo-HCT . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/397463 doi: bioRxiv preprint first posted online Aug. 22, 2018; 3 without giving conditioning chemotherapy also highlights the importance of achieving gene correction in long-term hematopoietic stem cells (LT-HSCs) to achieve sustained clinical benefit as patients who do not have corrected LT-HSC engraftment often end up losing a robust and functional T-cell immune system over time.Gene therapy is an alternative therapy to allo-HSCT. Using integrating viral vectors, such as gamma-retroviral and lentiviral vectors, extra copie...

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Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

Cited by 97 publications

References 81 publications

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

Long-Term Safety Follow-Up of Subjects Previously Treated with Non-Replicating Retroviral Vector-Based Gene Therapies

Gene Correction for SCID-X1 in Long-Term Hematopoietic Stem Cells

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