Lentiviral gene therapy for X-linked chronic granulomatous disease

Kohn, Donald B.; Booth, Claire; Kang, Elizabeth M.; Pai, Sung-Yun; Shaw, Kit L.; Santilli, Giorgia; Armant, Myriam; Buckland, Karen F.; Choi, Uimook; Ravin, Suk See De; Dorsey, Morna J.; Kuo, Caroline Y.; León-Rico, Diego; Rivat, Christine; Izotova, Natalia; Gilmour, Kimberly; Snell, Katie; Dip, Jinhua Xu-Bayford; Darwish, Jinan; Morris, Emma; Terrazas, Dayna; Wang, Leo D.; Bauser, Christopher A.; Paprotka, Tobias; Kuhns, Douglas B.; Gregg, John T.; Raymond, Hayley E.; Everett, J.K.; Honnet, Géraldine; Biasco, Luca; Newburger, Peter E.; Bushman, Frederic D.; Grez, Manuel; Gaspar, H. Bobby; Williams, David A.; Malech, Harry L.; Galy, Anne; Thrasher, Adrian J.

doi:10.1038/s41591-019-0735-5

Cited by 203 publications

(160 citation statements)

References 33 publications

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“…The ultimate goal for future gene therapies would be to transplant HSPCs with an engraftment advantage into a nonconditioned patient to avoid toxicity of the conditioning regimen. Currently, a complete myeloablative conditioning regimen is applied to X-CGD patients prior to infusion of gene-corrected cells to promote their long-term engraftment [ 9 ]. As a complete myeloablative conditioning regimen is quite toxic to the patient and can cause multiorgan damage, infertility, and secondary malignancies [ 51 , 52 ], long-term engraftment of corrected HSPCs without or after a reduced-intensity conditioning regimen is desirable for future gene therapies.…”

Section: Discussionmentioning

confidence: 99%

“…As many X-CGD patients lack a matched donor, other treatment strategies are required for these patients [ 7 , 8 ]. An alternative treatment option is retroviral gene therapy of hematopoietic stem cells (HSCs), which is tested in clinical trials [ 9 ]. Previous trials used LTR-driven gamma-retroviral vectors to deliver the therapeutic transgene and a partial myeloablative conditioning regimen to create space in the bone marrow niche, but resulted in only a short-term clinical benefit [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the clearance of pre-existing, refractory infections in some patients, the trials were hampered by the occurrence of insertional mutagenesis, transgene silencing, and lack of long-term engraftment [ 13 ]. To address these limitations, a self-inactivating (SIN) lentiviral vector with a myeloid-specific promoter and a complete myeloablative conditioning is used in a current clinical trial for X-CGD [ 9 ]. Preliminary results of this study demonstrated improved and prolonged presence of NADPH oxidase-positive neutrophils as well as polyclonal engraftment of corrected HSCs.…”

Section: Introductionmentioning

confidence: 99%

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Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Klatt

Schinke

et al. 2020

Cells

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Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Klatt

Schinke

et al. 2020

Cells

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“…Eine Gentherapie mit einem selbstinaktivierenden lentiviralen Vektor zeigte in den ersten Studien erfolgversprechende Resultate, wobei der langfristige Verlauf noch evaluiert werden muss [15]. Da man auch für die Gentherapie eine Konditionierung benötigt und man durch die HSZT dem Patienten eine bessere Produktion von reaktiven Sauerstoffmetaboliten als bei der Gentherapie ermöglicht, ist zurzeit die HSZT zu bevorzugen.…”

Section: Diskussionunclassified

Septische Granulomatose als seltene Differenzialdiagnose rezidivierender pulmonaler Infektionen bei Erwachsenen

et al. 2020

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ZusammenfassungDie septische Granulomatose (engl.: chronic granulomatous disease, CGD) ist bei Kindern und Jugendlichen mit häufigen Infektionen durch bestimmte Erreger differenzialdiagnostisch zu berücksichtigen.In vorliegender Kasuistik berichten wir über eine 64-jährige Patientin mit über Jahre zunehmenden bronchopulmonalen Infektionen, teilweise durch seltene Erreger, Autoimmunphänomenen, Malignomen und im weiteren Verlauf rezidivierenden organisierenden Pneumonien (OP) mit Nachweis von Granulomen. Ursächlich wurde bei der Patientin eine septische Granulomatose, Unterform p47phox-Defizienz diagnostiziert. Ein Überleben von Patienten mit einem primären Immundefekt (PID) bis ins hohe Erwachsenenalter wird trotz wiederholter Komplikationen in Einzelfällen beobachtet, insbesondere wenn die defekte Zellstruktur eine Restaktivität aufweist. Bei rezidivierenden bronchopulmonalen Infektionen insbesondere durch bestimmte seltene Erreger und in Kombination mit organisierend-granulomatösen Lungenreaktionen sowie Autoimmunphänomenen ist auch bei älteren Erwachsenen an eine CGD zu denken. Durch eine Diagnoseverzögerung kommt es oft zu einem erheblichen Anstieg der Morbidität und Mortalität.

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“…5 By improving safety features of viral vectors, current phase I/II gene therapy trials have been applied to the treatment of various PIDs, including adenosine deaminase-severe combined immunodeficiency (ADA-SCID), X linked-SCID (SCID-X1), chronic granulomatous disease (CGD) and Wiskott-Aldrich syndrome (WAS) with largely successful clinical outcomes. [6][7][8][9][10] Despite this, longterm safety/efficacy follow-up studies are still required for most of these gene therapy products to be approved as medicinal drugs, 11 as they come with some limitations, including the semirandom integration pattern of viral vectors and often unregulated transgene expression in transduced cells. 12 Precise targeting by means of gene editing has recently emerged as an alternative technology to overcome the limitations of conventional gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Gene Editing for the Treatment of Primary Immunodeficiency Diseases

2021

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With conventional treatments for primary immunodeficiency diseases (PIDs), such as allogeneic stem cell transplantation or autologous gene therapy, still facing important challenges, the rapid development of genome editing technologies to more accurately correct the mutations underlying the onset of genetic disorders has provided a new alternative, yet promising platform for the treatment of such diseases. The prospect of a more efficient and specific therapeutic tool has pushed many researchers to apply these editing tools to correct genetic, phenotypic, and functional defects of numerous devastating PIDs with extremely promising results to date. Despite these achievements, lingering concerns about the safety and efficacy of genome editing are currently being addressed in preclinical studies. This review summarizes the progress made toward the development of gene editing technologies to treat PIDs and the optimizations that still need to be implemented to turn genome editing into a next-generation treatment for rare monogenic life-threatening disorders.

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Lentiviral gene therapy for X-linked chronic granulomatous disease

Abstract: Peer Review Information: Kate Gao was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Cited by 203 publications

References 33 publications

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Septische Granulomatose als seltene Differenzialdiagnose rezidivierender pulmonaler Infektionen bei Erwachsenen

Gene Editing for the Treatment of Primary Immunodeficiency Diseases

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