Busulfan Combined with Immunosuppression Allows Efficient Engraftment of Gene-Modified Cells in a Rhesus Macaque Model

Uchida, Naoya; Nassehi, Tina; Drysdale, Claire; Gamer, Jackson; Yapundich, Morgan; Bonifacino, Aylin; Krouse, Allen E.; Linde, Nathaniel S.; Hsieh, Matthew M.; Donahue, Robert E.; Dunbar, Cynthia E.; Kean, Leslie S.; Tisdale, John F.

doi:10.1016/j.ymthe.2019.05.022

Cited by 29 publications

(33 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite having high indel rates (84.9%) in the infusion product of ZM26, and robust ex vivo γ-globin induction (65.9% vs. 24.7% in nonedited control), there was a significant drop in the indel frequencies (~25%-30%) at 4 weeks after transplantation that stabilized to about 5%-16% at 28 weeks after transplantation ( Figure 2A and Supplemental Figure 6, A-C). For prior efficient autologous reconstitution by gene-marked HSCs after lentiviral gene transfer, we infused cell products of at least approximately 3 × 10 6 CD34 + HSPCs/kg (28,29). The relatively low infused HSPC number of 1.78 × 10 6 CD34 + HSPCs/kg could have contributed to inefficient autologous engraftment of the edited cells (Table 1).…”

Section: Resultsmentioning

confidence: 99%

BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Demirci

Zeng

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Demirci

Zeng

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…Moreover, although there is no risk of GVHD for auto‐HSCT, prophylactic immunosuppression may still be necessary to address possible immune responses to the “normal” or modified transgene product, or to residual editing reagents, such as Cas9, especially when busulfan is used for conditioning, which is myeloablative but not immunosuppressive . The potential immunogenicity of gene modified cells in the context of autologous transplant was recently investigated by Uchida et al in nonhuman primates and will remain an important consideration in the development of such approaches.…”

Section: Medical and Procedural Risks Of Hsctmentioning

confidence: 99%

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Talib

Shepard

2020

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life‐threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM‐funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit.

show abstract

“…In addition, transgenic proteins can be processed by antigen-presenting cells and displayed by MHC class II, leading to activation of B-cell-mediated humoral responses with transgene-specific antibody production. When immunological rejection occurrs against transduced cells expressing intracellular GFP, both GFP-specific cytotoxic T lymphocyte (CTL) responses and antibody production are observed in a rhesus gene therapy model 15, 16, 17, 18. Both cellular and humoral immunoresponses are associated with HSC-targeted gene therapy; however, the type and strength of immunoresponses may depend on multiple factors, such as localization and immunogenicity of transgene products as well as tissue specificity and levels of transgene expression.…”

Section: Introductionmentioning

confidence: 99%

“…High-dose total body irradiation (TBI), which is both myelosuppressive and immunosuppressive, has been shown to produce stable engraftment of gene-modified HSCs (Figure 1A) 25, 26, 27. When employing busulfan conditioning, which is primarily myelosuppressive, the degree of dissimilarity between unmodified and modified cells appears to dictate the likelihood of a transgene-specific immunoresponse 17 . Myeloablative busulfan conditioning alone permits engraftment of HSCs expressing minimally immunogenic proteins, but it does not necessarily prevent immunoresponses to xenogenic or congenitally absent proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Myeloablative busulfan conditioning alone permits engraftment of HSCs expressing minimally immunogenic proteins, but it does not necessarily prevent immunoresponses to xenogenic or congenitally absent proteins. In these situations, additional immunosuppression may be necessary 17 Figure 1Concept of Immunoresponse to Gene-Modified HSCs(A) Intensities of myelosuppression and immunosuppression among conditioning regimens.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunoresponse to Gene-Modified Hematopoietic Stem Cells

Drysdale

Tisdale

Uchida

2020

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

Gene transfer to and correction of hematopoietic stem cells (HSCs) are ideal strategies to cure a number of congenital and acquired disorders. However, transgene products may trigger immunological rejection of modified cells, limiting their therapeutic benefits. Preclinical and clinical data indicate that myeloablative total body irradiation (TBI) allows for efficient engraftment and tolerance to gene-modified HSCs. In contrast, myeloablative chemotherapy using busulfan or similar agents is only sufficient to induce tolerance to genemodified HSCs producing no or non-immunogenic protein. If cells are modified to produce a protein that is xenogenic or congenitally absent in the patient, additional immunosuppression may be required to prevent an immunological reaction to the transduced cells. New gene editing and in vivo gene therapy techniques could pose additional immune concerns compared to ex vivo gene therapy methods. This review is intended to guide the design of conditioning and immunosuppression therapy in HSC-targeted gene therapy, as well as gene editing.

show abstract

Busulfan Combined with Immunosuppression Allows Efficient Engraftment of Gene-Modified Cells in a Rhesus Macaque Model

Cited by 29 publications

References 32 publications

BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Immunoresponse to Gene-Modified Hematopoietic Stem Cells

Contact Info

Product

Resources

About