Anti-human CD117 antibody-mediated bone marrow niche clearance in nonhuman primates and humanized NSG mice

Kwon, Hye-Sook; Logan, Aaron C.; Chhabra, Akanksha; Pang, Wendy W.; Czechowicz, Agnieszka; Tate, Keri; Le, Alan; Poyser, Jessica; Hollis, Roger P.; Kelly, Benjamin V.; Kohn, Donald B.; Weissman, Irving L.; Prohaska, Susan; Shizuru, Judith A.

doi:10.1182/blood-2018-06-853879

Cited by 70 publications

(58 citation statements)

References 23 publications

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“…Although myeloablative condi-tioning by TBI was performed in our study to facilitate engraftment of edited cells, clinical translation of this approach will require reduced-intensity conditioning regimens to minimize toxicity without compromising engraftment. For example, antibody-drug conjugates (ADCs) offer a nongenotoxic strategy to specifically target HSCs in the BM niche, and recent studies using anti-CD117 ADCs have demonstrated feasibility of this approach (34,35).…”

Section: Discussionmentioning

confidence: 99%

Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates

et al. 2019

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Reactivation of fetal hemoglobin (HbF) is being pursued as a treatment strategy for hemoglobinopathies. Here, we evaluated the therapeutic potential of hematopoietic stem and progenitor cells (HSPCs) edited with the CRISPR-Cas9 nuclease platform to recapitulate naturally occurring mutations identified in individuals who express increased amounts of HbF, a condition known as hereditary persistence of HbF. CRISPR-Cas9 treatment and transplantation of HSPCs purified on the basis of surface expression of the CD34 receptor in a nonhuman primate (NHP) autologous transplantation model resulted in up to 30% engraftment of gene-edited cells for >1 year. Edited cells effectively and stably reactivated HbF, as evidenced by up to 18% HbF-expressing erythrocytes in peripheral blood. Similar results were obtained by editing highly enriched stem cells, defined by the markers CD34+CD90+CD45RA−, allowing for a 10-fold reduction in the number of transplanted target cells, thus considerably reducing the need for editing reagents. The frequency of engrafted, gene-edited cells persisting in vivo using this approach may be sufficient to ameliorate the phenotype for a number of genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates

et al. 2019

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“…A humanized anti-CD117 mAb, AMG 191 has been developed and is currently undergoing testing as sole conditioning for patients with SCID. Large animal studies support the safety and efficacy of this agent in depleting HSC (38). Early data from the Phase 1 dose escalation trial show proof-of-concept that targeting CD117 with biologic agents may provide a strategy for safely replacing and/or augmenting the myeloablative component of conditioning (39).…”

Section: Emerging Types Of Conditioning For the (Near) Futurementioning

confidence: 91%

Conditioning Perspectives for Primary Immunodeficiency Stem Cell Transplants

et al. 2019

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The majority of children undergoing Hematopoietic Stem cell Transplantation (HSCT) require conditioning therapy to make space and prevent rejection of the donor stem cells. The exception is certain children with Severe Combined immune deficiency, who have limited or no ability to reject the donor graft. Transplant conditioning is associated with significant morbidity and mortality from both direct toxic effects of chemotherapy as well as opportunistic infections associated with profound immunosuppression. The ultimate goal of transplant practice is to achieve sufficient engraftment of donor cells to correct the underlying disease with minimal short- and long-term toxicity to the recipient. Traditional combinations, such as busulfan and cyclophosphamide, achieve a high rate of full donor engraftment, but are associated with significant acute transplant-related-mortality and late effects such as infertility. Less “intensive” approaches, such as combinations of treosulfan or melphalan with fludarabine, are less toxic, but may be associated with rejection or low level chimerism requiring the need for re-transplantation. The major benefit of these novel approaches, however, which we hope will be realized in the decades to come, may be the preservation of fertility. Future approaches look to replace chemotherapy with non-toxic antibody conditioning. The lessons learnt in refining conditioning for HSCT are likely to be equally applicable to gene therapy protocols for the same diseases.

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“…Though this regimen has less extra‐medullary toxicity, the investigators also infused a target dose of autologous 5 × 10 7 /kg CD3+ cells intravenously on day +3, to overcome the added immunosuppression related to this regimen 33 . Busulfan remains the favored drug in TDT clinical trials currently, till other non‐chemotherapeutic agents are shown to be efficacious for myeloablation (eg, antibodies to stem cells niches or hematopoietic markers, for example, anti‐CD45, anti‐CD117 with or without anti‐CD47) 94,95 …”

Section: Methodsmentioning

confidence: 99%

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

Soni

2020

American J Hematol

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Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of β‐globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene editing strategies now allow for efficient ex‐vivo genetic manipulation of human stem cells that can lead to production of hemoglobin, leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene‐therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase clinical trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β‐thalassemia.

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Anti-human CD117 antibody-mediated bone marrow niche clearance in nonhuman primates and humanized NSG mice

Cited by 70 publications

References 23 publications

Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates

Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates

Conditioning Perspectives for Primary Immunodeficiency Stem Cell Transplants

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

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