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GENOMICS AND GENE THERAPY

Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS)

Leukemia volume 36, pages 525–531 (2022)Cite this article

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Abstract

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare, aggressive, fatal disease characterized by blood eosinophilia and dysfunction of organs infiltrated with eosinophils. Clinically, the disease manifests with weight loss, cough, weakness, diarrhea, and multi-organ dysfunction that is unresponsive to therapy. We developed a one-time gene therapy for CEL-NOS using an adeno-associated virus (AAV) expressing an anti-eosinophil monoclonal antibody (AAVrh.10mAnti-Eos) to provide sustained suppression of eosinophil numbers in blood, thus reducing eosinophil tissue invasion and organ dysfunction. A novel CEL-NOS model was developed in NOD-scid IL2rγnull (NSG) mice by administration of AAV expressing the cytokine IL5 (AAVrh.10mIL5), resulting in marked peripheral and tissue eosinophilia of the heart, lung, liver, and spleen, and eventually death. Mice were administered AAVrh.10mAnti-Eos (1011 genome copies) 4 wk after administration of AAVrh.10mIL5 and evaluated for anti-eosinophil antibody expression, blood eosinophil counts, organ eosinophil invasion, and survival. AAVrh.10mAnti-Eos expressed persistent levels of the anti-eosinophil antibody for >24 wk. Strikingly, CEL-NOS treated mice had markedly lower blood eosinophil levels and reduced mortality when compared with control treated mice. These results suggest that a single treatment with AAVrh.10mAnti-Eos has the potential to provide substantial therapeutic benefit to patients with CEL-NOS, a fatal malignant disorder.

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Fig. 1: Murine model of CEL-NOS treated with AAVrh.10mAnti-Eos in NSG male mice.
Fig. 2: Murine model of CEL-NOS treated with AAVrh.10mAnti-Eos in NSG female mice.
Fig. 3: Male and female NSG CEL-NOS mice organ weights following AAVrh.10mAnti-Eos therapy.
Fig. 4: Survival of CEL-NOS NSG murine model mice treated with AAVrh.10mAnti-Eos.

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Acknowledgements

We thank S Duan and J Paulson (Scripps Research Institute) for providing the sequence of the anti-Siglec-F antibody and N Mohamed for editorial assistance. These studies were supported, in part, by the Department of Genetic Medicine, Weill Cornell Medicine.

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  1. These authors contributed equally: Odelya E. Pagovich, Katie M. Stiles.

Authors and Affiliations

  1. Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA

    Odelya E. Pagovich, Katie M. Stiles, Anna E. Camilleri, Anthony R. Russo, Saparja Nag & Ronald G. Crystal

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Contributions

ARR and SN: performed experimental work and data analysis/interpretation, reviewed manuscript for content. AC: performed experimental work and data analysis/interpretation, participated in the study design, prepared manuscript. RGC, OEP, and KMS: conceived study, performed data analysis/interpretation, prepared manuscript

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Correspondence to Ronald G. Crystal.

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Pagovich, O.E., Stiles, K.M., Camilleri, A.E. et al. Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS). Leukemia 36, 525–531 (2022). https://doi.org/10.1038/s41375-021-01400-4

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