Gene therapy in a murine model of chronic eosinophilic leukemia-not otherwise specified (CEL-NOS)
| Autor: | Odelya E. Pagovich, Anthony R. Russo, Katie M. Stiles, Saparja Nag, Ronald G. Crystal, Anna E Camilleri |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Genetic enhancement Spleen Mice SCID Mice Mice Inbred NOD Hypereosinophilic Syndrome Eosinophilic medicine Animals Eosinophilia Chronic eosinophilic leukemia Leukemia biology business.industry Organ dysfunction Antibodies Monoclonal Genetic Therapy Hematology Dependovirus respiratory system Eosinophil medicine.disease Eosinophils Disease Models Animal medicine.anatomical_structure Oncology Immunology biology.protein Female Interleukin-5 Antibody medicine.symptom business |
| Zdroj: | Leukemia. 36:525-531 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-021-01400-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink