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 IL2rγ^null (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.

慢性嗜酸性粒细胞白血病 - 未另行说明 (CEL-NOS) 是一种罕见的侵袭性致命性疾病，其特征是血液嗜酸性粒细胞增多和嗜酸性粒细胞浸润的器官功能障碍。临床上，该疾病表现为体重减轻、咳嗽、虚弱、腹泻和对治疗无反应的多器官功能障碍。我们使用表达抗嗜酸性粒细胞单克隆抗体 (AAVrh.10mAnti-Eos) 的腺相关病毒 (AAV) 开发了一种针对 CEL-NOS 的一次性基因疗法，以持续抑制血液中的嗜酸性粒细胞数量，从而减少嗜酸性粒细胞组织侵袭和器官功能障碍。在 NOD-scid IL2rγ ^null中开发了一种新的 CEL-NOS 模型(NSG) 小鼠通过给予表达细胞因子 IL5 (AAVrh.10mIL5) 的 AAV，导致心脏、肺、肝脏和脾脏的明显外周和组织嗜酸性粒细胞增多，并最终死亡。给小鼠施用 AAVrh.10mAnti-Eos (10 ¹¹基因组拷贝）AAVrh.10mIL5 给药后 4 周，并评估抗嗜酸性粒细胞抗体表达、血液嗜酸性粒细胞计数、器官嗜酸性粒细胞侵袭和存活率。AAVrh.10mAnti-Eos 表达持续水平的抗嗜酸性粒细胞抗体 > 24 周。引人注目的是，与对照治疗的小鼠相比，CEL-NOS 治疗的小鼠血液嗜酸性粒细胞水平显着降低，死亡率降低。这些结果表明，AAVrh.10mAnti-Eos 的单次治疗有可能为 CEL-NOS（一种致命的恶性疾病）患者提供实质性的治疗益处。