A novel xenograft mouse model for testing approaches targeting human kappa light-chain diseases.,Gene Therapy

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A novel xenograft mouse model for testing approaches targeting human kappa light-chain diseases.
Gene Therapy ( IF 4.6 ) Pub Date : 2019-03-29 , DOI: 10.1038/s41434-019-0070-y
Xun Ma ₁ , Ping Zhou ₁ , Adin Kugelmass ₁ , Denis Toskic ₁ , Melissa Warner ₁ , Lisa Lee _{1,

2} , Terry Fogaren _{1,

2} , Amandeep Godara _{1,

2} , Ming Wang ₃ , Yamin Li ₃ , Liu Yang ₃ , Qiaobing Xu ₃ , Raymond L Comenzo _{1,

2}

Affiliation

Patients with immunoglobulin (Ig) light-chain (LC) diseases such as LC light-chain amyloidosis die with organ failure and need new therapies. We sought a model to test anti-LC siRNA delivery to human plasma cells, requiring circulating LC, in vivo indicators of tumor presence, and capacity for multiple injections of delivery vehicle. The JJN-3 human myeloma reporter cell line expressing firefly luciferase (FFL) implanted intraperitoneally (IP) in the NOD scid γ (NSG) mouse has a 90% prompt tumor-take, rapid LC production, and in vivo indicators of tumor measurable on day 5 post-implant (κ LC, bioluminescent signal, and soluble B-cell maturation antigen [sBCMA]) with median day 5 serum levels of κ LC of 1482 ng/mL (range, 255-4831) and robust correlations with all in vivo indicators. In preliminary attempts to deliver siRNA against κ LC constant region mRNA, we identified the 306-O18B3 lipidoid nanoparticle (LNP) as promising, safe and efficient in vitro. In vivo in the JJN-3 NSG IP model, after daily IP 306-O18B3:siRNA injections on days 5-10, a reduction in κ LC was observed on day 8 between control and test groups that continued through day 12 at sacrifice. This model is potentially useful as a platform for refining anti-LC therapies.

中文翻译：

一种新颖的异种移植小鼠模型，用于测试针对人类κ轻链疾病的方法。

患有免疫球蛋白（Ig）轻链（LC）疾病（例如LC轻链淀粉样变性）的患者死于器官衰竭，需要新的疗法。我们寻求一种模型来测试将抗LC siRNA递送至人浆细胞的过程，需要循环LC，体内存在的肿瘤指示剂以及多次注射递送载体的能力。表达萤火虫荧光素酶（FFL）腹膜内（IP）植入NOD scidγ（NSG）小鼠的JJN-3人骨髓瘤报道细胞具有90％的迅速摄取肿瘤，快速产生LC和可在体内测量肿瘤的体内指标植入后第5天（κLC，生物发光信号和可溶性B细胞成熟抗原[sBCMA]），第5天的κLC中位数为1482 ng / mL（范围255-4831），并且与所有体内指标。在针对κLC恒定区mRNA传递siRNA的初步尝试中，我们将306-O18B3类脂质纳米颗粒（LNP）确定为有希望的，安全的和有效的体外。在JJN-3 NSG IP模型的体内，在第5-10天每天注射IP 306-O18B3：siRNA后，对照组和测试组之间在第8天观察到κLC的降低，并持续到第12天。该模型可能作为改进抗LC治疗的平台有用。

更新日期：2019-11-18

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