Novel nanopolymer RNA therapeutics normalize human diabetic corneal wound healing and epithelial stem cells,Nanomedicine: Nanotechnology, Biology and Medicine

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Novel nanopolymer RNA therapeutics normalize human diabetic corneal wound healing and epithelial stem cells
Nanomedicine: Nanotechnology, Biology and Medicine ( IF 4.2 ) Pub Date : 2020-11-10 , DOI: 10.1016/j.nano.2020.102332
Andrei A Kramerov ₁ , Ruchi Shah ₁ , Hui Ding ₂ , Eggehard Holler ₂ , Sue Turjman ₃ , Yaron S Rabinowitz ₄ , Sean Ghiam ₅ , Ezra Maguen ₆ , Clive N Svendsen ₇ , Mehrnoosh Saghizadeh ₈ , Julia Y Ljubimova ₉ , Alexander V Ljubimov ₁₀

Affiliation

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
American Eye Institute, Los Angeles, CA, USA.
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Human diabetic corneas develop delayed wound healing, epithelial stem cell dysfunction, recurrent erosions, and keratitis. Adenoviral gene therapy modulating c-Met, cathepsin F and MMP-10 normalized wound healing and epithelial stem cells in organ-cultured diabetic corneas but showed toxicity in stem cell-enriched cultured limbal epithelial cells (LECs). For a safer treatment, we engineered a novel nanobiopolymer (NBC) that carried antisense oligonucleotide (AON) RNA therapeutics suppressing cathepsin F or MMP-10, and miR-409-3p that inhibits c-Met. NBC was internalized by LECs through transferrin receptor (TfR)-mediated endocytosis, inhibited cathepsin F or MMP-10 and upregulated c-Met. Non-toxic NBC modulating c-Met and cathepsin F accelerated wound healing in diabetic LECs and organ-cultured corneas vs. control NBC. NBC treatment normalized levels of stem cell markers (keratins 15 and 17, ABCG2, and ΔNp63), and signaling mediators (p-EGFR, p-Akt and p-p38). Non-toxic nano RNA therapeutics thus present a safe alternative to viral gene therapy for normalizing diabetic corneal cells.

中文翻译：

新型纳米聚合物 RNA 疗法使人类糖尿病角膜伤口愈合和上皮干细胞正常化

人类糖尿病角膜会出现伤口愈合延迟、上皮干细胞功能障碍、反复糜烂和角膜炎。调节 c-Met、组织蛋白酶 F 和 MMP-10 的腺病毒基因疗法使器官培养的糖尿病角膜中的伤口愈合和上皮干细胞正常化，但在富含干细胞的培养的角膜缘上皮细胞 (LEC) 中显示出毒性。为了更安全的治疗，我们设计了一种新型纳米生物聚合物 (NBC)，它携带抑制组织蛋白酶 F 或 MMP-10 的反义寡核苷酸 (AON) RNA 疗法，以及抑制 c-Met 的 miR-409-3p。NBC 通过转铁蛋白受体 (TfR) 介导的内吞作用被 LEC 内化，抑制组织蛋白酶 F 或 MMP-10 并上调 c-Met。无毒 NBC 调节 c-Met 和组织蛋白酶 F 加速了糖尿病 LEC 和器官培养角膜的伤口愈合。控制全国广播公司。NBC 治疗使干细胞标记物（角蛋白 15 和 17、ABCG2 和 ΔNp63）和信号传导介质（p-EGFR、p-Akt 和 p-p38）水平正常化。因此，无毒的纳米 RNA 疗法为使糖尿病角膜细胞正常化提供了一种安全的病毒基因疗法替代方案。

更新日期：2020-12-03

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