Development of topical formulation of siRNA-nanoparticle for treating skin diseases

这一修订的第一阶段SBIR方案旨在开发siRNA纳米颗粒的局部配方 提供siRNA来治疗皮肤纤维化。我们的平台含有天然的抗氧化剂和消炎药。 性能，进一步有益于治疗皮肤纤维化，目前还没有有效的治疗方法。 完成后，该平台将具有广泛的适用性，因为siRNA可以被设计成敲打 任何导致其他疾病的基因，如牛皮癣、皮肤病和皮肤癌。 我们正在申请专利的输送平台是介孔二氧化硅纳米颗粒和共聚物的混合物 包被，比siRNA-Polyplex对应物更有效和更安全。初步数据 皮内注射siRNA-NP后显示出治疗皮肤纤维化的良好效果 老鼠。将在此第一阶段提案中开发的局部配方将显著减少患者 负担，因此是朝着这项技术的临床翻译迈出的不可或缺的一步。 目标1：我们将为局部siRNA-NP配方筛选合适的载体以最大限度地 三维人体皮肤模型中表皮和真皮的穿透性和siRNA敲除效率。 目的2：我们将应用优化的局部配方来传递针对HSP47的siRNA来治疗 3D人体皮肤模型中的纤维化和当前治疗(皮质类固醇)的基准。 目的3：将超声和靶向剂(抗EGFR抗体)应用于纳米颗粒 增强渗透率和细胞摄取，潜在地导致更大的治疗效果，这将 在活体小鼠研究中得到验证。 目的4：将在细胞系、3D人类皮肤和小鼠中进行初步毒性研究。 通过/不通过标准包括：1)有效的外用制剂，可穿透表皮和 真皮层，2)&GT；70%的靶基因(HSP47)下调，3)抗纤维化标志物的减少 (NOX4，α-SMA，COL I)和真皮厚度达到基线水平，4)和15%的非特异性细胞死亡， 5)比外用皮质类固醇的安全性和有效性更好。 该项目由PDX制药有限责任公司牵头，该公司是从生物医学工程公司剥离出来的公司 俄亥俄州立大学学部。该团队由siRNA的首席开发者NGamcherdtrakul博士组成。 作为纳米平台的联系人，Pi和Yantasee，博士，MBA，北京梅隆大学副教授 OHSU和俄勒冈州纳米医学的签名研究员作为OHSU的PI。哈迪，博士，前恶棍 ISIS制药公司总裁将担任我们的配方顾问。我们利用租用的空间 以及OHSU最先进的设备和OHSU医学院的临床专业知识。 Leachman教授，医学博士，OHSU皮肤科主任， 第一个针对遗传性皮肤病的人类siRNA将作为我们的临床顾问。

This revised Phase I SBIR proposal aims at developing a topical formulation of siRNA-nanoparticle that delivers siRNA to treat skin fibrosis. Our platform has inherent antioxidant and anti-inflammatory properties, further benefitting the treatment of skin fibrosis for which there is no effective treatment. Upon completion, the platform will have broad applicability since siRNA can be designed to knock down any gene responsible for other diseases, such as psoriasis, skin disorders, and skin cancers. Our patent-pending delivery platform is a hybrid of mesoporous silica nanoparticles and co-polymer coating, which is more effective and safer than the siRNA-polyplex counterpart. Preliminary data following intradermal injection of the siRNA-NP shows promising efficacy for treating skin fibrosis in mice. A topical formulation to be developed in this Phase I proposal will significantly reduce patient burden and thus is an integral step towards clinical translation of this technology. Aim 1: We will screen appropriate vehicles for a topical siRNA-NP formulation to maximize penetration to epidermis and dermis and siRNA knockdown efficacy in a 3D human skin model. Aim 2: We will apply the optimized topical formulation to deliver siRNA against HSP47 to treat fibrosis in a 3D human skin model and benchmark against a current treatment (corticosteroid). Aim 3: Ultrasound and targeting agent (anti-EGFR antibody) will be applied on the nanoparticle to enhance penetration and cellular uptake, potentially leading to greater treatment efficacy, which will be validated in in vivo mouse study. Aim 4: Preliminary toxicity studies in cell lines, 3D human skin, and mice will be performed. The Go/No-go criteria include 1) effective topical formulation that can penetrate both epidermis and dermis layers, 2) >70% knock-down of target (HSP47) genes, 3) reduction of anti-fibrotic markers (NOX4, α-SMA, COL I), and dermal thickness to the baseline level, 4) <15% non-specific cell death, and 5) more favorable safety and efficacy profile than the topical corticosteroid counterpart. This project is led by PDX Pharmaceuticals, LLC, a spin-off company from Biomedical Engineering Department at OHSU. The team consists of Ngamcherdtrakul, PhD, the lead developer of the siRNA- nanoparticle platform as the contact PI and Yantasee, PhD, MBA, Associate Professor at the BME of OHSU, and Oregon Nanomedicine Signature Researcher as OHSU's PI. Hardee, PhD, a former vice president of ISIS Pharmaceuticals, will serve as our formulation consultant. We utilize leased space and state-of-the-art equipment at OHSU and enjoy clinical expertise at OHSU School of Medicine. Prof. Leachman, MD, PhD, the chair of the OHSU's Dermatology Department and the pioneer of the first-in-human siRNA targeting an inherited skin disorder, will serve as our clinical consultant.