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

开发治疗皮肤病的 siRNA 纳米颗粒局部制剂

• 批准号: 9348486
• 负责人: Worapol Ngamcherdtrakul
• 金额: $ 32.5万
• 依托单位: PDX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348486
• 关键词: Adrenal Cortex Hormones; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Benchmarking; Biodistribution; Biological Markers; Biomedical Engineering; Bleomycin; Blood; Cations; Cell Death; Cell Line; Cells; Cetuximab; Charge; Clinical; Data; Dermal; Dermatologic; Dermatology; Dermis; Development; Disease; Doctor of Philosophy; Dose; Dyes; Enzymes; Epidermal Growth Factor Receptor; Epidermis; Equipment; Evaluation; Fibroblasts; Fibrosis; Fluorescence; Formulation; Gene Expression; Gene Silencing; Gene Targeting; Genes; Goals; Growth; Hepatocyte; Histology; Homing; Human; Hybrids; In Vitro; Inherited; Kidney; Lead; Legal patent; Life; Liver; Lung; Manufacturer Name; Mass Spectrum Analysis; Measurement; Messenger RNA; Modeling; Mus; Oregon; Outcome; Patients; Penetration; Pharmacologic Substance; Phase; Play; Polymers; Property; Proteins; Protocols documentation; Psoriasis; RNA Interference; Reactive Oxygen Species; Recipe; Renal function; Reporting; Research Personnel; Risk; Role; Safety; Self Administration; Silicon Dioxide; Skin; Skin Cancer; Small Business Innovation Research Grant; Small Interfering RNA; Specificity; System; Technology; Therapeutic; Thick; Time; Topical Corticosteroids; Topical application; Toxic effect; Transforming Growth Factor alpha; Transforming Growth Factor beta; Treatment Efficacy; Ultrasonography; Work; antibody conjugate; base; biomaterial compatibility; clinical translation; crosslink; cytokine; cytotoxicity; design; effective therapy; experimental study; fibrogenesis; in vivo; inhibitor/antagonist; intradermal injection; keratinocyte; kidney cell; knock-down; learning materials; liver function; medical schools; mid-career faculty; mouse model; nanomedicine; nanoparticle; nuclease; overexpression; skin barrier; skin disorder; skin fibrosis; systemic toxicity; targeted agent; treatment strategy; uptake

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.

修订后的I期SBIR提案旨在开发siRNA-Nananoparpicle的局部公式 这可以提供siRNA治疗皮肤纤维化的siRNA。我们的平台具有抗氧化剂和抗炎 特性，进一步受益于没有有效治疗的皮肤纤维化的治疗。 完成后，该平台将具有广泛的适用性，因为siRNA可以设计为敲门 降低任何负责其他疾病的基因，例如牛皮癣，皮肤疾病和皮肤癌。 我们申请专利的交付平台是介孔二氧化硅纳米颗粒和共聚物的混合体 涂层，比sirna-polyplex对应物更有效，更安全。初步数据 皮内注射后siRNA-NP显示出有望治疗皮肤纤维化的有希望的效率 老鼠。在此I阶段提案中要开发的局部公式将大大减少患者 负担，因此是迈向该技术临床翻译的不可或缺的一步。 AIM 1：我们将筛选适当的车辆用于局部siRNA-NP公式以最大化 在3D人体皮肤模型中渗透到表皮和真皮和siRNA敲低效率。 AIM 2：我们将应用优化的局部公式来提供针对HSP47的siRNA以治疗 3D人体皮肤模型中的纤维化和针对当前治疗的基准（皮质类固醇）。 AIM 3：将在纳米颗粒上应用超声和靶向剂（抗EGFR抗体） 增强穿透性和细胞摄取，可能导致更高的治疗效率，这将 在体内小鼠研究中得到验证。 AIM 4：将进行细胞系，3D人皮肤和小鼠的初步毒性研究。 GO/No-Go标准包括1）可以穿透表皮和的有效局部配方 真皮层，2）> 70％的靶标（HSP47）基因，3）抗纤维化标记的减少 （NOX4，α-SMA，Col I）和皮肤厚度至基线水平，4）<15％的非特异性细胞死亡， 5）与局部皮质类固醇相比，安全性和效率更大。 该项目由生物医学工程公司的衍生公司PDX Pharmaceuticals，LLC领导 OHSU部门。该团队由Ngamcherdtrakul博士组成，sirna-的首席开发商 纳米颗粒平台作为联系PI和Yantasee博士，MBA，BME的副教授 OHSU和俄勒冈州纳米医学签名研究人员，如OHSU的PI。 Hardee，博士，以前的恶习 ISIS Pharmaceuticals总裁将担任我们的公式顾问。我们利用了租赁空间 以及OHSU的最先进设备，并在OHSU医学院享受临床专业知识。 OHSU皮肤病学系主任的Leachman教授，博士，博士学位和 针对遗传性皮肤疾病的第一个人类siRNA将担任我们的临床顾问。