Establishing the pig as a large animal model for studying drug delivery to the inner ear

建立猪作为研究内耳药物输送的大型动物模型

基本信息

批准号：
10705773
负责人：
Alon Greenbaum
金额：
$ 19万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705773
关键词：
3-Dimensional Address Advocate Affect Age Anatomy Animal Model Apical Basilar Membrane Biodistribution Biological Blood Cardiovascular system Chemicals Cochlea Dementia Dexamethasone Diffuse Diffusion Drug Delivery Systems Drug Modelings Drug Transport Ear Encapsulated Etiology Evaluation Exposure to External auditory canal Family suidae Future Genetic Genetic Diseases Goals Hair Cells Hour Human Image Impaired cognition Injections Intelligence Label Labyrinth Length Liquid substance Livestock Loudness Measures Medical Medicine Membrane Mental Depression Methodology Methods Microscopy Modeling Molecular Mus Neurons Newborn Infant Noise Nutritional Study Operative Surgical Procedures Organ Transplantation Outcome Pathway interactions Penetration Perforation Perilymph Permeability Persons Pharmaceutical Preparations Physicians Public Health Research Resolution Rodent Rodent Model Sampling Scientist Social isolation Study models Surgical incisions System Techniques Testing Therapeutic Therapeutic Intervention Thick Thinness Tissues Tympanic membrane Variant Viral Vector Virus Work base cell injury drug distribution effective therapy hearing impairment hearing restoration image guided in vivo in vivo Model in vivo imaging insight local drug delivery membrane model meter middle ear minimally invasive neurotrophic factor noise exposure novel novel therapeutics ototoxicity porcine model pre-clinical round window simulation software small molecule success translational potential wound healing

项目摘要

PROJECT SUMMARY In the US, one out of eight people suffers from hearing loss. Common causes of hearing loss are age, frequent exposure to loud noise, genetic disorders, and more. Hearing loss is often accompanied by other medical conditions such as higher rate of depression, social isolation, and cognitive decline (e.g., dementia). Many diverse and novel therapeutic methods are developed to treat hearing loss, but one common challenge that they all share is how to safely deliver therapeutics to the inner ear. Often, non-invasive methods to deliver drugs to the inner ear cannot penetrate the inner ear’s barriers, and consequently, only a small fraction of the drug reaches its target. Alternatively, invasive surgical methods such as direct injection to the inner ear could potentially cause damage to the cells that populate the inner ear. Although rodent models vastly expanded our understanding of hearing loss and its treatment at a molecular level, rodent models are less suitable to address the drug delivery problem. This is due to the fact that the size of the rodent’s inner ear, and the thickness of its protective barriers do not match the human’s, therefore, evaluation of the translational potential of new drug delivery methods using rodent models is challenging. To address this gap, we would like to advocate for the use of the pig as a translational animal model to study non-invasive drug delivery strategies to the inner ear. Pigs are large animal models, and their size, anatomy, intelligence, and genetics are by far closer to humans than rodents. Consequently, the pig is becoming a popular animal model and it is commonly used in cardiovascular research, wound healing, organ transplantation, nutritional studies, and more. In general, pigs are readily available for research as they are a popular form of livestock, and in the US alone, over 100 million pigs are slaughtered annually. Here, to establish the pig as a large animal model to study local delivery to the inner ear, we will: (i) Validate an ex-vivo porcine RWM model for drug permeability studies. (ii) Develop a method to deliver therapeutics to the middle and inner ear of the porcine model. Technically, we will utilize tissue clearing and labeling techniques together with advanced microscopy to image the whole porcine inner ear with cellular resolution. This methodology facilitates the biodistribution of drugs in the tissue. Overall, the success of these goals will open future avenues for testing minimally invasive drug delivery methods to the inner ear and studying in-vivo drug delivery in a big animal model.

项目概要在美国，八分之一的人患有听力损失，常见的听力损失原因是年龄、频率。暴露于喧闹的噪音、遗传性疾病等往往伴随着其他疾病。抑郁症、社会孤立和认知能力下降（例如痴呆症）的发生率较高。人们开发了多种新颖的治疗方法来治疗听力损失，但他们面临的一个共同挑战所有的分享都是如何安全地将治疗药物输送到内耳，通常是采用非侵入性方法将药物输送到内耳。内耳无法穿透内耳屏障，因此，只有一小部分药物达到目标。侵入性手术方法，例如直接注射到内耳可以可能会对内耳细胞造成损害。尽管啮齿动物模型极大地扩展了我们对听力损失及其分子治疗的理解水平上，啮齿动物模型不太适合解决药物输送问题，这是由于尺寸的事实。啮齿类动物的内耳，其保护屏障的厚度与人类不匹配，因此，使用啮齿动物模型评估新药物输送方法的转化潜力具有挑战性。为了解决这一差距，我们提倡使用猪作为转化动物模型进行研究内耳非侵入性药物输送策略猪是大型动物模型，其体型、解剖结构、智力和遗传学都比啮齿类动物更接近人类，猪正在成为一种流行的动物。动物模型，常用于心血管研究、伤口愈合、器官移植、营养研究等一般而言，猪很容易用于研究，因为它们是一种流行的形式。仅在美国，每年就有超过 1 亿头猪被屠宰。在这里，为了将猪建立为大型动物模型来研究内耳的局部传递，我们将：（i）验证用于药物渗透性研究的离体猪 RWM 模型 (ii) 开发一种向猪提供治疗药物的方法。从技术上讲，我们将利用组织透明化和标记技术来制作猪模型的中耳和内耳。与先进的显微镜相结合，以细胞分辨率对整个猪内耳进行成像。方法有利于药物在组织中的生物分布。总体而言，这些目标的成功将为测试微创给药方法开辟未来的途径到内耳并在大型动物模型中研究体内药物输送。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing.

DOI：
10.1016/j.joa.2015.12.001
发表时间：
2016-02
期刊：
Journal of arrhythmia
影响因子：
2
作者：
Wilkoff BL;Fauchier L;Stiles MK;Morillo CA;Al-Khatib SM;Almendral J;Aguinaga L;Berger RD;Cuesta A;Daubert JP;Dubner S;Ellenbogen KA;Estes NA 3rd;Fenelon G;Garcia FC;Gasparini M;Haines DE;Healey JS;Hurtwitz JL;Keegan R;Kolb C;Kuck KH;Marinskis G;Martinelli M;McGuire M;Molina LG;Okumura K;Proclemer A;Russo AM;Singh JP;Swerdlow CD;Teo WS;Uribe W;Viskin S;Wang CC;Zhang S
通讯作者：
Zhang S

Assessment of drug permeability through an ex vivo porcine round window membrane model.

DOI：
10.1016/j.isci.2023.106789
发表时间：
2023-06-16
期刊：
ISCIENCE
影响因子：
5.8
作者：
Moatti, Adele;Silkstone, Dylan;Martin, Taylor;Abbey, Keith;Hutson, Kendall A.;Fitzpatrick, Douglas C.;Zdanski, Carlton J.;Cheng, Alan G.;Ligler, Frances S.;Greenbaum, Alon
通讯作者：
Greenbaum, Alon

2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias: Executive summary.

DOI：
10.1016/j.hrthm.2019.03.014
发表时间：
2020-01
期刊：
Heart rhythm
影响因子：
5.5
作者：
Cronin EM;Bogun FM;Maury P;Peichl P;Chen M;Namboodiri N;Aguinaga L;Leite LR;Al-Khatib SM;Anter E;Berruezo A;Callans DJ;Chung MK;Cuculich P;d'Avila A;Deal BJ;Della Bella P;Deneke T;Dickfeld TM;Hadid C;Haqqani HM;Kay GN;Latchamsetty R;Marchlinski F;Miller JM;Nogami A;Patel AR;Pathak RK;Saenz Morales LC;Santangeli P;Sapp JL Jr;Sarkozy A;Soejima K;Stevenson WG;Tedrow UB;Tzou WS;Varma N;Zeppenfeld K
通讯作者：
Zeppenfeld K

2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias.

DOI：
10.1016/j.hrthm.2019.03.002
发表时间：
2020-01
期刊：
Heart rhythm
影响因子：
5.5
作者：
Cronin EM;Bogun FM;Maury P;Peichl P;Chen M;Namboodiri N;Aguinaga L;Leite LR;Al-Khatib SM;Anter E;Berruezo A;Callans DJ;Chung MK;Cuculich P;d'Avila A;Deal BJ;Della Bella P;Deneke T;Dickfeld TM;Hadid C;Haqqani HM;Kay GN;Latchamsetty R;Marchlinski F;Miller JM;Nogami A;Patel AR;Pathak RK;Saenz Morales LC;Santangeli P;Sapp JL Jr;Sarkozy A;Soejima K;Stevenson WG;Tedrow UB;Tzou WS;Varma N;Zeppenfeld K
通讯作者：
Zeppenfeld K

Demographics, Treatment Patterns, and Morbidity in Patients with Exercise-Induced Bronchoconstriction: An Administrative Claims Data Analysis.