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

• 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
• 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

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.

项目总结 在美国，八分之一的人患有听力损失。听力损失的常见原因是年龄、频率 暴露在嘈杂的噪音、遗传病等环境中。听力损失通常伴随着其他医学上的 抑郁、社交孤立和认知能力下降(如痴呆症)等情况。许多 各种新的治疗方法被开发出来治疗听力损失，但一个共同的挑战是，他们 所有的共同之处是如何安全地将治疗药物输送到内耳。通常，非侵入性的方法将药物输送到 内耳无法穿透内耳的屏障，因此，只有一小部分药物 达到了目标。或者，像直接注射内耳这样的侵入性外科方法可以 可能会对内耳的细胞造成损害。 虽然啮齿动物模型极大地扩展了我们对听力损失及其治疗的分子水平的理解 在这一层面上，啮齿动物模型不太适合解决药物输送问题。这是因为它的大小 啮齿动物内耳的厚度，以及它的防护屏障的厚度与人类的不匹配，因此， 使用啮齿动物模型评估新药物传递方法的翻译潜力是具有挑战性的。 为了解决这一差距，我们主张使用猪作为研究的翻译动物模型 内耳的非侵入性药物输送策略。猪是大型动物模型，它们的大小，解剖， 智力和遗传学与人类的关系比啮齿动物要近得多。因此，猪成为一种受欢迎的 动物模型，常用于心血管研究、伤口愈合、器官移植、 营养研究，以及更多。一般来说，猪是一种很受欢迎的动物，很容易进行研究。 牲畜，仅在美国，每年就有超过1亿头猪被屠宰。 在这里，为了建立猪作为研究局部内耳递送的大型动物模型，我们将：(I)验证 用于药物渗透性研究的猪RWM体外模型。(2)开发一种方法，将疗法提供给 猪模型的中耳和内耳。从技术上讲，我们将利用组织清除和标记技术 与先进的显微镜一起，以细胞分辨率对整个猪内耳进行成像。这 方法学有助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道路 并在一个大型动物模型中研究体内给药。

项目成果

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

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

• DOI: 10.2147/jaa.s338447
• 发表时间: 2021
• 期刊: Journal of asthma and allergy
• 影响因子: 3.2
• 作者: Lanz MJ;Gilbert IA;Gandhi HN;Goshi N;Tkacz JP;Lugogo NL
• 通讯作者: Lugogo NL

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