Long-acting ghrelin for neuropathy

长效生长素释放肽治疗神经病

• 批准号: 9907592
• 负责人: Tarik Soliman
• 金额: $ 53.53万
• 依托单位: EXTEND BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907592
• 关键词: Affect; Aftercare; Amino Acids; Animal Model; Animals; Anxiety; Attenuated; Binding Proteins; Biological Availability; Biological Markers; Biological Response Modifier Therapy; Biological Sciences; Biology; Blindness; Blood Circulation; Blood specimen; Cell Differentiation process; Cell Line; Cell Survival; Cells; Chemotherapy-induced peripheral neuropathy; Clinic; Clinical Trials; Data; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Disease; Disease Marker; Disease Progression; Dose; Drug Kinetics; Filtration; GC gene; General Population; Glucose; Goals; Half-Life; Hormones; Human; Hypersensitivity; Incidence; Inflammation; Inflammatory; Inflammatory Response Pathway; Infusion procedures; Injections; Intravenous infusion procedures; Kidney; Lead; Measures; Mechanics; Mental Depression; Modeling; Mus; NF-kappa B; Nerve; Nerve Growth Factors; Nerve Regeneration; Neural Conduction; Neurites; Neurons; Neuropathy; Opioid; Pain; Palliative Care; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Preparation; Production; Property; Protocols documentation; Quality of life; Reactive Oxygen Species; Regimen; Rivers; SOD2 gene; Safety; Self Administration; Sleep disturbances; Small Business Innovation Research Grant; Stimulus; Subcutaneous Injections; Techniques; Technology; Therapeutic; Therapeutic Effect; Toxicology; Trypan Blue; Vitamin D; Work; addiction; base; chemotherapy; chronic pain; cytokine; db/db mouse; efficacy testing; experimental study; gabapentin; ghrelin; improved; in vitro Assay; in vivo; mouse model; novel; oxaliplatin; pain relief; pain symptom; painful neuropathy; peptide hormone; prevent; response; side effect

Project Summary Neuropathy is an acquired disease that can lead to debilitating chronic pain affecting 7% to 10% of the general population. Among patients with symptomatic neuropathy, sleep disturbances, anxiety and depression are common, negatively impacting quality of life. Diabetes is a leading cause of neuropathy and is expected to become more prevalent as the incidence of diabetes increases. Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of numerous common chemotherapeutics. Unfortunately, there are no disease modifying therapeutics that can prevent neuropathy or regenerate nerves. While there are palliative treatments for pain symptoms, they are effective in less than 50% of patients and use of opioids is restricted for the most severe cases of chronic pain as they can lead to addiction. Clearly there is a need for safe, effective, well- tolerated drugs to treat painful neuropathy by halting or reversing the underlying pathology of the disease. One promising approach to treating painful neuropathy without opioids is the use of ghrelin, a 28-amino acid acylated peptide hormone. However, it has a short half-life and must be delivered via a constant intravenous infusion to have a therapeutic effect. Extend Biosciences' D-VITylation platform technology is truly enabling for small peptide-based therapeutics that are rapidly cleared from the bloodstream by renal filtration. Our platform harnesses the naturally long half-life of vitamin D and its dedicated binding protein, VDBP. When our vitamin D molecule is conjugated to a biological therapeutic, it dramatically improves the half-life and bioavailability of the drug. In addition, use of the technology should also allow the drug to be self-administered by subcutaneous injection. This would be of significant benefit to patients. In our preliminary experiments, we applied D- VITylation to this promising peptide to generate EXT405 as a therapeutic for neuropathy. Pharmacokinetic data show an extended half-life compared to the native peptide. In this Phase I SBIR, we propose to test the efficacy of EXT405 in a cell-based model of neuropathy as well as in animal models of CIPN and diabetes- induced neuropathy.

项目摘要 神经病是一种获得性疾病，可导致使人衰弱的慢性疼痛，影响7%至10%的一般 人口在有症状的神经病患者中，睡眠障碍、焦虑和抑郁是 对生活质量有负面影响的常见问题。糖尿病是神经病变的主要原因， 随着糖尿病发病率的增加而变得更加普遍。化学治疗引起的周围神经病变 CIPN是许多常见化疗药物的严重副作用。不幸的是，没有疾病 修改可以预防神经病变或再生神经的治疗方法。虽然有姑息治疗 对于疼痛症状，它们在不到50%的患者中有效，并且阿片类药物的使用大多数受到限制。 严重的慢性疼痛病例，因为它们可能导致成瘾。很明显，需要一种安全，有效，良好的- 耐受性药物通过停止或逆转疾病的潜在病理来治疗疼痛性神经病。一 一种有前途的方法来治疗疼痛性神经病变，而不使用阿片类药物是使用生长激素释放肽，一种28-氨基酸 酰化肽激素然而，它的半衰期很短，必须通过持续的静脉注射来递送。 输注以具有治疗效果。Extend Biosciences的D-VITylation平台技术真正实现了 通过肾过滤从血流中快速清除的小肽类治疗剂。我们的平台 利用维生素D及其专用结合蛋白VDBP的天然长半衰期。当我们的维生素D 当分子与生物治疗剂缀合时，它显著改善了药物的半衰期和生物利用度。 药此外，该技术的使用还应允许药物通过皮下注射自我给药。 注射这将对患者有很大的好处。在我们的初步实验中，我们应用了D- 对这种有前途的肽进行VITylation以产生作为神经病治疗剂的EXT 405。药代动力学数据 与天然肽相比显示出延长的半衰期。在第一阶段SBIR中，我们建议测试 EXT405在基于细胞的神经病模型以及CIPN和糖尿病动物模型中的功效- 诱发性神经病