NICOTINAMIDE RIBOSIDE FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY, DRY EYE SYNDROME, AND HEARING LOSS

烟酰胺核苷用于治疗化疗引起的神经病、干眼症和听力损失

• 批准号: 10311115
• 负责人: Marta Veronica Hamity
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311115
• 关键词: Address; Adult; Adverse effects; Affective; Auditory Brainstem Responses; Automobile Driving; Award; Cancer Patient; Cancer Survivor; Cisplatin; Clinical Trials; Cochlea; Coenzymes; Cornea; Data; Detection; Dimensions; Distress; Drops; Dry Eye Syndromes; Dysesthesias; Evidence based treatment; Female; Filament; Goals; Healthcare; Hypersensitivity; Incidence; Laboratories; Life; Light; Malignant Neoplasms; Measures; Mission; Neuraxis; Neuropathy; Newly Diagnosed; Niacinamide; Nicotinamide adenine dinucleotide; Nociception; Numbness; Outcome; Oxidation-Reduction; Paclitaxel; Pain; Patients; Peripheral Nervous System Diseases; Photophobia; Platinum; Platinum Compounds; Play; Production; Prophylactic treatment; Proprioception; Quality of life; Rattus; Reflex action; Research Personnel; Rodent; Rodent Model; Role; Saline; Severities; Sex Differences; Source; Stimulus; Strabismus; Survivors; Tactile; Testing; Time; Tinnitus; Toxic effect; Translating; Veterans; Walking; Withdrawal; Work; allodynia; auditory pathway; axon injury; base; cancer therapy; chemotherapy; chemotherapy induced neuropathy; cisplatin induced hearing loss; dietary supplements; disability; effective therapy; efficacious intervention; experience; experimental study; hearing impairment; improved; male; nicotinamide-beta-riboside; otoacoustic emission; ototoxicity; physical symptom; pre-clinical; prevent; prophylactic; rehabilitation research; response; side effect; social; tactile stimulation; taxane

Continuing advances in detection and treatment have greatly increased the number of cancer survivors, as well as more Veterans living with cancer because of continued therapy. However, while these therapies prolong life, they are accompanied by adverse effects that introduce functional limitations and significantly reduce quality of life of Veterans. For example, taxane and platinum-based chemotherapies produce very painful and debilitating peripheral neuropathies that greatly diminish patients’ quality of life. These agents can also cause dry eye syndrome (DES), and in the case of platinum-based therapies, hearing loss and tinnitus due to ototoxicity in 40-80% of adults. Currently, no effective treatment exists to reduce the incidence of these debilitating side effects of therapy and they remain a significant unmet need in healthcare. In recent years, evidence has accrued that nicotinamide adenine dinucleotide (NAD+), an essential redox coenzyme, plays an important role in protection against axonal injury. This laboratory recently demonstrated that a naturally occurring vitamin B3 precursor of NAD+, nicotinamide riboside (NR; NIAGEN®) can both prevent and reverse paclitaxel-induced peripheral neuropathy in rodents. The main goal of this application is to obtain preclinical data to evaluate the ability NR to improve the quality of life and function of Veterans with cancer as well as cancer survivors who suffer the sequelae of chemotherapy. The proposed studies will focus on a platinum compound, cisplatin, that is associated with a high incidence of painful peripheral neuropathy, as well as ocular toxicity, and ototoxicity. The first aim of this proposal will determine whether prophylactic treatment with NR prevents cisplatin-induced allodynia (hypersensitivity) to tactile and cool stimuli, as well as blunts the aversive/affective dimension of the neuropathy. Hypersensitivity to tactile and cool stimuli will be assessed in vehicle- and NR-treated rats by determining threshold to withdrawal from application of calibrated von Frey filaments or a cool stimulus to the hind paw. The place escape avoidance paradigm will be used to assess changes in the aversive/affective components of nociception. The second aim of the proposal will determine whether prophylactic treatment with NR can prevent photophobia (light aversion), as well as corneal hypersensitivity and deficits in tear production induced by cisplatin. Photophobia will be assessed in vehicle- and NR-treated rats by measuring time spent in a brightly-lit chamber, while corneal hypersensitivity will be assessed by changes in withdrawal responses to tactile stimulation of the cornea or degree of squinting induced by application of hyperosmolar saline drops. Reflex and basal tear production will be assessed by Schirmer's test. The final aim of this proposal will determine whether prophylactic treatment with NR can prevent cisplatin-induced loss of hearing. Cochlear function will be assessed in vehicle- and NR-treated rats by distortion product otoacoustic emissions, and functionality of central nervous system auditory pathways will be assessed by auditory brainstem responses. These experiments will be conducted in both male and female rats to assess possible sex-dependent differences. The three aims will be conducted in parallel because they are not dependent on one another. Moreover, a positive outcome in any one would support a clinical trial of a treatment that could be prevent chemotherapy-induced disabilities in Veterans and substantially improve their quality of life. This work addresses an unmet need in healthcare and has the potential to be transformative for the patient and clinician alike.

检测和治疗方面的不断进步大大增加了癌症幸存者的数量， 以及更多的退伍军人生活与癌症，因为继续治疗。然而，虽然这些疗法 延长寿命，它们伴随着引入功能限制和显著 降低退伍军人的生活质量。例如，紫杉烷和铂基化疗产生非常 疼痛和使人衰弱的周围神经病变，极大地降低了患者的生活质量。这些试剂可以 也会导致干眼综合征（DES），在铂类药物治疗的情况下，会导致听力损失和耳鸣 因为40-80%的成年人有耳毒性。目前，还没有有效的治疗方法来减少这些疾病的发生率。 治疗的使人衰弱的副作用，并且它们仍然是医疗保健中显著未满足的需求。近年来， 有证据表明，烟酰胺腺嘌呤二核苷酸（NAD+），一种重要的氧化还原辅酶， 在防止轴突损伤中起重要作用。这个实验室最近证明， NAD+的维生素B3前体，烟酰胺核苷（NR; NIAGEN®）可以预防和逆转 紫杉醇诱导的啮齿类动物周围神经病变。本申请的主要目标是获得临床前 评估NR改善癌症退伍军人生活质量和功能的能力， 遭受化疗后遗症的癌症幸存者。拟议的研究将集中在铂 化合物顺铂，与疼痛性周围神经病变以及眼神经病变的高发病率相关， 毒性和耳毒性。本提案的第一个目的是确定是否使用NR进行预防性治疗 预防顺铂诱导的触觉和冷刺激异常性疼痛（超敏反应），以及钝化 神经病变的厌恶/情感维度。对触觉和冷刺激的超敏反应将在 通过测定从应用校准的von Frey中退出的阈值，测定溶媒和NR处理的大鼠 细丝或对后爪的冷刺激。地点逃避回避范式将用于评估 伤害感受的厌恶/情感成分的变化。该提案的第二个目标将决定 NR的预防性治疗是否可以预防畏光症（光厌恶）以及角膜 顺铂诱导的泪液产生的超敏反应和缺陷。畏光症将在车辆中进行评估- 和NR治疗的大鼠通过测量在明亮的室内花费的时间，而角膜超敏反应将是 通过对角膜触觉刺激或斜视程度的退缩反应变化进行评估 通过应用高渗性盐水滴剂诱导。反射和基础泪液产生将通过以下方式进行评估： 席尔默试验。本提案的最终目的是确定NR的预防性治疗是否可以 预防顺铂引起的听力损失。将通过以下方法评估溶媒和NR处理大鼠的皮质功能： 畸变产物耳声发射和中枢神经系统听觉通路的功能将被 通过听觉脑干反应进行评估。这些实验将在雄性和雌性大鼠中进行 评估可能的性别差异。这三个目标将同时进行，因为它们是 不互相依赖。此外，任何一个积极的结果都将支持一项临床试验， 治疗可以预防退伍军人化疗引起的残疾，并大大改善他们的生活质量。 生活质量这项工作解决了医疗保健中未满足的需求，并有可能成为变革性的， 患者和临床医生都一样。