Novel Immunotoxin and IGF Therapy for Strabismus

新型免疫毒素和 IGF 治疗斜视

• 批准号: 6986087
• 负责人: LINDA K. MCLOON
• 金额: $ 29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986087
• 关键词: Macaca fascicularis; diphtheria toxin; extraocular muscle; eye coordination disorder; immunoconjugates; immunotherapy; insulinlike growth factor; laboratory rabbit; monoclonal antibody; nicotinic receptors; ricin; therapy design /development

DESCRIPTION (provided by applicant): Strabismus is a common ophthalmologic problem, affecting between 2-5% of the population of preschool aged children in the U.S. It is manifested by a misalignment of the eyes and untreated results in amblyopia and permanent visual deficits. Many of these children require a surgical procedure for correction of their binocular alignment. The goal of this study is to develop pharmacologic treatments that will result in both muscle strengthening and muscle weakening. Current options include incisional surgery and botulinum toxin. Incisional surgery may be limited by induced scarring, altered muscle-globe dynamics, and disruption of extraocular muscle relationships with soft-tissue pulleys. These changes affect extraocular muscle function and may influence surgical outcomes. Botulinum toxin injection avoids most of these complications and has been used effectively for both childhood and adult strabismus. However, the treatment of congenital strabismus with botulinum toxin often yields inconsistent results, particularly where the initial deviation is large. The principle limitation of botulinum toxin injection is its relatively short duration of action. Ideally, injected agents should allow titratable adjustment of extraocular muscle force generation so that, in the presence of abnormal efferent motor signals, binocular alignment can be achieved. These effects must last sufficiently long so that sensory and motor adaptation can occur to create a permanent change in the rotational position of the globe. Immunotoxins are biological toxins, such as ricin, conjugated to antibodies that target the toxin against specific cells and tissues that express the selected antigen. This study is designed to test the primary hypothesis that immunotoxins, targeted against extraocular muscle, can be used in the treatment of strabismus by producing long-term muscle weakness. We will continue to test ricin-mAb 35 and a new immunotoxin we are developing, DR-iTox, a fusion protein composed of the ricin A chain and the diphtheria A chain conjugated to a monoclonal antibody to the nicotinic acetylcholine receptor. Both immunotoxins are myotoxic and targeted to mature myofibers; they spare satellite cells and myoblasts, permitting muscle regeneration. We will determine if the increased myotoxicity of the DR-iTox will extend the duration of muscle weakening compared to treatment with ricin-mAb35. We will also attempt to strengthen selected extraocular muscles by direct injection of insulin growth factor I or II. Increasing the motive force of the antagonist could augment the long-term weakening effect of an immunotoxin in an extraocular muscle, and this represents a unique approach to strabismus treatment. These novel treatments may allow titratable and sustained changes in the rotational position of the globe, the goal of strabismus surgery, without requiring an incisional procedure.

描述（由申请人提供）：斜视是一种常见的眼科问题，影响美国2-5%的学龄前儿童。它表现为眼睛错位，未经治疗导致弱视和永久性视力缺陷。 这些儿童中的许多人需要手术来矫正他们的双眼对准。 这项研究的目的是开发药物治疗，将导致肌肉加强和肌肉减弱。 目前的选择包括切口手术和肉毒杆菌毒素。 切口手术可能会受到瘢痕形成、眼球肌肉动力学改变以及眼外肌与软组织滑轮关系破坏的限制。 这些变化影响眼外肌功能，并可能影响手术结果。 肉毒毒素注射避免了大多数这些并发症，并已被有效地用于儿童和成人斜视。 然而，用肉毒杆菌毒素治疗先天性斜视经常产生不一致的结果，特别是在初始偏差较大的情况下。肉毒杆菌毒素注射的主要局限性是其作用持续时间相对较短。理想情况下，注射的药物应允许可滴定调节眼外肌力的产生，以便在存在异常传出运动信号的情况下，可以实现双眼对准。 这些效应必须持续足够长的时间，以便感觉和运动适应能够发生，从而在地球仪的旋转位置中产生永久的变化。 免疫毒素是生物毒素，如蓖麻毒素，与抗体结合，使毒素靶向表达所选抗原的特定细胞和组织。 本研究旨在验证主要假设，即针对眼外肌的免疫毒素可通过产生长期肌无力来治疗斜视。 我们将继续测试蓖麻毒素单克隆抗体35和我们正在开发的一种新的免疫毒素DR-iTox，这是一种由蓖麻毒素A链和白喉A链与烟碱乙酰胆碱受体单克隆抗体结合组成的融合蛋白。 这两种免疫毒素都是肌毒性的，靶向成熟的肌纤维;它们不影响卫星细胞和成肌细胞，允许肌肉再生。 我们将确定DR-iTox的增加的肌肉毒性与用蓖麻毒素-mAb 35治疗相比是否将延长肌肉减弱的持续时间。 我们还将尝试通过直接注射胰岛素生长因子I或II来加强选定的眼外肌。 增加拮抗剂的动力可以增强免疫毒素在眼外肌中的长期减弱作用，这代表了斜视治疗的独特方法。 这些新的治疗方法可以允许地球仪的旋转位置的可滴定的和持续的变化，斜视手术的目标，而不需要切口手术。