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）：Strabismus是一个常见的眼科问题，影响了美国2-5％的学龄前儿童人口的人口，这表现为眼睛的未对准和未经治疗的弱视和永久的视觉缺陷。 这些儿童中有许多需要手术程序来校正其双眼比对。 这项研究的目的是开发药物治疗，从而导致肌肉增强和肌肉减弱。 当前的选择包括切口手术和肉毒杆菌毒素。 切除手术可能会受到诱发的疤痕，肌肉全球动力学改变以及与软组织皮带轮的破坏外科手术的限制。 这些变化会影响眼外肌肉功能，并可能影响手术结果。 肉毒杆菌毒素注射避免了大多数这些并发症，并已有效地用于儿童和成人斜视。 但是，先天性斜视用肉毒杆菌毒素的治疗通常会产生不一致的结果，尤其是在初始偏差很大的情况下。肉毒杆菌毒素注射的主要限制是其作用持续时间相对较短。理想情况下，注射的药物应允许对眼外肌肉产生的可滴定调整，以便在存在异常的传出运动信号的情况下，可以实现双眼对准。 这些效果必须持续足够长的时间，以便可以进行感觉和运动适应性，以在地球的旋转位置发生永久性变化。 免疫毒素是生物毒素，例如ricin，与抗体相结合的抗体，这些抗体将毒素靶向表达选定抗原的特定细胞和组织。 这项研究旨在检验主要假设，即针对眼外肌肉的免疫毒素可通过产生长期肌肉无力来治疗斜视。 我们将继续测试Ricin-MAB 35和我们正在开发的新免疫毒素，DR-ITOX，一种由Ricin a链组成的融合蛋白和链二链蛋白和链链链，链结合了与烟碱乙酰胆碱受体的单克隆抗体。 两种免疫毒素都是肌毒性的，靶向成熟的肌纤维。他们避免了卫星细胞和成肌细胞，允许肌肉再生。 我们将确定与用Ricin-Mab35的治疗相比，DR-utox的肌毒性增加是否会延长肌肉减弱的持续时间。 我们还将尝试通过直接注入胰岛素生长因子I或II来增强选定的眼外肌肉。 增加拮抗剂的动力可以增强免疫毒素在眼外肌肉中的长期弱化作用，这代表了斜视治疗的独特方法。 这些新颖的治疗方法可以使地球旋转位置的可滴定和持续变化，即斜视手术的目标，而无需切开手术。