Novel Immunotoxin and IGF Therapy for Strabismus

斜视是一种影响2-5%学龄前儿童的眼睛错位。正常的双眼 对齐对于融合和立体视觉的发展和维持是至关重要的。对于年轻的病人， 斜视，缺乏及时或有效的治疗可能会导致融合中断， 弱视，这可能会永久性地降低非固定眼睛的视力。目前的治疗方案包括 切口手术、肉毒杆菌毒素（Botox）或两者的组合。切开手术会导致疤痕， 改变肌肉-眼球动力学，并破坏眼外肌（EOM）与软组织滑轮的关系。 肉毒杆菌素注射避免了大多数这些并发症。然而，肉毒杆菌治疗往往产生不一致的 结果，特别是在初始偏差较大的情况下。肉毒杆菌素的主要局限性，一种肌肉弱化 它的作用时间相对较短。更广泛地说，斜视的药物治疗是有限的 缺乏能够加强行动不力的EOM的特工理想情况下，注射药剂 可滴定地调节EOM力的产生，使得可以实现足够的双眼对准 持续时间以允许感觉和运动适应以及地球仪的永久旋转位置改变。一 最初的假设认为，针对眼外肌的免疫毒素可以通过产生长时间的 术语肌肉无力。免疫毒素是生物毒素，如蓖麻毒素或白喉毒素， 抗体的我们将测试蓖麻毒素单克隆抗体35，蓖麻毒素结合到单克隆抗体的烟碱乙酰胆碱 受体，DR-iTox（蓖麻毒素A链和白喉A链与mAb 35缀合的融合蛋白）和 CMR 107-mAb 35（白喉点突变）单独使用以及与肉毒杆菌毒素联合使用， 肌肉衰弱这些免疫毒素将毒素靶向成熟的肌纤维，不影响成肌细胞和卫星细胞。 使肌肉再生的细胞。第二种假说认为，直接注射肌源性生长 因素可以产生短期和长期的EOM肌肉强化。改变激动剂的动力- 拮抗剂对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，不需要切开手术。在非人类灵长类动物中，我们将测试 免疫毒素和生肌生长因子单独和组合在婴儿和成年猴中， 力的产生和EOM纤维特性的影响。关于终末器官的变化知之甚少， 眼外肌，斜视。最后一个假说指出，收缩蛋白和神经支配模式的变化， 人类和非人类灵长类动物肌肉在斜视或眼球震颤的存在。我们将检查EOM 从患有斜视和眼球震颤的人类患者和猴子身上。

Strabismus is a misalignment of the eyes affecting 2-5% of preschool aged children. Normal binocular alignment is critical for the development and maintenance of fusion and stereopsis. For the young patient with strabismus, lack of timely or effective treatment may result in disruption of fusion and the development of amblyopia, which can permanently reduce vision in the non-fixing eye. Current treatment options include incisional surgery, botulinum toxin (Botox), or a combination of both. Incisional surgery can induce scarring, alter muscle-globe dynamics, and disrupt extraocular muscle (EOM) relationships with soft-tissue pulleys. Botox injection avoids most of these complications. However, Botox treatment often yields inconsistent results, particularly where the initial deviation is large. The main limitation of Botox, a muscle-weakening agent, is its relatively short duration of action. More broadly, pharmacologic treatment of strabismus is limited by the lack of agents capable of strengthening an underacting EOM. Ideally, injected agents would allow titratable adjustment of EOM force generation so that binocular alignment can be achieved of sufficient duration to allow sensory and motor adaptation and a permanent rotational position change of the globe. One primary hypothesis states that immunotoxins, targeted against EOM, can treat strabismus by producing long- term muscle weakness. Immunotoxins are biological toxins, such as ricin or diphtheria, bound to targeting antibodies. We will test ricin-mAb35, ricin conjugated to a monoclonal antibody to the nicotinic acetylcholine receptor, DR-iTox (a fusion protein of the ricin A chain and the diphtheria A chain conjugated to mAb35) and CMR107-mAb35 (a diphtheria point mutation) alone and in combination with Botox to produce long-term muscle weakening. These immunotoxins target toxins to mature myofibers, sparing myoblasts and satellite cells permitting muscle regeneration. A second hypothesis states that direct injection of myogenic growth factors can produce short and long term muscle strengthening of EOM. Altering the motive forces of agonist- antagonist pairs could allow titratable and sustained changes in the rotational position of the globe, the goal of strabismus surgery, without requiring an incisional procedure. In the non-human primate, we will test immunotoxins and myogenic growth factors alone and in combination in infant and adult monkeys to measure effects on force generation and EOM fiber characteristics. Little is known about changes in the end organ, the EOM, in strabismus. The final hypothesis states that contractile proteins and patterns of innervation change in human and non-human primate muscle in the presence of strabismus or nystagmus. We will examine EOM from human patients and monkeys with strabismus and nystagmus.