Novel Immunotoxin and IGF Therapy for Strabismus

斜视是一种影响2-5%学龄前儿童的眼睛对齐不正。正常双目望远镜 对准对于融合和立体视觉的发展和维持至关重要。对于年轻的患者来说 斜视，缺乏及时或有效的治疗可能会导致融合中断和发展 弱视，这会永久性地降低非固视眼的视力。目前的治疗方案包括 切开手术，肉毒杆菌毒素(肉毒杆菌毒素)，或两者的组合。切开手术会导致疤痕形成， 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。 注射肉毒杆菌可以避免这些并发症中的大多数。然而，肉毒杆菌治疗常常产生不一致的结果。 结果，特别是在初始偏差较大的情况下。肉毒杆菌毒素的主要局限性是一种肌肉衰弱 代理人，是其相对较短的诉讼期限。更广泛地说，斜视的药物治疗是有限的。 由于缺乏能够加强作用不足的EOM的代理人。理想情况下，注射的试剂将允许 可滴定调节EOM力产生，以实现足够的双目对准 允许感觉和运动适应的持续时间以及地球的永久旋转位置改变。一 初步假设认为，针对EOM的免疫毒素可以通过产生长斜视来治疗斜视。 肌肉无力一词。免疫毒素是结合靶向的生物毒素，如蓖麻毒素或白喉毒素。 抗体。我们将测试蓖麻毒素-mAb35，这是一种与烟碱乙酰胆碱的单抗相结合的蓖麻毒素。 受体DR-iTox(与单抗35连接的蓖麻毒素A链和白喉A链的融合蛋白)和 CMR107-mAb35(白喉点突变)单独和与肉毒杆菌联合产生长期 肌肉变弱了。这些免疫毒素将毒素靶向成熟的肌纤维，而不是成肌细胞和卫星细胞。 允许肌肉再生的细胞。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- 拮抗剂对可以使地球的旋转位置发生可滴定和持续的变化，这是目标 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 免疫毒素和成肌生长因子在幼猴和成年猴中的单独和联合检测 对力产生和EOM纤维特性的影响。人们对末端器官的变化知之甚少 EOM，斜视。最后一个假设指出，收缩蛋白和神经支配模式在 有斜视或眼球震颤的人和非人灵长类动物的肌肉。我们将检查EOM 来自人类患者和患有斜视和眼球震颤的猴子。

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.