Novel Immunotoxin and IGF Therapy for Strabismus

描述（由申请人提供）：斜视是一种影响2-5%学龄前儿童的眼睛错位。正常的双眼对位对融合和立体视觉的发展和维持至关重要。对于患有斜视的年轻患者，缺乏及时或有效的治疗可能会导致融合中断和弱视的发展，这可能会永久性地降低非固定眼的视力。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。切口手术可诱导瘢痕形成，改变眼球肌肉动力学，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，肉毒杆菌素治疗往往产生不一致的结果，特别是在初始偏差很大的情况下。肉毒杆菌素是一种肌肉弱化剂，其主要局限性在于其作用持续时间相对较短。更广泛地说，斜视的药物治疗受到缺乏能够加强作用不足的EOM的药物的限制。理想地，注射的试剂将允许EOM力产生的可滴定调节，使得双眼对准可以实现足够的持续时间，以允许感觉和运动适应以及地球仪的永久旋转位置改变。一个主要的假设是，针对眼外肌的免疫毒素可以通过产生长期的肌无力来治疗斜视。免疫毒素是与靶向抗体结合的生物毒素，如蓖麻毒素或白喉毒素。我们将测试蓖麻毒素-mAb 35，蓖麻毒素与烟碱乙酰胆碱受体的单克隆抗体结合，DR-iTox（蓖麻毒素A链和白喉A链与mAb 35结合的融合蛋白）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，以产生长期的肌肉减弱。这些免疫毒素将毒素靶向成熟的肌纤维，保留允许肌肉再生的成肌细胞和卫星细胞。第二种假说认为，直接注射肌源性生长因子可以使眼外肌产生短期和长期的肌肉强化。改变激动剂-拮抗剂对的动力可以允许地球仪的旋转位置的可滴定和持续的变化，这是斜视手术的目标，而不需要切开手术。在非人灵长类动物中，我们将在婴儿和成年猴中单独和联合测试免疫毒素和生肌生长因子，以测量对力生成和眼外肌纤维特征的影响。很少有人知道的变化，最终器官，眼外肌，斜视。最后一个假设指出，在斜视或眼球震颤的存在下，人类和非人类灵长类动物肌肉中的收缩蛋白和神经支配模式发生变化。我们将研究眼外肌从人类患者和猴子斜视和眼球震颤。

DESCRIPTION (provided by applicant): 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.