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.
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