Novel Immunotoxin and IGF Therapy for Strabismus

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DESCRIPTION (provided by applicant): Our studies are directed at advancing treatments to cure infantile and acquired strabismus. At least 3% of the children born in the U.S. are diagnosed with strabismus each year. Early treatment of strabismus can prevent loss of visual function, but strabismus management remains challenging. This is partly because we lack a definitive understanding of its etiology. Our studies will fill this gap in knowledge and lead to improved therapies for strabismus. Eye misalignment in some cases is likely due to improper calibration of the tonic innervation of individual extraocular muscles (EOM) or specific muscle compartments. Acquired strabismus may follow injury of EOM or their innervation. Ultimately, eye alignment, gaze-holding and eye movements all depend on the quality of ocular motor innervation supplied to the EOM. Our studies will determine how current surgical methods and novel application of growth factors alter oculomotor neuronal properties associated with eye alignment. Our long term goal is to develop pharmacologic therapies to modulate force in an "underacting" or "overacting" EOM by changing intrinsic neuronal firing properties and innervational density and modulating perineuronal nets on the motor neurons that innervate the EOM to allow for synaptic plasticity and motor fusion. We will test these strategies in a non-human primate model of sensory-induced strabismus. We also hope to prevent maladaptations that occur after normal human strabismus surgery in order to reduce surgical failure rate. We have 5 specific aims: I. What are the molecular signals that influence the growth of axons and maintain the innervational pattern of the extraocular muscles? We will analyze patterns of growth factor and receptor expression in rabbit EOM, followed by use of exogenously added growth factors or antibodies to modulate the innervational pattern and density. II. Can EOM innervation be manipulated so that maladaptations at the muscle level that occur after surgical recession and/or resection are prevented? We will manipulate nerve growth in EOM by either promoting or preventing proliferation of satellite cells and/or nerve sprouting and neuromuscular junction formation. III. Can we modulate the perineuronal nets around mature motor neurons, and does this result in altered synaptic connections after sustained growth factor treatments? We will define perineuronal net structure and determine efficacy of sustained release BDNF, IGF1, and BMP4 to modulate perineuronal nets, and determine if it will restore motor neuron synaptic plasticity. IV. How do our proven growth factors alter oculomotor neuronal firing properties in the ocular motor system of normal non- human primates? We will analyze neuronal firing rates after treatments we pioneered, IGF-1 and BMP4, which increase or decrease force generation and muscle size. V. We hypothesize that growth factors can effectively treat strabismus. We will use our established methods to produce sensory-induced strabismus in infant monkeys, and then evaluate novel treatments employing growth factor treatments to correct eye misalignment.