Novel Immunotoxin and IGF Therapy for Strabismus

ABSTRACT Strabismus is a common eye alignment disorder found in 3-5% of children and 3-4% of adults. If left untreated in children, strabismus can lead to loss of stereopsis and amblyopia; the brain silences connections from the misaligned eye, resulting in poor visual acuity. In strabismus, the ocular motor control of eye alignment is unbalanced. One potential cause for this imbalance is disruption of the normal two-way neurotrophic factor communication between the ocular motor system and the extraocular muscles (EOM). Our preliminary and published data show that we can produce strabismus in infant monkeys or improve eye alignment in adult strabismic monkeys. With those neurotrophic factors that were effective, the eye alignment was altered by 8 to 14o. We believe improved treatment efficacy for strabismus will require larger angles of correction to eye misalignment. Gene array and our own data suggest that deficits in neurotrophic factor communication associated with strabismus may involve multiple neurotrophic factors. Thus, to increase efficacy we predict that we need to use a combination of neurotrophic factors. We will test two approaches. First, we predict that combinations of neurotrophic factors that used singly on EOM had a demonstrated ability to alter eye alignment in non-human primates. We will test efficacy of neurotrophic factor “cocktails” in adult rabbits, and the most efficacious will be tested for the ability to produce a significant eye misalignment in infant monkeys. Second, we predict that blocking retrograde signaling of neurotrophic factors will produce a significant eye misalignment. We will examine efficacy of mixtures of neutralizing antibodies or inhibitory binding peptides to block binding of endogenously produced neurotrophic factors to their receptors. This will prevent retrograde signaling by these factors, which we predict are critical for normal eye alignment. The key for success of these experiments is the use of a sustained delivery approach. One issue that we believe precipitates surgical failure rates is that the change in eye alignment is larger than the ability of the ocular motor system to adapt. There is substantial evidence that there is a significant amount of inherent plasticity possible when slow adaptation strategies are used. Our approach uses a sustained delivery method that releases low doses of neurotrophic factors for 3 months. Our data show that unilateral treatment is sufficient to produce altered eye alignment . In addition, the largest change in eye alignment occurs during the final month of treatment, suggesting that ocular motor system plasticity between brainstem nuclei requires 3 months. This timing agrees with literature showing that visual deprivation period in infant monkeys needs to approach 3 months to produce a strabismus. We will test our most efficacious approach for its ability to correct the eye alignment in adult strabismic monkeys. Our long term goal is to develop effective strategies for modulating neurotrophic factor signaling, whether neuron- or muscle-derived, based on a combination treatment strategy. This will inform future choices for moving this strabismus treatment into human patients, with the ultimate goal of preventing loss of visual acuity.