Neurotrophic factor delivery to extraocular muscle: uncovering mechanisms of strabismus

Abstract

Strabismus is an ocular motor disorder characterized by eye misalignment, where clinically the extraocular muscle (EOM) pairs are presumed to be "overacting", and "underacting". There is currently a need for effective treatments that could act to strengthen an underacting muscle to aid in establishing eye alignment. Neurotrophic factors, such as insulin like growth factor-1 (IGF-1) and brain derived neurotropic factor (BDNF) have emerged as potential treatment options that could strengthen extraocular muscle. Neurotrophic factors have the ability to alter properties of EOM myofibers, neuromuscular junctions, and the motor neurons themselves through retrograde transport from the target muscle. A multi-action pharmacological agent that could be applied directly to the readily accessible EOM could present a clinically simple treatment for strabismus. In chapter 2, I build on previous work, which demonstrated that IGF-1 makes myofibers stronger. Rabbit EOM was pre-injected hepatocyte growth factor prior to IGF-1 treatment. With combined treatment, increased muscle force was obtained with lower doses of IGF-1. This work supports the potential therapeutic use of IGF-1 to correct strabismus by increasing muscle force. Despite the strong evidence that IGF-1 treatment strengthens EOM, the efficacy of IGF-1 to alter eye alignment in a binocular animal model is currently unknown. In chapters 3 and 4, I test the hypothesis that persistent bilateral (Chapter 3) or unilateral (Chapter 4) IGF-1 treatment to the medial rectus of a nonhuman primate can alter eye positioning. For these studies, we treated visually normal infant nonhuman primates during the postnatal development of the ocular motor system, which allowed us not only to assess if persistent IGF-1 treatment could disrupt the eye alignment, but also to investigate if aberrant neurotrophic factor signaling during development of the ocular motor system in the EOM is a possible cause of strabismus. In chapter 3, bilateral treatment did not result in strabismus. However, myofiber size increased in both the treated EOM and the untreated antagonist muscles. I hypothesize that over the three months of sustained treatment, the ocular motor system adapted to maintain eye alignment. In chapter 4, unilateral IGF-1 did create strabismus. This novel finding strongly suggests that altered molecular signaling by the EOM could be cause of strabismus. Finally, in Chapter 5, I extend my studies of neurotrophic factor treatment to infant nonhuman primates to test if another promising neurotropic factor, BDNF, could alter eye alignment during development of the ocular motor system. At the end of the three-month treatment period, no strabismus developed. However, there were marked changes to a subpopulation of myofibers that contain slow myosin heavy chain isoform. These results have interesting implications for the role of BDNF in selectively influencing tonic properties of the EOM. This work strongly demonstrates that sustained release of neurotrophic factors can significantly alter extraocular muscle properties, and disrupt eye alignment. Future studies will further investigate both the role of neurotrophic factors in determining normal EOM properties, and test if sustained release with IGF-1 can treat an animal model with strabismus.