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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015313-08
Application #
8004985
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (07))
Program Officer
Araj, Houmam H
Project Start
2004-01-01
Project End
2012-07-31
Budget Start
2011-01-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$361,277
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Verma, Mayank; Fitzpatrick, Krysta; McLoon, Linda K (2017) Extraocular Muscle Repair and Regeneration. Curr Ophthalmol Rep 5:207-215
Nelson, Krysta R; Stevens, Shanlee M; McLoon, Linda K (2016) Prolongation of Relaxation Time in Extraocular Muscles With Brain Derived Neurotrophic Factor in Adult Rabbit. Invest Ophthalmol Vis Sci 57:5834-5842
McLoon, Linda K; Christiansen, Stephen P; Ghose, Geoffrey M et al. (2016) Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment. Invest Ophthalmol Vis Sci 57:6070-6078
McLoon, Linda K; Willoughby, Christy L; Anderson, Jill S et al. (2016) Abnormally Small Neuromuscular Junctions in the Extraocular Muscles From Subjects With Idiopathic Nystagmus and Nystagmus Associated With Albinism. Invest Ophthalmol Vis Sci 57:1912-20
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment. Invest Ophthalmol Vis Sci 56:3484-96
Walton, Mark M G; Mustari, Michael J; Willoughby, Christy L et al. (2015) Abnormal activity of neurons in abducens nucleus of strabismic monkeys. Invest Ophthalmol Vis Sci 56:10-9
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates. Invest Ophthalmol Vis Sci 56:3467-83
Graber, Ted G; Kim, Jong-Hee; Grange, Robert W et al. (2015) C57BL/6 life span study: age-related declines in muscle power production and contractile velocity. Age (Dordr) 37:9773
Stager Jr, David; McLoon, Linda K; Felius, Joost (2013) Postulating a role for connective tissue elements in inferior oblique muscle overaction (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 111:119-32
Hebert, Sadie L; Daniel, Mark L; McLoon, Linda K (2013) The role of Pitx2 in maintaining the phenotype of myogenic precursor cells in the extraocular muscles. PLoS One 8:e58405

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