Novel Immunotoxin and IGF Therapy for Strabismus

新型免疫毒素和 IGF 治疗斜视

• 批准号: 10228548
• 负责人: LINDA K. MCLOON
• 金额: $ 47.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228548
• 关键词: Adult; Aftercare; Amblyopia; Antibodies; Bilateral; Binding; Biochemical; Blindness; Brain; Brain Stem; Cell Nucleus; Child; Childhood; Ciliary Neurotrophic Factor; Communication; Data; Depth Perception; Development; Diagnosis; Disease; Dose; Early treatment; Etiology; Eye; Eye Movements; Failure; Future; Genes; Goals; Growth Factor; Human; IGF1 gene; IGF2 gene; Immunotoxins; Infant; Insulin; Insulin-Like Growth Factor II; Lateral; Lead; Left; Literature; Masks; Medial; Methods; Monkeys; Morphology; Motor Neurons; Muscle; Muscle function; Mutation; Nerve; Neurons; Ocular Motility Disorders; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Patients; Peptides; Peripheral; Physiological; Plant Roots; Play; Publishing; Recording of previous events; Role; Signal Pathway; Signal Transduction; Strabismus; Structure; Supplementation; System; Testing; Treatment Efficacy; Vision; Visual Acuity; base; combinatorial; deprivation; effective therapy; effectiveness evaluation; efficacy evaluation; efficacy testing; experimental study; glial cell-line derived neurotrophic factor; improved; insulin signaling; mind control; motor control; neurotrophic factor; neutralizing antibody; nonhuman primate; novel; oculomotor; orbit muscle; preclinical study; prevent; receptor; success; treatment strategy; visual deprivation

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.

抽象的 斜视是3-5％的儿童和3-4％的成年人中发现的一种常见的眼睛对准障碍。如果不处理 在儿童中，斜视会导致立体望台和弱视的丧失。大脑沉默的连接 眼睛错位，导致视力差。在斜视中，眼睛对齐的眼部运动控制是 不平衡。这种不平衡的潜在原因是正常双向神经营养因子的破坏 眼运动系统与眼外肌肉（EOM）之间的通信。我们的初步和 发布的数据表明，我们可以在婴儿猴子中产生斜视或改善成人的眼睛对齐 斜视猴子。使用有效的那些神经营养因素，眼睛比对的改变是8至 14o。我们认为，提高斜视的治疗效率将需要更大的矫正角度 错位。基因阵列和我们自己的数据表明，在神经营养因素通信中定义 与斜视相关的可能涉及多种神经营养因素。为了提高效率，我们预测 我们需要结合神经营养因素。我们将测试两种方法。首先，我们预测 在EOM上单独使用的神经营养因素的组合具有改变眼睛的能力 非人类素数的对齐。我们将测试成年兔子中神经营养因子“鸡尾酒”的效率，以及 最有效的效率将测试是否能够在婴儿猴子中产生严重的眼对准。 其次，我们预测阻塞神经营养因子的逆行信号将产生明显的眼睛 错位。我们将检查中和抗体或抑制性结合肽的混合效率 内源性产生的神经营养因子与其受体的结合。这将防止逆行 这些因素的信号传导，我们预测这对于正常眼对准至关重要。这些成功的关键 实验是使用持续交付方法。我们认为引起外科手术失败的一个问题 速度是，眼对准的变化大于眼运动系统适应的能力。有 大量证据表明，缓慢适应时可能会有很大的继承可塑性 使用策略。我们的方法使用一种持续的递送方法，可释放低剂量的神经营养 3个月的因素。我们的数据表明，单方面治疗足以产生改变眼对准。 此外，眼睛对齐的最大变化发生在治疗的最后一个月，这表明眼 脑干核之间的运动系统可塑性需要3个月。这个时机与显示的文学一致 婴儿猴子的视觉剥夺时期需要接近3个月才能产生斜视。我们将 测试我们最有效的方法，以纠正成人斜视猴子的眼睛对齐的能力。我们的 长期目标是制定调节神经营养因子信号传导的有效策略，是否神经元 - 或基于组合治疗策略的肌肉衍生。这将为将来的选择提供信息 斜视治疗人类患者，其最终目的是防止视力丧失。