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 斜视是一种常见的眼睛排列障碍，有 3-5% 的儿童和 3-4% 的成人患有斜视。如果不及时治疗 对于儿童来说，斜视会导致立体视觉丧失和弱视；大脑会沉默来自 眼睛错位，导致视力不佳。在斜视中，眼球运动控制眼睛的排列是 不平衡。造成这种不平衡的一个潜在原因是正常双向神经营养因子的破坏 眼运动系统和眼外肌（EOM）之间的通讯。我们的初步和 已发表的数据表明，我们可以在幼年猴子中产生斜视，或改善成年猴子的眼睛排列 斜视猴子。使用那些有效的神经营养因子，眼睛的排列改变了 8 至 14点。我们相信斜视治疗效果的提高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神经营养因子通讯存在缺陷 与斜视相关的可能涉及多种神经营养因子。因此，为了提高功效，我们预测 我们需要结合使用神经营养因子。我们将测试两种方法。首先，我们预测 单独使用 EOM 的神经营养因子组合已被证明能够改变眼睛 非人类灵长类动物的排列。我们将测试神经营养因子“鸡尾酒”对成年兔子的功效，以及 最有效的方法将被测试是否能够在幼​​猴身上产生明显的眼睛错位。 其次，我们预测阻断神经营养因子的逆行信号传导将产生显着的眼睛 错位。我们将检查中和抗体或抑制性结合肽混合物的功效 阻断内源性产生的神经营养因子与其受体的结合。这样可以防止逆行 这些因素发出的信号，我们预测这些信号对于正常的眼睛排列至关重要。这些成功的关键 实验是使用持续交付方法。我们认为导致手术失败的一个问题 比率是眼睛对准的变化大于眼球运动系统的适应能力。有 大量证据表明，缓慢适应时可能存在大量固有可塑性 使用策略。我们的方法采用持续递送方法，释放低剂量的神经营养物质 3个月的因素。我们的数据表明，单侧治疗足以改变眼睛的排列。在 此外，眼睛排列的最大变化发生在治疗的最后一个月，这表明眼部 脑干核之间的运动系统可塑性需要3个月。这个时间与文献显示一致 幼猴的视觉剥夺期需要接近3个月才会产生斜视。我们将 测试我们最有效的方法是否能够纠正成年斜视猴的眼睛对齐。我们的 长期目标是开发有效的策略来调节神经营养因子信号传导，无论神经元 或肌肉来源，基于联合治疗策略。这将为未来的移动选择提供信息 对人类患者进行斜视治疗，最终目标是防止视力丧失。