GENE THERAPY FOR LARYNGEAL PARALYSIS

喉麻痹通常是由于手术切除了累及头颈部和颅底的肿瘤而发生的。 甲状腺手术、颈动脉内膜切除术、心胸外科手术和原发性肺部手术也可能导致喉麻痹。 喉麻痹的患者通常表现出残疾症状，包括失声、吞咽困难和气道阻塞。 虽然存在外科手术来治疗这些症状，但其成功受到伴随喉麻痹的肌肉萎缩的限制。此外，目前的手术修复受损神经的方法对喉功能的恢复几乎没有影响，并且没有被广泛接受为治疗选择。为了解决这一临床问题，我们设计了一个大鼠喉麻痹模型，研究新的基因转移策略，使用肌肉特异性表达系统，以提高当地交付的生长因子。 在初步研究中，将含有α-肌动蛋白启动子和人IGF-I基因序列的非病毒载体注射到麻痹的成年大鼠喉肌中。在单次注射该hIGF-I基因制剂后一个月，证明了对肌肉和神经的积极作用。这些作用与每日局部或全身注射hIGF-I蛋白3至6周后观察到的作用相当。基于初步的研究结果，我们推测hIGF-1的肌营养和神经营养作用将在神经再生和肌肉神经再支配过程中产生更大的影响。 本研究将探讨使用非病毒和病毒基因转移的hIGF-I和其他生长因子的应用于喉肌神经再支配的交付。 我们的研究结果将直接关系到为人类疾病创造一个更实用的治疗策略，包括喉麻痹和其他周围神经损伤的治疗。

Laryngeal paralysis usually occurs as a result of the surgical removal of tumor involving the head and neck region and skull base. Thyroid surgery, carotid endarterectomy, cardiothoracic and primary lung procedures may also result in laryngeal paralysis. Patients with laryngeal paralysis typically present with disabling symptoms including loss of voice, difficulty swallowing and airway obstruction. While surgical procedures exist to remedy these symptoms, their success has been limited by the muscle atrophy that accompanies laryngeal paralysis. Moreover, current approaches to the surgical repair of injured nerves have had little impact on return of laryngeal function and are not widely accepted as treatment options. To address this clinical problem, we have designed a rat laryngeal paralysis model to study novel gene transfer strategies using a muscle specific expression system to enhance local delivery of growth factors. In preliminary studies, a non-viral vector containing the a-actin promoter and human IGF-I gene sequence was injected into paralyzed adult rat laryngeal muscle. Positive effect on both muscle and nerve were demonstrated one month following single injection of this hIGF-I gene formulation. These effects were comparable to those observed following daily, local or systemic, injections with hIGF-I protein given over 3 to 6 weeks. Base on preliminary findings, it is hypothesized that the myotrophic and neurotrophic effects of hIGF-1 will have greater impact during the process of nerve regeneration and muscle reinnervation. This study will explore the use of non-viral and viral gene transfer for the delivery of hIGF-I and other growth factors applied to reinnervation of laryngeal muscle. Our results will have direct relevance towards creating a more practical treatment strategy for human disorders, including treatment of laryngeal paralysis and other peripheral nerve injuries.