GENE THERAPY FOR LARYNGEAL PARALYSIS

喉麻痹通常是由于手术切除累及头颈部和颅底的肿瘤而发生。甲状腺手术、颈动脉内膜切除术、心胸手术和原发性肺手术也可能导致喉麻痹。喉麻痹患者通常表现为致残症状，包括失声、吞咽困难和气道阻塞。虽然外科手术可以治疗这些症状，但由于喉部麻痹引起的肌肉萎缩，手术的成功受到限制。此外，目前手术修复受损神经的方法对喉功能的恢复影响不大，并没有被广泛接受为治疗选择。为了解决这个临床问题，我们设计了一个大鼠喉麻痹模型来研究新的基因转移策略，利用肌肉特异性表达系统来增强生长因子的局部传递。在初步研究中，将含有a-actin启动子和人IGF-I基因序列的非病毒载体注射到瘫痪的成年大鼠喉肌中。单次注射该higf - 1基因制剂一个月后，对肌肉和神经均有积极作用。这些效果与每天局部或全身注射3至6周的higf - 1蛋白所观察到的效果相当。根据初步研究结果，我们推测在神经再生和肌肉神经再生过程中，hIGF-1的肌营养和神经营养作用会产生更大的影响。本研究将探索利用非病毒和病毒基因转移的方法，将hIGF-I和其他生长因子用于喉肌再神经支配。我们的研究结果将直接关系到创造一种更实用的治疗人类疾病的策略，包括治疗喉麻痹和其他周围神经损伤。

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.