GENE THERAPY FOR LARYNGEAL PARALYSIS

喉部瘫痪通常是因为手术切除了累及头颈部和颅底的肿瘤而导致的。甲状腺手术、颈动脉内膜切除术、心胸手术和原发肺部手术也可能导致喉部瘫痪。喉麻痹患者通常会出现包括失声、吞咽困难和呼吸道阻塞在内的致残症状。虽然有外科手术可以纠正这些症状，但由于伴随着喉部瘫痪的肌肉萎缩，手术的成功受到了限制。此外，目前手术修复受损神经的方法对喉功能恢复的影响很小，也没有被广泛接受为治疗方案。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，使用肌肉特异性表达系统来增强局部生长因子的传递。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瘫痪的成年大鼠喉肌中。单次注射该hIGF-I基因制剂1个月后，对肌肉和神经均有积极作用。这些效果与每日、局部或全身注射hIGF-I蛋白3至6周后观察到的效果相当。根据初步的研究结果，推测hIGF-1的肌肉营养和神经营养作用在神经再生和肌肉再支配过程中将产生更大的影响。本研究将探索利用非病毒和病毒基因转导hIGF-I和其他生长因子应用于喉肌的神经再支配。我们的结果将直接关系到为人类疾病创造更实用的治疗策略，包括治疗喉部瘫痪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.