Abstract
Recurrent laryngeal nerve (RLN) injury has considerable clinical implications, including voice and swallowing dysfunction, which may considerably impair the patient’s quality of life. Recovery of vocal fold movement is an essential novel treatment option for RLN injury. The potential of gene therapy for addressing this issue is highly promising. The target sites for RLN gene therapy are the central nervous system, nerve fibers, laryngeal muscles, and vocal cord mucosa. Gene transduction has been reported in each site using viral or non-viral methods. The major issues ensuing after RLN injury are loss of motoneurons in the nucleus ambiguus, degeneration and poor regeneration of nerve fibers and motor end plates, and laryngeal muscle atrophy. Gene therapy using neurotrophic factors has been assessed for most of these issues, and its efficacy has been reported. Another important matter for functional vocal fold movement recovery is misdirected regeneration, in which the wrong neurons may innervate other laryngeal muscles, where even if innervation is reestablished, proper motor function is not restored. Novel strategies involving gene therapy bear promise for overcoming this issue and further investigations are underway.
Highlights
The recurrent laryngeal nerve (RLN), which carries motor, sensory, and parasympathetic fibers to the larynx [1], is a branch arising from the vagus nerve (VN), known as the 10th cranial nerve
A significant decrease in expression of type IIA/X. These findings suggest that the myotrophic effect of insulin-like growth factor I (IGF-I) gene transfer results in normalization of Myosin heavy chain (MHC) composition in denervated muscle, with suppression of type IIA/X MHC and promotion of type IIL expression [35]
Treatment with brain-derived neurotrophic factor (BDNF) and/or glial cell line-derived neurotrophic factor (GDNF) after avulsion suppressed the activity of nitric oxide synthase (NOS) in lesioned motoneurons in the nucleus ambiguus. These results indicate that adenovirus-mediated BDNF and/or GDNF gene transfer may prevent the degeneration of motoneurons after either vagal nerve injury or recurrent laryngeal nerve injury [18]
Summary
The recurrent laryngeal nerve (RLN), which carries motor, sensory, and parasympathetic fibers to the larynx [1], is a branch arising from the vagus nerve (VN), known as the 10th cranial nerve. The failure of reinnervation after RLN injury may be attributed to multiple factors, including decreases in motor fiber density, atrophy of laryngeal muscle, loss of motoneurons in the motoneuronal nucleus (nucleus ambiguus in medulla oblongata) [5], and inappropriate or misdirected innervation by antagonistic motoneurons [7,8] (Figure 1). Recent advances in neurology have led to the discovery of several neurotrophic and growth factors These factors have regenerative and protective effects on the central nervous system and myoneural function through motoneurons, nerve fibers, motor endplates, and muscles. The impact of these factors using gene therapy is often investigated on peripheral nerve regeneration. Treatment targets for functional recovery in RLN injury include vocal cords, laryngeal muscles, neuromuscular junctions, axons fibers of RLN, and motor neurons in nucleus ambiguus. Future prospective strategies to overcome the misdirected reinnervation which is as the most important and challenging problem is discussed
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