Vocal fold paralysis occurs when the recurrent laryngeal nerve (RLN) is injured, frequently during surgery in the neck or chest. Immobility of one vocal fold often creates a hoarse, breathy voice, loss of volume, and aspiration of liquids with swallowing that can potentially lead to pneumonia. Many people recover from vocal fold paralysis as the RLN can regenerate some of its fibers, but more than half of patients with paralysis need some form of intervention to correct the problem. Most often, this takes the form of a procedure that adducts the vocal fold, by injection, implant, or reinnervation. Because of the potential for possible recovery, current practice is to wait for 6-12 months before any permanent correction is offered. An alternative, proactive approach was previously proposed by the PI. Rather than wait for possible recovery, it was proposed that an injection be performed soon after paralysis has occurred, with the goal of preventing recovery of the abductor muscle, and thereby favoring a natural adduction recovery pattern. In a canine study, it was found that a single dose of vincristine injected into the posterior cricoarytenoid (PCA) muscle resulted in significantly stronger closing force, measured 6 months after the injury. This project seeks to further study this concept using an intervention pattern that mimics the common clinical scenario in which the patient first comes for treatment months after the injury has occurred. In the same canine model, the vincristine will be given at 3, 4, and 5 months after injury, and the recovered strength measured at 6 months. Some of the dogs in this study will be followed for a longer time period (12 months) to make sure the effect is permanent. If a 3 or 4 month post-injury vincristine injection does result in permanent improvement, as hypothesized, this approach could represent a new paradigm for preventive medicine with vocal fold paralysis, and a clinical trial would be next. Sometimes the RLN is known to be injured during surgery, or is intentionally sectioned, such as for cancer. There are a number of neurotrophic factors that could enhance nerve regrowth, but they need to be present at the site of injury for months in order to have a benefit. . A new way of incorporating these neurotrophins has been developed, that allows the agent to slowly leak into the region of the injured nerve so that it maintains a high enough concentration throughout the nerve recovery period. One factor, neurotrophin 3 (NT-3), is known to favor regeneration of fast-twitch fibers such as those found in the adductor muscles of the larynx. In this study, NT-3 will be tested using this new delivery system, for its effects on nerve regeneration, using a rat model and then the canine model. A second neurotrophin, glial-derived neurotrophic factor (GDNF), strong affects recovering nerves, but in a non-specific way;this agent will be used for comparison. These approaches would require that the nerve is exposed in the neck and would have their greatest use for known or planned nerve transection injuries, such as with thyroid cancer surgery, laryngeal reinnervation procedures, or potentially with laryngeal transplantation.

Public Health Relevance

This project explores two new possible treatments for patients with an injured laryngeal nerve, using animal models. The first treatment involves injection of a drug, vincristine, into the laryngeal abductor (opening) muscle to prevent it from regaining a nerve supply and competing with the adductor (closing) muscles that produce voice;this preventive medicine approach is very different from the wait-and-see approach that ENT doctors currently use. The second treatment investigates ways to get the injured laryngeal nerve to grow back stronger and in a more desirable alignment with its original muscles, using some new bioengineering materials that help the growth factors remain at the site of nerve injury to do their job.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DC010884-05
Application #
8686812
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130