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At �ٺ���Ƶ’s Voice Center, research efforts have led investigators to an evolved understanding of the mechanisms behind voice, swallowing, and airway disorders. Three recent, groundbreaking studies could transform these insights into novel treatment options for patients.

These studies, co-led by Milan R. Amin, MD, clinical associate professor of otolaryngology—head and neck surgery, chief of the Division of Laryngology, and director of the Voice Center, and , associate professor of otolaryngology—head and neck surgery and associate director of the Voice Center, reveal promising new therapies that could transform treatment for vocal cord paralysis, scarring, and recurrent respiratory papillomatosis.

Vocal Fold Augmentation Improves Airflow, Reduces Pneumonia Risk

One of the most significant issues confronting patients with vocal cord paralysis is aspiration that can lead to pneumonia. A recent Voice Center study revealed that vocal fold augmentation can improve cough strength and peak airflow in patients with glottic insufficiency, potentially preventing aspiration and pneumonia in high-risk patients with Parkinson’s disease and other neuromuscular diseases. In the study, published in the July 2017 issue of JAMA Otolaryngology—Head and Neck Surgery, 14 patients underwent vocal fold augmentation.

Of the 14 patients, 11 showed improved cough strength at follow-up and 12 met established peak airway thresholds (160-180 L/min) required for effective clearance.

“Our investigation suggests that improving glottic closure improves cough strength,” notes Dr. Amin, senior author of the study. “This finding is critical considering the significant morbidity and mortality associated with pneumonia, particularly in the elderly and the neurologically impaired.”

New Treatment Target Uncovered for Vocal Fold Scarring

The nuclear receptor NR4A1 is implicated in multiple disease processes, including vocal fold scarring. NR4A1 is known to inhibit transforming growth factor beta (TGF-β)—which plays a key role in wound healing and tissue repair but which can cause fibrosis when overexpressed—yet the receptor’s specific role in preventing or treating vocal fold disease was unclear. In new in vitro and in vivo studies, Dr. Branski showed that NR4A1 expression increased following vocal fold injury and that knocking down the expression of NR4A1 enhanced production of TGF-β. These findings, published in the September 2017 issue of The Laryngoscope, suggest that therapies targeting NR4A1 could effectively treat vocal fold fibrosis.

“NR4A1 could be an easily accessible target for intervention,” says Dr. Branski, senior author of the study. “We’re now looking at whether local injection of cytosporone B, an NR4A1 agonist, could treat scarring without systemic side effects.”

Injectable Treatment May Offer Alternative for RRP-Associated Lesions

For patients with recurrent respiratory papillomatosis (RRP), repeated surgeries are often the only course of action to manage the wart-like lesions on the vocal folds spurred by the human papillomavirus (HPV). Recent research conducted by Dr. Amin and Dr. Branski may offer an alternative treatment option: an injectable formulation of imiquimod, a nucleoside analogue currently used in topical form to treat other HPV-mediated diseases. Using an animal model, the investigators sought to establish the safety of imiquimod, which has been shown to cause local inflammatory reactions in other tissues. Injections were well tolerated in all animals, without any acute airway morbidity.

These findings, published in the February 2017 issue of Otolaryngology—Head and Neck Surgery, provide a foundation for future investigation of imiquimod as an injectable therapy for RRP, says Dr. Branski, senior author of the study. “We now have the preclinical safety data needed to begin planning early-phase trials in humans as well as further mechanistic studies,” he notes.

Taken together, these three studies hold great promise for improving outcomes for patients with vocal fold disease and dysfunction, adds Dr. Amin. “For the past decade we have focused on gathering data and understanding the underlying causes of voice, swallowing, and airway disorders,” he says. “Now we’re transitioning from discovery to intervention.”