Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

Abstract

Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

Chemogenetic stimulation of phrenic motor output and diaphragm activity

“…In the remaining studies, excitatory DREADDs were applied to spinal motoneurons as way to improve axon regeneration follow peripheral nerve injury 43, 44 . A small but growing body of work has employed DREADDs to activate hypoglossal (XII) motoneurons in the brainstem 8 . Collectively, these studies show that once hM3D(Gq) is expressed in XII motoneurons, DREADD ligands will rapidly produce an increase in the EMG activation of tongue muscles 14, 15 .…”

“…This provides a means to selectively stimulate cells expressing the DREADD. Prior studies have used DREADDs to stimulate upper airway muscle activation during breathing 8 . For example, following expression of DREADDs in murine hypoglossal motoneurons, tongue electromyogram (EMG) activity can be increased using DREADD ligands 12–16 .…”

“…Treatment options that target increased respiratory motoneuron activation to improve breathing ability are limited. However, designer receptors exclusively activated by designer drugs (DREADDs) may have use in this regard 8 . Structurally derived from naturally occurring G-protein coupled receptors, DREADDs have been engineered to respond exclusively to exogenous ligands that are otherwise biologically inert 9–11 .…”