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

Brendan M. Doyle, Michele L. Singer, Thomaz Fleury-Curado, Sabhya Rana, Ethan S. Benevides, Barry J. Byrne, Vsevolod Y. Polotsky, David D. Fuller

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)402-412
Number of pages11
JournalGene Therapy
Issue number7-8
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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