Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction.

Disabling hearing loss is expected to affect over 900 million people worldwide by 2050. The World Health Organization estimates that the annual economic impact of hearing loss globally is US$ 750 billion. The inability to hear may complicate effective interpersonal communication and negatively impact personal and professional relationships. Recent advances in the genetic diagnosis of inner ear disease have keenly focused attention on strategies to restore hearing and balance in individuals with defined gene mutations. Mouse models of human hearing loss serve as the primary approach to test gene therapies and pharmacotherapies. The goal of this review is to articulate the rationale for fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. The differential onset of hearing in mice and humans suggests that a prenatal window of therapeutic efficacy in humans may be optimal to restore sensory function. Mouse studies demonstrating the utility of early fetal intervention in the inner ear show promise. We focus on the modulation of gene expression through two strategies that have successfully treated deafness in animal models and have had clinical success for other conditions in humans: gene replacement and antisense oligonucleotide-mediated modulation of gene expression. The recent establishment of effective therapies targeting the juvenile and adult mouse provide informative counterexamples where intervention in the maturing and fully functional mouse inner ear may be effective. Distillation of the current literature leads to the conclusion that novel therapeutic strategies to treat genetic deafness and imbalance will soon translate to clinical trials.