Congenital and childhood sensorineural hearing loss (SNHL) is a multifactorial, complex disease that severely impacts quality of life. The single most important etiology of congenital SNHL is prenatal human cytomegalovirus (HCMV) infection, accounting for 20-30% of all deafness in infants and children. This may be an underestimate, as most newborns are not routinely screened for HCMV infection. SNHL can be either bilateral or unilateral, and the severity of the hearing loss as well as its progression varies widely. Although the association of congenital HCMV infection and SNHL has been recognized for 50 years, how HCMV induces the hearing loss is unknown, particularly in cases of delayed SNHL. Embryonic stem cells (ES) provide an abundant source of precursors that can be differentiated to neural cells. We have developed a method to induce differentiation of human ES into progenitors that can be further differentiated to hair cell-like cells and auditory neurons in the inner ear. The goal of our proposed studies is to determine how HCMV infection compromises the function of human ES-derived inner ear cells and to use this information to develop new strategies for the treatment and prevention of hearing loss in congenitally infected children.
Statement of Benefit to California:
Congenital and childhood sensorineural hearing loss (SNHL) is a multifactorial, complex disease that severely impacts quality of life. The single most important etiology of congenital SNHL is prenatal human cytomegalovirus (HCMV) infection, accounting for 20-30% of all deafness in infants and children. In 2011, there were 502,203 births in California, resulting in congenital HCMV infection in approximately 5,000 newborns, with at least 800 infants expected to have long-lasting disabilities. In contrast, before the development of the rubella vaccine, less than 70 infants per year in the entire US were reported to have congenital rubella syndrome, also associated with deafness. The burden to families and the economic costs to society of congenital cytomegalovirus infection are immense, and there is no vaccine available. Our proposed research builds upon our novel finding that HCMV directly alters the regulation of genes critical for cochlear development. It will serve to form the basis of future therapies to ameliorate this serious medical burden.
Our research will provide the knowledge base to understand the mechanisms by which HCMV infection leads to SNHL. It will also provide a foundation for studies of how specific changes in cells in neural and sensory cell lineages contribute to deafness. Intellectual property from this work will also feed into opportunities for antiviral strategies and increased jobs in the biotech industry for Californians.