By Rideeta Raquib ’19

Inner ear disease disrupts a key sense of hearing for many people worldwide. However, gene therapy can treat inner ear disease if reagents are introduced into appropriate cells. A group of researchers from Harvard Medical School and the Massachusetts Hospital managed to effectively restore hearing in mice by utilizing gene therapy.

The inefficacy of vectors transferred into hair cells is a challenge that researchers have when constructing gene therapy. The two types of hair cells are inner hair cells (IHC), which are responsible for converting mechanical stimulus of the sound vibrations to neural signals that are transmitted via type I ganglion neurons to the brain, and outer hair cells (OHC), which connect to type II neurons. Genes that express deafness tend to affect cell function in both hair cell types. Adeno-associated virus (AAV) vectors tend to be restricted to only IHC and not OHC. Exosome-associated AAV vectors (exo-AAVs) were tested for delivery to cochlea hair cells in mice to analyze the different injection routes. Exosomes are natural lipid structures found in cells that play a part in intracellular communication and could potentially be therapeutic carriers of proteins or nucleic acids. Exo-AAVs were utilized, because transduction of cells was enhanced in vitro and in vivo by exosome incorporation with AAV. One of the AAV types, AAV1 was reported to be the most effective for cochlear hair transduction, thus AAV1 and exo-AAV1 were prepared by isolating them from the lysate and culture medium. In the first postnatal day, the cochleas were dissected and placed in an organ culture, and then the vectors were added the next day. The culturing process proceeded for three days and tissues were fixed.

Overall, the exo-AAV1 vector was more efficient compared to conventional AAV1 vector in gene delivery to both inner and outer hair cells. In order to test whether efficient gene levels in hair cells translated to expression of relevant hair cell genes, the expression of Lipoma HMGIC Fusion Partner-Like (Lhfpl5) gene after exo-AAV treatment of mice was evaluated and it was determined that they showed improved response to sounds. HMGIC is a high-mobility protein group, and the Lhfpl5 gene causes autosomal recessive hearing loss.

This study advanced gene-delivery treatment for hearing restoration. Although full hearing was not restored, further studies could certainly utilize such strategies to test how AAV treatment affects the expression of other types of genes in hair cells and a possible therapeutic measure could be developed.

References:

1. B. György, et. al. Rescue of hearing by gene delivery to inner-ear hair cells using exosome-associated AAV. Molecular Therapy (2017). doi: 10.1016/j.ymthe.2016.12.010.
2. Image retrieved from: http://www.shelbyearnoseandthroat.com/wp-content/uploads/2015/12/Dollarphotoclub_73607640.jpg