Exosome Gene Therapy for Treating Inner Ear Disease

Extracellular Vesicles Directly Target Inner Ear Cells to Correct Malfunctioning Genes In Vivo

This in vivo gene therapy strategy combines selective gene editors with the cell targeting capability using extracellular vesicles for safe and targeted delivery., Hearing loss affects at least 1 in 500 newborns, and over 50% are hereditary in nature. One in three adults over age 65 will suffer from age-related hearing loss. Gene therapy has been the most promising curable approach to treating hearing loss. Traditionally, gene therapy in treating hearing diseases lacks durable therapeutic efficiency in reaching the inner ear cells, and approaches are invasive, with immunogenic concerns. Extracellular vesicles, which can transport biomolecular “cargo” between cells, can bind with molecules on the surface of cells, enabling them to deliver cargo to the gene of interest.

Researchers at the University of Florida have developed CRISPR extracellular vesicles for efficient and direct delivery of gene editor, in vivo, to inner ear hair cells for gene therapy. This delivery strategy minimizes the chances of an immune response, potentially mitigating harmful side effects, and is non-invasive.

Application

Extracellular vesicle-based delivery of gene therapy for in vivo treatment of sensorineural hearing loss -associated gene mutations

Advantages

• Encapsulates gene therapy machinery in extracellular vesicles, achieving in vivo correction of the genetic mutations linked to SNHL
• Employs biocompatible exosomes to deliver gene therapy, reducing immunotoxicity associated with traditional viral delivery and protecting cargoes from degradation
• Directly targets hair cells in the inner ear, delivering gene therapy more efficiently than conventional therapies
• CRISPR/Cas9 system is adaptable to target other mutations associated with hearing loss, enabling the potential treatment of a wide variety of hearing conditions

Technology

Genetic mutations in hair cells of the inner ear are one of the primary causes of sensorineural hearing loss (SNHL). The identification of mutations of the MYO7A gene as a driver of SNHL enables the development of gene therapy for the treatment of this condition. However, in vivo, gene therapy requires a delivery system bringing nucleic acids into the inner ear and directly targeting hair cells without triggering the patient’s side effects and immunogenicity. To meet these criteria, this therapy utilizes biocompatible exosomes enclosing a CRISPR/Cas9 machinery to eliminate MYOA7 mutations, protecting it from degradation and reducing the risk for immunotoxicity, making them an ideal vector. The gene therapy cargos are versatile and either consist of an RNP complex or a template nucleic acid (donor), such as single-stranded DNA, an endonuclease (Cas9) capable of cleaving a region in the mutated gene, and a single guide RNA to direct the endonuclease to the target site. This system is adaptable to target other hearing loss-associated mutations, enabling the potential treatment of various hearing conditions.