Gene therapy to restore hearing: a new portal

One of the most significant obstacles to providing genetic therapies for hearing loss is access to the inner ear. Our ears are intricate and have complex structures that make it difficult to receive treatment in the cochlea. Recently, a study led by Mathiesen and colleagues has revealed a new method for delivering gene therapy to the inner ear via the cerebrospinal fluid. But what does this mean and how does it work?

How does cerebrospinal fluid improve access to the ear?

Accessing the adult cochlea, embedded deep within the temporal bone, has been challenging. The cochlea is a spiral-shaped, fluid-filled structure located in the inner ear that is vital to hearing. It converts sound vibrations into electrical signals, which are then transmitted to the brain for processing. The cochlea houses thousands of tiny hair cells that detect different pitches and volumes of sound. These hair cells convert mechanical sound energy into nerve signals, allowing us to perceive and interpret different sounds.

Cerebrospinal fluid (CSF) is a possible way to enter the cochlea due to its connection with the fluid of the inner ear. In a study published in Science Translational Medicine, researchers explored a bony canal called the cochlear aqueduct, which connects the cerebrospinal fluid to the cochlear fluid in adult mice. The study aimed to use this pathway to deliver gene therapy to restore hearing in adult deaf mice. Using this natural route aims to administer therapeutic genes directly into the inner ear without the need for invasive procedures that can damage delicate structures.

Methodology and Findings

The study used advanced imaging techniques, including time-lapse magnetic resonance imaging (MRI), computed tomography (CT) and optical fluorescence microscopy, to track the movement of large particle tracers injected into the cerebrospinal fluid. These tracers reached the inner ear via the cochlear aqueduct. This approach was applied to gene therapy using an adeno-associated virus that carries it Solute carrier family 17 member 8 (Slc17A8) gene, which can help restore hearing. The results showed that the administration of cerebrospinal fluid gene therapy is feasible for adult genetic deafness. A single injection restored vesicular glutamate transporter protein-3 (VGLUT3) to the inner hair cells of the cochlea, effectively rescuing hearing.

Implications for future research

The success of this study has important implications for future gene therapy research. The ability to deliver therapeutic genes through the cerebrospinal fluid provides a noninvasive, efficient method to target the inner ear and potentially other neurological conditions. This method minimizes the risk of damage to critical structures inside the ear. It can be adjusted for various genetic disorders that affect hearing and balance.

This approach could also change the way we administer gene therapies for conditions other than genetic deafness. The flow of cerebrospinal fluid through the lymphatic system, which helps transport drugs throughout the brain, may work just as well in humans. This opens up new opportunities for the treatment of genetically linked progressive neurological diseases that require precise targeting of therapeutic agents.

Study limitations and future directions

While the study’s findings are promising, it is important to acknowledge its limitations. The research was conducted in mice, and translation of these results to humans will require extensive clinical trials. Furthermore, the long-term effects and safety of cerebrospinal fluid gene therapy need a thorough evaluation. Future research should optimize the delivery method, ensure sustained expression of therapeutic genes, and assess possible off-target effects.

However, the study by Mathiesen and colleagues represents a step forward in gene therapy for genetic deafness in adults. By exploiting the natural pathway of the cochlear aqueduct, researchers have demonstrated a novel, noninvasive method to deliver therapeutic genes to the inner ear. While challenges remain, this innovative approach holds tremendous promise for future treatments.

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This story is part of a series on current progress in Regenerative Medicine. In 1999, I defined regenerative medicine as a collection of interventions that restore disease-damaged, trauma-damaged, or time-worn tissues and organs to normal function. I include a full spectrum of chemical-based, gene- and protein-based drugs, cell-based therapies, and biomechanical interventions that achieve this goal.

In this subseries, we focus specifically on gene therapies. We explore current treatments and examine advances poised to transform healthcare. Each article in this collection delves into a different aspect of the role of gene therapy within the larger narrative of Regenerative Medicine.

To learn more about regenerative medicine, read more stories at www.williamhaseltine.com