Patrick Cody, Ph.D.
The Research
University of Pittsburgh
Comprehensive hearing recovery evaluation of novel targeting sequences for cell-type–specific gene therapy for hearing loss
Gene replacement therapy has the potential to restore natural hearing in individuals with congenital deafness, potentially overcoming the limitations of cochlear implants. While cochlear implants provide substantial benefits, they rely on artificial signals to bypass affected inner ear structures that are essential for accurate speech perception in noisy environments. In contrast, gene therapy treats congenital hearing loss by delivering a functional copy of affected genes to restore natural mechanisms of the inner ear. However, evaluations of current therapies fail to capture hearing recovery in complex listening situations and hearing restoration is limited due to imprecise targeting of the affected inner ear cell types. There are over 100 forms of congenital deafness that impact specific inner ear cell types making treatments challenging to scale.
This project addresses these limitations through two innovations. First, using an established animal model of congenital deafness, we introduce a comprehensive approach to gene therapy evaluation that tracks how the auditory pathway adapts to complex sound environments and recovers over time. We will explore whether improved cell-type targeting of gene delivery can improve how the brain recovers and adapts to sound. Second, we apply a model-based platform to design gene regulatory elements that target gene therapy to specific inner ear cell types. This generalizable approach can be tailored to target various cell types for delivery at specific ages and thus can accelerate the development of therapies for other forms of gene linked deafness.
Long-term goal: Precise cell-type targeting is critical to the success of cochlear gene therapy for congenital deafness to avoid detrimental effects of off-target gene expression. Using analytical approaches, we have previously identified a promoter sequence that targets gene replacement therapy specifically to hair cells to recover hearing in deaf mice lacking TOMT. This award will fund the validation of our proposed generalizable model-based approach in our established platform to identify novel gene regulatory sequences that target hair cells for gene therapy delivery at specific ages. Upon validation of our scalable approach, we will next design gene regulatory elements that are optimized for physiological expression across the cochlea and target cell-types affected by other forms of congenital deafness. Current gene therapies in clinical trials solely address a single form congenital deafness. This phase in our plan would mark a significant step for accelerating cochlear gene therapy development to benefit patients with a broad range of congenital hearing loss forms.
Validation of candidate targeting sequences using our current screening platform is limited to at most 3 candidates per delivery experiment. Concurrent with scaling to additional cell-types, within the next 2 years, we will work towards greater screening throughput using multiplexed screening methods that rely on candidate barcoding such as Xenium. This will enable screening of 80+ candidates in one run and would significantly accelerate therapy development.
Restoring natural hearing with biological therapies can translate to transformative benefits for those suffering from hearing loss by enhancing their ability to communicate effectively, reducing cognitive effort required for listening, and preventing the social isolation often associated with hearing impairment. Our proposed evaluations of central processing, sound context adaptation, and perception will fill a critical gap in both cochlear gene therapy development and our understanding of hearing loss recovery mechanisms. Our next step is to the evaluate therapeutic benefit on listening effort such as with a pupillometry based assay. This will mark a critical step to improving therapies for speech perception in challenging listening environments.
Finally, before safety studies and clinical implementation, the next stage of our plan is preclinical therapeutic optimization. To better optimize viral serotype and dosing parameters for the scale of the human cochlea, we will work with a department colleague with expertise in viral gene delivery in a porcine model.
Recipient of an Elizabeth M. Keithley, Ph.D. Early Stage Investigator Award, generously funded by Zellis Family Foundation