According to a study published in the Proceedings of the National Academy of Sciences, a team of Harvard Medical School scientists has developed a drug cocktail that can regenerate the hair cells that enable hearing in the inner ear. Researchers identified a combination of drug-like molecules composed of small molecules and siRNAs that effectively reprogrammed fully mature wild-type supporting cells for hair cell-like cell regeneration in a mouse model.
This discovery represents a significant step forward in the treatment of hearing loss, which affects millions of people without a single FDA-approved drug for treatment. The loss of inner ear sensory cells, the hair cells, is considered one of the most common causes of hearing loss, which is generally permanent. Cochlear hair cell (HC) damage and loss are considered one of the most common causes of hearing loss that is generally permanent.
The terminally differentiated supporting cells cannot compensate such loss, which do not readily transdifferentiate into new hair cells in adult mouse cochleae. The scientists stimulated the regeneration of hair cells in mice’s inner ear by modifying genetic pathways through reprogramming. Previous research has primarily focused on the regeneration of hair cells (HCs) in neonatal mice. However, the current study has shown the potential for regenerating adult HCs, albeit with low efficiency.
Researchers have developed a two-step approach for regenerating auditory HCs in the adult Organ of Corti to address this issue. The first step involves the transient co-activation of two genes: the cell cycle activator Myc and the inner ear progenitor gene Notch1. This reprograms adult cochlear supporting cells (SCs) into a state more receptive to HC regeneration.
In the second step, the researchers overexpressed the transcription factor Atoh1 in the reprogrammed SCs, causing them to transdifferentiate into HC-like cells in vitro and in vivo. Using single-cell RNAseq, the researchers identified the pathways underlying the MYC/NOTCH-mediated reprogramming of adult mouse cochlea. This information helped them develop a combination of drug-like molecules to achieve reprogramming and HC-like cell regeneration in mature inner ear tissues.
The researchers tested their cocktail on adult WT cochlea and detected HC-like cell regeneration after Ad.Atoh1 infection in vitro, achieving similar efficiency to that of rtTA/tet-Myc/tet-NICD mice, which are more efficient than VPA/siF/siM. Moreover, the researchers observed that HC-like cell transdifferentiation was more efficient in the limbus region, suggesting deeper reprogramming by MYC/NICD.
In a mouse model with severe HC loss, the researchers observed HC-like cell regeneration in reprogrammed SCs treated with the “VLFsiFsiM” cocktail but not in non-reprogrammed SCs treated with vehicle. Adenovirus infection directed the new HC-like cells to the appropriate location within the SOX2+ supporting epithelium.
Although the results are promising, the researchers plan to test their approach on larger animals before attempting human trials. The study demonstrates the potential for chemical-mediated reprogramming and HC regeneration in the mature mammalian cochlea.
The development of this drug cocktail could profoundly impact individuals who have lost part of their hearing. However, the treatment still needs to undergo clinical trials, and it remains to be seen if it will work as effectively in humans as it did in mice. Still, the discovery represents an important step forward in treating hearing loss, a condition affecting millions of people worldwide.
