It was an exciting discovery at the time, but Chen says such an approach could not be directly translated to humans. It cannot be turned on.
Drug therapy must be introduced into the inner ear to activate the Myc and Notch pathways, he explained.
Previous studies have shown that a compound called valproic acid can activate Notch, but no molecule exists that effectively activates Myc. As a result, researchers have instead sought drug molecules that can alter the downstream pathways that turn Myc on and off when it is activated.
Through single-cell RNA sequencing, they found that activation of Myc and Notch had downstream effects in which two other pathways, Wnt and cAMP, were activated. Importantly, we have discovered compounds that can directly activate Wnt and cAMP.
We then used small biological molecules called small interfering RNAs (siRNAs) to remove downstream genes that suppress Myc pathway activation.
“Think about the brakes when driving a car,” Chen explained. “You can’t drive with your brakes on all the time. We’ve discovered an siRNA that can unlock this gene pathway.”
The researchers then combined the compounds with siRNA molecules to create drug-like cocktails. They delivered it to the inner ear of normal adult mice with damaged hair cells — An important difference is that wild-type non-transgenic mice are more translatable to humans.
they delivered more genes Trace 1 By a gene therapy approach that utilizes a cocktail of harmless adenoviruses in the inner ear.
Amazingly, they found that this drug-like cocktail combined with adenovirus turned on Myc and Notch, leading to the regeneration of new hair cells. I’ve confirmed that it’s working by imaging and other techniques.
Regeneration of hair cells by gene therapy
Studies like Chen’s show the potential of gene therapy to treat incurable diseases like deafness. Last year, this research project was selected from among hundreds. Destructive Dozen At the Mass General Brigham World Medical Innovation Forum, gene and cell therapy technologies are most likely to have a major impact on healthcare over the next few years.
Mass General Brigham recently launched the Gene and Cell Therapy Laboratory to translate the scientific discoveries made by researchers like Chen into first-in-human clinical trials and, ultimately, life-changing treatments for patients. is supporting the
Researchers are conducting ongoing research and refinement of this therapeutic approach in larger animal models necessary before applying to initiate clinical trials.
They point out that more research is needed to address the limitations and challenges of delivering treatments to the inner ear.
Scientists are investigating a variety of gene therapy and surgical methods. An approach honed previously in Mass Eye and EarIn this study, another viral vector called adeno-associated virus (AAV) was able to precisely and safely deliver gene therapy to the inner ear through novel surgery.
A similar AAV surgical approach is now used in Mass Eye and Ear in approved and experimental pharmacotherapy for patients with hereditary retinal disorders that can lead to blindness.
“My colleagues and I are frequently contacted by people with hearing loss who are desperate for effective treatment,” Chen said. “If we can combine surgical procedures with sophisticated methods of gene therapy delivery, we hope to achieve our ultimate goal of introducing new therapies into the clinic.”
Authorship, Funding and Disclosure
Co-authors on this study include Yizhou Quan, Wei Wei, Volkan Ergin, PhD of Mass Eye and Ear, Arun Prabhu Rameshbabu, Mingqian Huang, ChunJie Tian, Srinivas Vinod Saladi, and Artur Indzhykulian.
This study was supported by the National Institutes of Health (NIH grants R01DC006908, R01DC016875, R56DC006908, UG3TR002636, and R01DC017166), Department of Defense (DOD grant W81XWH1810331, W81XWH2110957), Fredrick and Ines Yeatts Hair Cell Regeneration Fellowship, Harvard Catalyst Translational Innovator Program The Five Senses, and Mike Toth Head and Neck Cancer Center.
Chen is a co-founder, SAB member and owner of more than 5% stake in Salubritas Therapeutics, which develops hearing loss treatments including genome editing, inner ear regeneration, de novo delivery and gene therapy. Quan and Chen are co-inventors of a patent application filed based on this research. A patent has also been filed for a small molecule/siRNA combination in hair cell regeneration.
Adapted from Misa’s eyes and ears news release.