Prevention of communicable disease via hygiene, antibiotics, vaccines, amongst other innovations has provided the largest life expectancy gains in human history. It is increasingly appreciated that pathogens age humans by driving their cell senescence. Our team has identified chemistry that acts as a cellular ‘soap’ to concomitantly thwart pathogens and senescent cells. What’s exciting about the invention is that, as the aforementioned innovations, it not only appears to be a generalizable strategy against many pathogens but also many aging pathologies.
The relationship between infectious disease and aging is increasingly appreciated. Perhaps most well-known now is that advancing age predicts a worse COVID-19 prognosis. However, the relationship is not just correlative – several common pathogens have been implicated as causal mechanisms in models of aging-related disease. For example, with Herpes Simplex Virus (HSV) and Alzheimer’s disease, and the periodontal pathogen P. gingivalis and cardiovascular disease. In most cases, there are neither prophylactics nor therapies to combat these common pathogens and thus to prevent the lifespan-limiting effects they have.
Senolytics have emerged as an intriguing new therapeutic paradigm for aging-related disease. Senolytics selectively kill pathogenic senescent cells compared with healthy proliferating cells, but it is unclear what their molecular target is that provides this selectivity. Without this rationale, it has been hard to make progress in identifying new senolytics. Through combined deep learning and genome-wide screening, we have identified chemical features present in several FDA-approved drugs that provide this long-sought-after rationale. Considering that pathogens render healthy cells senescent, this approach has the potential to “kill two birds with one stone” in thwarting both pathogens and senescent cells. The objective of the project is to conduct a series of in vitro and in vivo experiments to design new drugs that perform against a wide range of senescence inducers. Moreover, there is a clear path to iterate on the chemistry to: 1. Increase drug potency several-fold 2. Eliminate the original use of the drug (i.e., reducing unwanted effects) without affecting its anti-pathogen or senolytic activity 3. Increase the list of patentable compounds from 5 to 100s, providing plentiful patenting opportunities. 4. Use structure / function relationships to design novel scaffolds and compounds with senolytic effects. Commercial Viability The project will generate new compounds, which will provide opportunities for IP-NFT value creation. The IP strategy is extensively mapped out. Therefore, the applicants will be able to begin drafting the provisional patent application promptly upon funding. Intellectual property will focus on novel compositions of matter as that will be the most valuable to future investors.
Novel compositions of matter that will be the basis of the IP-NFT will be tested in multiple cell types using multiple senescence inducers, both pathogen and more classic (DNA damage). These experiments will tell us how broadly vs. context-dependent our drug candidates are. The primary readout will be the well-accepted senescence measures.
Lead compounds will be tested using a mouse model. The mouse model is commonly used in the senescence field and is a well-accepted experimental paradigm. In addition to lifespan, behavioral and neurological scoring (e.g., paralysis), as well as blood and CSF biomarkers, will be assessed.