Foxo3

Summary

Dr. Lorna Harries’ lab has identified an innovative way to modulate FOXO3, a well known and yet undrugged longevity target, and propose leveraging it to address chronic lower back pain stemming from degenerative disc disease. They plan to make short, lab-made modified RNA molecules (antisense oligonucleotides) that selectively switch FOXO3’s “good” message on, first in human cells and mini-disc models. Success would yield 1) a lead drug candidate, 2) proof it can restore disc health, and 3) the data needed for patenting and further development. The same molecules could later be adapted to treat many other age-related conditions, helping people stay healthy for longer.

Problem

FOXO3, a critical "hub" gene that orchestrates cellular maintenance and is linked to an increased chance of exceptional longevity in humans, remains an undrugged target: previous attempts to activate it failed due to a lack of specificity, causing unwanted effects on other signaling pathways. Simultaneously, Degenerative Disc Disease (DDD) represents a major unmet medical need as the leading cause of physical disability and lower back pain. Current treatments are inadequate: steroids have adverse side effects, while surgery is invasive, risky, and can accelerate degeneration, leaving patients without disease-modifying options.

Impact

Prof. Harries’ team proposes a disease-modifying intervention by modulating FOXO3 mRNA isoforms, aiming to restore the "youthful" long-to-short ratio that diminishes with age and stress. This approach utilizes oligonucleotide drugs (such as saRNAs or ASOs) to precisely control gene expression with a high safety profile, avoiding the pleiotropic effects of small molecules. In the context of Degenerative Disc Disease (DDD), FOXO3 overexpression helps prevent nucleus pulposus cell death and ameliorates degeneration. The proposed therapy involves direct injection into the intervertebral space, offering a long duration of action (up to 6 months) and the potential for naked delivery without complex lipid carriers.

DDD is strategically chosen for its clear causal link to FOXO3, the feasibility of local administration, and a substantial market projected to reach $45 billion by 2029. Unlike highly saturated fields such as cancer, the DDD landscape is less crowded, and the proposed targeted oligonucleotide therapy offers superior safety and precision compared to non-specific competitors like stem cells or hydrogels. Success in DDD validates a platform for future label expansion into massive markets, including neurodegeneration ($20B) and cardiovascular disease ($160B). Ultimately, this intervention has the potential to extend both healthspan, by reducing the burden of prevalent age-related diseases, and lifespan. For more information, please see: https://gov.vitadao.com/t/vdp-163-funding-foxo3-oligos-revised/2033