VDP-163 [Funding] FOXO3 oligos - Revised

One-Liner: This project will design a new RNA therapeutic that nudges the longevity-linked FOXO3 gene into its health-promoting form to halt the tissue breakdown behind degenerative disc disease—opening a precise, scalable route to drugs that extend healthspan. FULL Proposal: https://gov.vitadao.com/t/vdp-163-funding-foxo3-oligos-revised/

Simple 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 safety and efficacy testing in animal models (not included in this project). Because this method is highly specific and can be injected straight into the spine, it promises fewer side effects than current steroids or surgery. The same molecules could later be adapted to treat many other age-related conditions, ultimately helping people stay healthy for longer.

Problem

FOXO3, a key yet undrugged longevity gene

To influence multiple facets of ageing simultaneously, we must identify ‘hub’ genes that coordinate multiple cellular processes. The FOXO3 gene is one of four human FOXO genes that forms part of an evolutionarily conserved central network orchestrating autophagy, mitochondrial quality control, DNA-damage repair, metabolic flexibility, and inflammatory restraint—integrating signals from multiple pathways (2-5). As such, it has been implicated in the regulation of ageing (3) and its associated diseases (6-8). One haplotype of FOXO3 (rs13217795-rs4946932-rs9400239) is reproducibly associated with a ≈36% increased chance of exceptional longevity across >11 human populations (2). Despite this compelling genetic validation, FO​XO3 has never been successfully pharmacologically targeted. There have been previous efforts to increase FOXO3 activity using agonists, and benefits have been demonstrated in cells, tissues, and human participants (9, 10), but the molecules concerned were not specific to FOXO3 and had pleiotropic effects on a variety of crucial cellular signalling pathways intersecting with FOXO3 (and the other FOXOs) such as AKT, PI3K and AMPK.

For more background information on FOXO3, please see the “Problem” section of VDP-146.

Lower back pain, a serious unmet need

Lower back pain is the leading cause of physical disability, and Degenerative Disc Disease (DDD), also known as Intervertebral Disc Degeneration (IDD), is the most common cause of lower back pain; 12% to 16% of all adults visit their GP every year for this reason. The UK Office for National Statistics estimates that the annual incident population experiencing back pain is about 3.5 million and the prevalent population experiencing back pain is 17.3 million, with 3.1 million adults suffering during the entire year in the UK alone. Over a 1-year period, 116 million production days were lost to back pain.

There are currently few treatment options. The standard of care (SoC) for DDD is steroids (which have many adverse side effects and adverse long term outcomes) or surgery—which involves protracted recovery time, infection risk (and associated risk of post-operative delirium), and anaesthesia-induced mortality in older patients. Surgery is invasive, costly, not durable, and can even worsen the disease: for example arthrodesis of two vertebrae, induces additional stresses on nearby intervertebral discs (IVD), accelerating their degeneration, leading to the need for more procedures. In summary there is currently no good option, and none disease-modifying.

Solution

Drugging FOXO3 by modulating its isoforms

Prof. Harries’ team discovered that the association between extreme lifespan and FOXO3 genetic variation was likely mediated by the production of alternatively expressed mRNA isoforms of FOXO3 (11).

FOXO3 expresses three linear mRNA isoforms and one circular RNA. The full-length FOXO3-long isoform encodes the complete fork-head DNA-binding domain and is ubiquitous, whereas FOXO3-short lacks key regulatory motifs and is enriched in ageing muscle and degenerating tissues (11). Ageing and metabolic stress progressively tilt the balance toward the short form, diminishing the cell’s ability to mount stress responses and maintain tissue integrity (17). Restoring the youthful long-to-short ratio may therefore represents a precise, mechanistically grounded entry point for gerotherapeutic intervention.

For additional information on FOXO3 isoforms, please see the “Solution” section of VDP-146.

The therapeutics proposed by the lab would be delivered directly to the intervertebral space by injection, a standard route administration. Oligonucleotide therapeutics have a long duration of action; in some cases up to 6 months. They would be delivered naked: the PI, through her role as founder and CSO of SENISCA, has a proven track record of delivering oligonucleotides to human primary cell models by gymnosis, and delivering nucleic acids in simple invertebrate systems is routine. Efficacy could be enhanced with a DDD-specific formulation, adding later growth potential.

Opportunity

While a gerodrug can treat or prevent multiple age-related disease and even extend lifespan, the project will focus on an exemplar and very common disease of ageing: degenerative disc disease (DDD), also known as intervertebral disc disease (IDD), for which no disease-modifying interventions exist. Demonstrating proof of principle in one condition then creates the opportunity to extend the drug’s application to additional aging-associated disorders in the future.

Financing and VitaDAO Funding Terms

This project will be financed through the issuance of Intellectual Property Tokens (IPTs) on Bio Protocol’s platform, anchored by a $50,000 commitment from VitaDAO on the same terms as all contributors, including aligned DAOs, such as SpineDAO.

The funding terms are an agreement for contract research services with Exeter University, granting Vitality Now, the Swiss association representing VitaDAO, ownership to the intellectual property developed by the project.

Team and Research Environment

Professor Lorna Harries

Professor Lorna Harries gained her PhD from University College London in 1994. Lorna established the RNA-mediated disease mechanisms group at Exeter in 2006 and holds a personal chair in Molecular Genetics at the University of Exeter Medical School and a position as co-founder, co-director and Chief Scientific Officer at SENISCA Ltd, a spin out company founded on the Harries lab’s research. Lorna was awarded the Diabetes UK RD Lawrence rising star award in 2011, was a team member of the Queen’s Anniversary Prize for research excellence in 2006 and a direct recipient in 2019. She was awarded the Proteomass Lifetime Career Award in 2021 for her work on senescence and RNA processing. The Harries lab has interests in -omics approaches to the study of ageing and age-related disease processes in humans. She has published over 160 peer reviewed publications in her career which have accrued over 20000 citations, and she has an H index of 56. She has a proven track record of translating basic research and is an inventor on two patents to date, with 7 more in draft.

Research Team

The scientist appointed using these funds (“PDRA” for Post Doctoral Research Associate) will be exclusively focused on this project and will benefit from the wider Harries academic team which consists of 7 individuals with multidisciplinary skills ranging from primary cell biology, multi-omics, organ on a chip systems, bioinformatics, and molecular genetics. This is complemented by the co-location of the lab to the Harries R&D team of SENISCA, for whom Lorna is Founder and CSO. SENISCA has a head count of 16 people and specialises in the development of oligonucleotide drugs.