VDP-146 [Funding] The development of oligonucleotide drugs for healthspan

One-liner: To generate a new RNA drug capable of activating a human healthspan switch mediated by the FOXO3 gene

Longevity Dealflow WG team

• Scientific evaluation: 1 biotech executive, 1 VC, 1 biotech manager, 2 academics
• Shepherd: Adrian Matysek
• Other squad members: Eleanor Davies, Paolo Binetti
• Sourced by: Adrian Matysek
• Project PI: Lorna Harries, PhD

Simple Summary

FOXO3 is a major longevity gene, which acts as a central integration point for many aspects of cellular health and stress resilience, especially in the context of ageing and its associated diseases. Prof. Lorna Harries has identified a druggable mode of action for a longevity-associated genetic variant in the FOXO3 gene, which regulates FOXO3 isoform usage and has potential to act as a ‘switch’ for longevity and improved health span in humans. Here, she plans to exploit this finding by developing a portfolio of oligonucleotide drugs which act to influence FOXO3 isoform usage and to evaluate these in vitro and in vivo.

Full proposal on Discourse

Problem

At present, we take a reactive, rather than proactive, approach to ageing and its associated diseases. The UK Chief Medical Officer’s Health in an Ageing society report in 2023 (which Prof. Harries contributed to) highlighted these issues; whilst we may be living longer, we are not living better. A better approach to dealing with the multimorbidity of ageing needs to be applied (1).

The FOXO3 gene represents one such pivotal intervention point. FOXO3 forms part of an evolutionarily conserved central hub network which integrates multiple molecular and cellular inputs that regulate cellular and organismal ageing (2).

Solution

The FOXO3 gene produces multiple RNA transcripts including 3 linear isoforms (FOXO3-long and FOXO3-short) and a circular RNA (circFOXO3). The longevity haplotype resides in the region of a bioinformatically-predicted alternative promoter and non-coding first exon located in intron 2, and my team proposed in 2021 that it may determine the relative expression of long and short FOXO3 isoforms (8).

My proposed approach is to design a precise intervention that acts only on very specific sequences within the FOXO3 gene alone to upregulate FOXO3-long isoforms or decrease FOXO3-short isoforms, or both in combination, and thus mimic the effects of inheritance of the longevity haplotype on FOXO3 isoform expression in those that do not possess it.

Opportunity

This project will allow us to drug the isoform specific expression of FOXO3, a known geroprotective gene, for physiological enhancement of its activity in a precise and tuneable manner.

The value of a drug that is able to cause even a 1 year increase in healthspan is estimated at $38 trillion. A 10 year increase in healthspan equates to $367 trillion.

Relevance to Longevity

Successful design of an oligonucleotide therapeutic targeting a known geroprotective gene would impact multiple aspects of longevity, healthspan and lifespan. FOXO3 is one of only a handful of genes reliably and reproducibly associated with extreme longevity, which highlights its role as a systemic geroprotector.

IP Roadmap

​​The data packages produced from funding these early stages of this work would form the basis for a patent application to protect the IP. I envisage the end point of the initial funding would be to file an initial application. C. elegans, although a simple organism will fulfil at least part of the necessity for an in vivo model if therapeutic claims are to be made. Following filing, claims would be bolstered by provision of additional data from more complex in vivo systems within the following 12 months, this would be contingent on further funding. Figure 4 illustrates the path to IND status we would take.

Figure 4: The path to clinical for a new oligonucleotide geroprotective drug

Experimental Plan

Hypothesis

Targeted moderation of FOXO3 isoform expression profiles will attenuate cellular ageing phenotypes in vitro and being healthspan and lifespan benefits in vivo.

Objectives

Milestone 1: To use oligonucleotides to influence FOXO3 isoform expression in human primary fibroblasts (dermal and lung), endothelial cells and skeletal muscle cells, and measure effect on FOXO3-FL and TR isoform levels, FOXO3 activity and subcellular localisation, autophagy and mitochondrial function, and on the phenotype and rate of accumulation of senescent cells.

Milestone 2: To specifically express human FOXO3-FL or FOXO3-TR isoforms or both, in a transgenic C. elegans model followed by assessment of lifespan or healthspan parameters (movement, avoidance of noxious stimuli, lipofucin accumulation, lifespan). The experimental plan is illustrated in figure 5 below.

Figure 5: Diagrammatic workplan of proposed project. A. Design and in vitro validation of antisense oligonucleotides capable of attenuating FOXO3 isoform usage. B. Characterisation of the effect of expression of different FOXO3 isoforms on lifespan and healthspan phenotypes in a systemic invertebrate model system C. elegans.

Budget

Financing and VitaDAO Funding Terms

VitaDAO, the Researcher and the University of Exeter will enter into a Sponsored Research Agreement. Payments will be unlocked per milestone accomplished. Such operations will fall under the supervision of the VitaDAO Builder Squad.

If milestones 1 and 2 are met, the project will be spun out as a VitaDAO-supported company. The team will proceed to raise via Intellectual Property Token (IPT) mechanism. Details will be determined in a future VDP. Reference spin out frameworks include Fission Pharma and Matrix Bio.

Team

Professor Lorna Harries

Professor Lorna Harries 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 has a proven track record of translation of basic research; she is inventor on two patents to date.

Dr Sam Gould

Dr Gould is a cell and molecular biologist with a background in cellular ageing. Sam brings a background in tissue engineering and cellular ageing biology and will contribute to the in vitro workplan alongside Dr Appleby.

Dr Sarah Appleby

Dr Appleby has valuable skills in gene editing, primary cell culture and xenotransplantation.

Collaborators

Professor Tim Etheridge

Professor Tim Etheridge is an established expert in the use of C. elegans as a model for understanding human ageing. His work established a new cell-adhesion mechanism regulating C. elegans muscle health and since directly translated this into human clinical trials investigating ageing muscle regeneration.

References

Full proposal on Discourse

Senior Review Digest - Quantitative Below are the average score out of 5 per category from 5 reviewers who all recommended that the project should be advanced for token-holder vote.

Average Scores Team Expertise: 4.4 Feasibility & Data: 4.4 Commercial Potential & Impact: 4.0 Novelty & Market Advantage: 3.8 IP Defensibility: 4.0 Relevance to Longevity: 5.0 Deal Terms: 3.8

General Conviction Score 4.4 (for reference, the average score of past funded projects is 3.7)

Majority of reviewers think the project is a moonshot.

Senior Review Digest - Qualitative Each reviewer was asked whether they would endorse the project, below are their answers.

Reviewer 1 I am enthusiastic about the idea and approach to modulate FOXO3 isoforms to promote healthspan. A tantalising idea that needs more research in order to be feasible for translation. Thus, recommend funding to enrich our biological understanding.

Reviewer 2 Yes, and will refer the project to an investment firm which i am actively involved.

Reviewer 3 Yes. If the tech is indeed unique and the IP can be protected, this project has high scientific merit and would allow VitaDAO to engage with high impact tech at an early phase, potentially increasing future ROI.

Reviewer 4 I fully endorse funding this project. Lorna and her team have identified a druggable mechanism for a longevity-associated genetic variant in the FOXO3 gene. This mechanism regulates FOXO3 isoform usage and has the potential to act as a "switch" for longevity. This discovery is very promising and offers potential for treating various age-related conditions. Shortcomings of prior attempts in targeting FOXO3 have been thoroughly considered and are addressed by the proposed approach.

Reviewer 5 Yes. The final decision making criteria was answered satisfactorily from the team, I endorse the project.