This proposal asks for 50,000 USD to contribute to a 4 year doctoral research program probing DNA quadruplexes in age-related proteostasis.

Summary

We are proposing to contribute $50,000 USD to a 4 year doctoral research program at the Institute of Chemical Biology, Imperial College London. This doctoral research will aim to establish the role of DNA Helicases (WRN and BLM) as positive regulators of proteostasis and understand their impact of declining function prior to the onset of age-related proteostasis. Furthermore, the project will aim to develop genetic and pharmacological tools to modify DNA helicase activity, that may form the basis of intellectual property and therapeutics. In exchange for supporting this doctoral program, VitaDAO expects to have access to IP licensing rights (potentially related to therapeutic compounds or biologics) derived from the research program via an IP-NFT via Molecule.

Agree: Support the VDP and permit VitaDAO to pursue IP-NFT agreements and transfer funds to the investigators once in place.

Disagree: Do not support the VDP and further action under this VDP.

Details

Project PI: Marco di Antonio, Imperial College and John Labbadia, UCL

Problem

​​The ability to generate and maintain an optimal proteome is of paramount importance for long-term health. As such, cells have evolved a highly conserved network of protein quality control pathways, commonly referred to as the Protein homeostasis (Proteostasis) Network (PN), that operates across cells to neutralize the threat of misfolded, mislocalized and aggregated proteins throughout life. Despite this, the accumulation and persistence of aberrant protein species (known as a loss of proteostasis) is a common feature of aging in worms, flies, mice and humans, and is associated with the dysfunction of multiple tissues in aged individuals.

These observations raise the possibility that maintaining proteostasis throughout life may be a powerful way to promote healthy aging; however, the cause of age-related proteostasis collapse remains poorly understood. A comprehensive interrogation of the relationship between PN activity, proteostasis capacity and aging in Caenorhabditis elegans, has revealed that the capacity of the PN declines in early adulthood due to the transcriptional repression of multiple PN components. Recently, the Di Antonio and Labbadia groups (of this proposal) have discovered that the DNA helicases, WRN-1/WRN and HIM-6/BLM, are required for the maintenance of proteostasis capacity in adulthood, suggesting that genome integrity early in life is intimately coupled with the propensity for proteostasis collapse with age.

In this project the investigators will explore the hypothesis that WRN-1 and HIM-6 activity positively regulate proteostasis capacity by preventing the inappropriate persistence of DNA G-quadruplex (G4) structures at the promoters of PN genes, and that the loss of DNA helicase activity and G4 homeostasis early in life underlies the repression of PN genes and proteostasis collapse with age. This will re-shape our understanding of the origins of age-related proteostasis collapse and highlight new mechanisms and pathways that can be targeted to preserve proteome integrity and prolong healthy tissue function.

Opportunity

This project provides VitaDAO an opportunity to contribute to developing novel science around the role of G4 structures in healthy and unhealthy aging. Particularly of unique interest is the probing of both the wanted and unwanted G4 structures and their impact on proteostasis maintenance, which may create the opportunity for novel drug targets. The project specifically highlights the intent to produce a library of ligands and biological tools (possibly CRISPR, mRNA etc.) to perturb G4 structures which could form the basis of intellectual property around mechanism of action and molecular entities.

The research plan outlines the production of G4 stabilizing and disrupting tools (ligands etc.) and measuring the impact of these within physiological conditions across multiple organisms including C. elegans and human cell lines.

For a $50,000 USD “Top Up” contribution to the doctoral program, VitaDAO will be supporting the doctoral research student for 4 years within the Institute of Chemical Biology, Imperial College London and University College London, between the research groups of Marco Di Antonio and John Labbadia. Over the course of the 4 year program the doctoral researcher will be pursuing the research proposal provided below in this VDP.

As part of the program the researcher will be supported to work with VitaDAO (in the role as the industrial partner from the Longevity field) as part of their professional development which could take the form of research within the lab of another VitaDAO project performer or exposure of more commercial aspects of Longevity life science.

As part of Imperial College's research agreement, Imperial College would grant VitaDAO the option to take exclusive or non-exclusive license to the intellectual property rights, with additional good-faith negotiation once the option is exercised. The terms have been reviewed by Molecule and deemed to be sufficient for the current state of the research program.

Highlights

• Opportunity to identify novel therapeutic targets relevant to longevity research, based on a molecular scaffold already identified by the investigators
• Opportunity to contribute novel research to the field on the role of DNA helicases and G4 structures related to age related diseases
• Opportunity for partially fund a PhD thesis via VitaDAO
• Opportunity for a member of VitaDAO to co-supervise the doctoral student throughout the 4 year program
• UCL and Imperial College London are highly entrepreneurial institutions and will provide support to the investigators in steering the project through commercial or IP generating activities when appropriate

Risks

• Doctoral research projects can be quite risky and are sometimes far away from filing IP, however this work is not completely green field and there is already published work this project extends
• Whilst our colleagues are familiar managing relationships with technology transfer offices there is always some risk, that an agreement cannot be reached regarding representing IP as an on chain IP-NFT

Reviews from the Longevity Working Group

Outcome of the evaluation and recommendation

Of all the evaluators, 3 independently scored the project proposal on different categories as either: (1) Outstanding, (2) Strong, (3) Satisfactory, (4) Weak, (5) Unacceptable, (N/A) Not enough information provided, or (N/A) Not my area of expertise.

This is a summary of the results:

• Novelty and Impact: -- (2) Strong (3/3 evaluators)
• Feasibility and Data: -- (2) Strong (3/3 evaluators)
• Relevance to longevity: -- (2) Strong (3/3 evaluators)
• Science Team: -- (2) Strong (3/3 evaluators)
• Market Advantage: -- (N/A) Not area of expertise (1/1 evaluators) -- (4) Weak (2/2 evaluators)
• IP-NFT Potential: -- (N/A) Not enough information (1/1 evaluators) -- (3) Satisfactory (2/2 evaluators)

For more information, please see the phase 2 proposal and discussion on Discourse.