VDP-152 [Funding] Project TransFidelity

One-liner Project TransFidelity aims to develop small molecules and peptides that enhance translation fidelity to prevent harmful protein misfolding, thereby addressing neurodegenerative diseases (NDDs) like Alzheimer’s and Parkinson’s from their root cause.

Team

Principal Investigator: Dr. Dimitri Scherbakov

Project Managers: Ella McCarthy-Page, Kishore Kumar, Amine Chaherli, Benji Leibowitz

Sourcer: Michele Gallia

Key Researchers and Collaborators: Dr. Rashid Akbergenov, Prof. Dr. David Wolfer, Prof. Dr. Dennis Gillingham

Simple Summary

Project TransFidelity focuses on preventing neurodegenerative diseases by improving the accuracy of protein synthesis, thereby reducing the formation of harmful protein aggregates. This approach targets the root cause of these diseases, aiming to provide a novel treatment strategy that goes beyond symptom management. This proposal is to provide $50k USD in (ETH) funding for the project.

Problem

Neurodegenerative diseases (NDDs) like Alzheimer’s and Parkinson’s are devastating conditions that affect millions worldwide. These diseases are driven by the misfolding and aggregation of proteins, which leads to brain cell death and cognitive decline. Project TransFidelity aims to solve this by improving the accuracy of protein synthesis, preventing harmful protein misfolding from the start.

Solution

Project TransFidelity proposes a novel approach to treating NDDs by improving the fidelity of protein translation. This strategy addresses the core problem of protein misfolding at its source. By identifying compounds that enhance translation fidelity, we aim to prevent the formation of toxic protein aggregates. Think of it as upgrading the factory’s quality control system to ensure that only correctly assembled proteins are made.

Opportunity

By improving the accuracy of ribosomes, we can reduce the production of faulty proteins. Here’s how our approach works:

Small Molecules and Peptides: Screen molecules that help ribosomes print proteins more accurately. Reducing Misfolded Proteins: Once the protein has been printed, it needs to be folded into its correct form. With fewer errors, folding accuracy improves. It reduces the working load to the cell’s cleanup system and decreases protein aggregation with its negative consequences such as chronic inflammation. Easing Cellular Stress: Reducing the rate of misfolded proteins eases the burden on our cell systems, granting them the ability to spend more energy on cell vital functions, resulting in cells that function better and stay healthy longer. The ultimate goal is to develop new treatments that halt or reverse the progression of NDDs,

providing new hope for millions of patients.

Budget

This proposal, if passed, will allocate $50k (in ETH) of the $100k allocated to Catalyst projects as part of VDP-147 2. Again, if the terms are not agreed upon by the funders, then the ETH will be returned to VitaDAO.

Senior Review Digest - Quantitative

The project was reviewed by four reviewers: a scientist, an entrepreneur, a VC, and a professor. Below is the average scores from the reviewers out of 5 per category.

Average Scores

Team Expertise: 3.5 Feasibility & Data: 3.0 Commercial Potential & Impact: 4.3 Novelty & Market Advantage: 3.5 IP Defensibility: 2.8 Relevance to Longevity: 4.5 Deal Terms: N/A (the terms have not yet been set) General Conviction Score 3.0 (for reference, the average score of past funded projects is 3.7) The majority of the reviewers think that this project is a moonshot.

Two reviewers recommended that the project should be advanced for token-holders vote, one that it should be followed-up with the applicant for more information, one that it should be denied outright giving constructive feedback.

Senior Review Digest - Qualitative

Each reviewer was asked whether they would endorse the project, as well as the pros and cons they see: below are their answers.

Reviewer 1 Until the group can find new chemical entities there is limited commercial viability and I would not endorse the project. Also, data are contradictory regarding enhancing/reducing translation and the researchers have no drug target in mind other than a biological process. Systemically changing anything in the body is a bad idea.

Pros Dysregulation of translation is known in a lot of diseases. Targeting it might be beneficial.

Cons No molecular target and no viable IP. Systemically targeting translation is likely dangerous and the literature suggesting enhancing/decreasing has both positive/negative consequences. Team lacks any BD/Development experience.

Reviewer 2 I am familiar with most of the past potential projects that VitaDAO has brought to the table, and this is one of the strongest so far. It has my clear endorsement.

Pros Known mode-of-action, allowing to deploy the typical paths to bring a target/drug to market. Evolutionarily conserved and robust lifespan extension in invertebrates and unicellular models. Disruptive potential of a huge market.

Cons

Mammalian pro-longevity results lacking. Aggravating this mode-of-action clearly shortens lifespan and compromises health, but breaking a system is dissimilar and easier than improving upon it.

Reviewer 3 I’d put this in the top 50% of project i’ve reviewed, but not top 10%. The research seems interesting and worth supporting; likely a reasonable project for VitaDAO to fund.

Pros Solid academic foundation. Conceptually promising approach. Feasible patent plan.

Cons Lack of clinical/regulatory experience. Crowded market concerns. Indirect alignment with longevity mission.

Reviewer 4 At this stage I would endorse the idea behind the project but not the project itself. This is a very early stage research which is likely to fail within the timeframe of the proposed project as a lot more research is required to improve feasibility. Nevertheless, the idea is exciting and I would be happy to discuss it publicly or even become involved scientifically.

Pros Novelty of the approach. Evidence of chemistry with apparently desired biological effect. Good expertise in biology with support from medicinal chemist.

Cons very early stage project with uncertainties about whether improving translation fidelity would have any benefit for health/longevity/disease prevention. research programme is broad with no guarantee of success.