One-liner : Proposal to allocate $231,000 to Tim Peterson's project developing a cellular "soap" (sphingolipid mimetics) to thwart pathogens and senescent cells.

Longevity Dealflow WG team

Scientific evaluation: Sebastian Brunemeier, Diane Seimetz, Anonymous reviewer (professor) Business evaluation: Sebastian Brunemeier, Diane Seimetz Shepherd: Laurence Ion Other squad members: Tuan Dinh Sourced by: Tim Peterson

Project PI: Dr. Tim Peterson

Simple Summary

Prevention of communicable disease via hygiene, antibiotics, vaccines, amongst other innovations has provided the largest life expectancy gains in human history. It is increasingly appreciated that pathogens age humans by driving their cell senescence. The team led by Dr. Tim Peterson has identified chemistry that acts as a cellular ‘soap’ to concomitantly thwart pathogens and senescent cells. What’s exciting about the invention is that, as with the aforementioned innovations, it not only appears to be a generalizable strategy against many pathogens but also many aging pathologies.

Problem

The relationship between infectious disease and aging is increasingly appreciated. Perhaps most well-known now is that advancing age predicts a worse COVID19 prognosis. However, the relationship is not just correlative – several common pathogens have been implicated as causal mechanisms in models of aging-related disease. For example, with Herpes Simplex Virus (HSV) and Alzheimer’s disease, and the periodontal pathogen P. gingivalis and cardiovascular disease. In most cases, there are neither prophylactics nor therapies to combat these common pathogens and thus to prevent the lifespan-limiting effects they have.

Opportunity

Senolytics have emerged as an intriguing new therapeutic paradigm for aging-related disease. Senolytics selectively kill pathogenic senescent cells compared with healthy proliferating cells, but it is unclear what their molecular target is that provides this selectivity. Without this rationale, it has been hard to make progress in identifying new senolytics.

Through combined deep learning and genome-wide screening, Dr. Peterson has identified chemical features present in several FDA-approved drugs that provide this long-sought-after rationale. Considering that pathogens render healthy cells senescent, this approach has the potential to “kill two birds with one stone” in thwarting both pathogens and senescent cells.

The objective of the project is to conduct a series of in vitro and in vivo experiments to design new drugs that perform against a wide range of senescence inducers.

Moreover, there is a clear path to iterate on the chemistry to:

1. Increase drug potency several-fold.
2. Eliminate the original use of the drug (i.e., reducing unwanted effects) without affecting its anti-pathogen or senolytic activity.
3. Increase the list of patentable compounds from 5 to 100s, providing plentiful patenting opportunities.
4. Use structure / function relationships to design novel scaffolds and compounds with senolytic effects.

Experimental plan

Stage 1: IP generation - In vitro screening:

Novel compositions of matter that will be the basis of the IP-NFT will be tested in multiple cell types using multiple senescence inducers, both pathogen and more classic (DNA damage). These experiments will tell us how broadly vs. context-dependent our drug candidates are. The primary readout will be the well-accepted senescence measures.

Stage 2: IP validation - In vivo validation:

Lead compounds will be tested using a mouse model. The mouse model is commonly used in the senescence field and is a well-accepted experimental paradigm. In addition to lifespan, behavioral and neurological scoring (e.g., paralysis), as well as blood and CSF biomarkers, will be assessed.

IP Roadmap

The project will generate new compounds, which will provide opportunities for IP-NFT value creation.

The IP strategy is extensively mapped out. Therefore, the applicants will be able to begin drafting the provisional patent application promptly upon funding. Intellectual property will focus on novel compositions of matter as that will be the most valuable to future investors.

Team

Dr. Tim Peterson, Ph.D., CEO BIOIO, Assistant Professor Washington University School of Medicine https://petersonlab.wustl.edu

Dr. Peterson is an MIT- and Harvard-trained faculty member at Washington University in St. Louis (a.k.a. WashU or WUSTL) School of Medicine (WUSM). WUSM is a perennially top-five US institution in terms of research funding and publishing and is tied to 19 Nobel Prize winners since its founding in 1909. Over his 15-year research career, Dr. Peterson has published in Nature, Science, and Cell and their affiliated journals and has received grant funding from the NIH, American Diabetes Association, the Nathan Shock Aging Center, Amazon Web Services amongst others. Dr. Peterson’s focus on longevity started with his PhD at MIT. At MIT, he made multiple seminal discoveries on rapamycin and the pathway it targets the mTOR pathway. Rapamycin and mTOR are arguably the most widely validated longevity therapy and pathway, respectively. At Harvard, Dr. Peterson trained under Erin O’Shea, PhD who now leads HHMI. There Dr. Peterson focused on longevity drug mechanisms, e.g., on the osteoporosis drug bisphosphonates and the diabetes drug metformin, which he has since carried with him into his academic lab and companies. In addition to his role at WashU and BIOIO, Dr. Peterson is a co-founder of Healthspan Technologies, which is developing mRNA lipid nanoparticle (LNP)-based therapeutics with a focus on vaccines for aging-accelerating infectious agents. Prior to his professional career, Dr. Peterson trained with the US Rowing Team from 1999-to 2001.

Potential conflict of interest ⚠️

The PI of this project, Tim Peterson is also a Steward of the Longevity Dealflow Working Group.

Laurence Ion, the shepherd of this deal is also a Steward.

The evaluation process at VitaDAO is designed to be transparent, as unbiased as possible, giving the community ample time to review, with unhindered access to confidential information that the applicant is comfortable sharing, and an independent board of 3-5 Senior Reviewers that have expertise and the community's trust, with their conviction level and summary reviews carrying weight in the decision of the tokenholders.

Prof. Roland (Ron) Dolle, Ph.D., Director of Center of Drug Discovery https://cdd.wustl.edu

Dr. Dolle is an Associate Professor in the Department of Biochemistry and Molecular Biophysics. Having spent 20 years in industry before coming to WashU, Ron’s expertise includes medicinal chemistry and many aspects of drug design and preclinical development. His accomplishments include the advancement of more than a dozen drug candidates into preclinical and clinical studies including at least 7 investigational new drug (IND) applications.

Budget

Stage 1: 6 months (IP generation)

Medicinal chemistry: $40,000
In vitro screening:  $20,000
Patent filing:       $20,000
Salaries:            $20,000
Overhead (10%):      $10,000

Subtotal:            $110,000 

Stage 2: 12 months (IP validation)

In vivo validation:  $70,000
Salaries:            $40,000
Overhead (10%):      $11,000

Subtotal:            $121,000


Total:               $231,000 

Strengths

• Senescence plays an important role in the aging process. Targeting senescence makes sense.
• The approach targets both pathogens and aging - linking between pathogens and aging is understudied
• The project team has strong credentials, led by Dr. Tim Peterson. Dr. Peterson brings expertise in aging sciences, and Dr. Ron Dolle is a medicinal chemist who will handle hit/lead optimizations.
• Early data using existing drugs demonstrates that the mechanism of action (MOA) works as expected (not for public disclosure at this point), which supports further research
• The lab has experience with senescence. Also, the project will be supported by an expert in the field of senolytics.

Risks

• The MOA is novel and not tested outside of Dr. Tim Peterson’s group
• Only initial in vitro data available, unclear how the drugs would work in vivo
• New compounds will be produced - whose PKPD and safety profiles are unknown

Longevity WG scientific evaluation digest:

The 3 senior reviewers have expressed a vote in agreement to fund this proposal and are ready to give a final digest:

Quantitative reviews:

To quantify the level of conviction, they have provided a score on a scale of 1-5 (with 5 being the highest). The average score was 3.35/5

Brief qualitative review summaries:

1)

There are some aspects to the project that are not clear-cut. The ALS model is one of them. I also think the budget is a bit low for doing any kind of med chem (comment from shepherd: the applicant answered that they'll cover the rest with their funds). The preliminary hit compounds are promising though, but it's still early. That said, we know Tim is a good PI and is mission-aligned, so he will likely put the funds to good use.

2)

The cellular "soap" proposal aims to investigate the senolytic properties of FDA approved drugs with cationic amphiphilic properties (CAD) in different cell-based systems (aim 1), and determine the aging-accelerating effects of a common pathogen and the protective effects of CADs against it (aim 2). During the review process it was clarified that the project is not a re-purposing project. Instead, based on the scientific findings, the aim is to generate novel composition of matter with the requested funds from VitaDAO. Therefore, the main concern has been addressed and I would support funding of the project.

3)

Things I like:

• Promising preliminary data with priority compounds (see prior comments)
• Sound medicinal chemistry plan with appropriate expertise (again, assuming the specifics can be flushed out)
• Strong cell biology experimental plan, with a good range of diversity built in
• Clear relevance to the mission of the DAO

Things I don’t like:

• Preclinical ALS animal model. There is just too much hand waving here for me to be assured of a clear result. I think if we are going to pay for the in vivo experiments, we need to believe they will generate a definitive conclusion (works or doesn’t). I’m not sure the ALS model does that. See specifics in previous comments. But perhaps that deserves further discussion after phase I (medicinal chemistry and cell testing) has been completed. I certainly think the project here rates similarly to many others we have considered and funded.

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