Background

Pathological inflammation is a key hallmark of aging - one significant consequence of which is damage to mitochondria. Cells employ dynamin-related protein 1 (DRP1) in a conserved metabolic stress response during inflammation, shifting mitochondria towards ROS production and glycolysis, a process that damages mitochondria, DNA, proteins, and ultimately tissues during chronic inflammation. DRP1-dependent mitochondrial fission drives a broad range of inflammatory diseases. FIS1, a protein that becomes activated and interacts with DRP1 exclusively during stress responses and not during normal function, making it a promising therapeutic target.

P110 is a mito-protective peptide, originating from Stanford University, which selectively inhibits DRP1-FIS1-mediated mitochondrial damage. The efficacy of P110 in treating neurodegenerative and cardiac disease is supported by 13 years of research, resulting in 20 scientific publications across 11 disease models and collaboration with 15 independent labs globally. P110 has highly generalized anti-degenerative activity, increasing lifespan in mouse models of neurodegeneration and also a model of ischemic heart disease. However, its peptide nature limits its pharmacokinetics. 

Aims, Hypothesis & Results

Fission Pharma is creating the first drug-like small molecule P110 mimetics. Dr. Luis Rios published the first small molecule P110 mimetics in 2023 and showed comparable efficacy to P110 in mouse models of ALS and sepsis. These inhibitors have a unique property, they inhibit the downstream pathological consequences of inflammation without inhibiting immune signals.

These compounds aim to be the first effective and generalized orally available and brain penetrant treatments for chronic inflammation and mitochondrial dysfunction, critical hallmarks of aging, and may do so without causing immunosuppression, the limiting factor in chronic inflammation treatment. The most tractable go-to-market strategy will be in a rare neurodegenerative disease (ALS) and they will expand to age-related degenerative indications such as AD and ischemic heart disease, the major limiting factors in human lifespan.

Timeline

This project is divided into four phases, with go/no go milestones to trigger funding tranches for each one of them.
Co-funding of $ 84,300 from CerebrumDAO will be used to accomplished the milestones.

Pilot Screen
Required Funding: $56,700
Status: Ongoing
Duration: 1 Month


Primary Screen
Required Funding: $136,400
Status: Planned
Duration: 2 Months


Hit-to-Lead Screen
Required Funding: $89,400
Status: Ongoing
Duration: 2 Months


Secondary Screen
Required Funding: $50,800
Status: Ongoing
Duration: 2 Months


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VitaDAO Board Evaluation Write-up

The background science is solid and has been validated in several mice disease models. These compounds act via a novel mechanism of action and target site which could be applicable to several age-related diseases. It’s a risky project as it uses computational chemistry to screen for a new compound, and it is unclear whether this therapy will work in humans. However, the risk/reward is worth it as there is clear unmet need, and a huge market, for ALS and other neurodegenerative diseases. Furthermore, there is a straightforward path to produce composition of matter patents on compounds discovered. VitaDAO should take an active role in tracking the progress of the company and help in reaching the next milestones.

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