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Methuselah Health Using Protein PTM Analysis to Tackle Age-Related Diseases

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NEW YORK (GenomeWeb) – UK biotech startup Methuselah Health plans to use analysis of protein post-translational modifications to develop drugs and diagnostics for age-related diseases.

The company, which launched in 2015 but has only recently begun publicizing its work, believes protein PTMs can provide insights into protein damage that can be used to address common late-onset conditions like atherosclerosis, Alzheimer's, and auto-immune disorders, said David Grainger, Methuselah's executive chairman and CEO.

He said the firm has used mass spec to generate large collections of data on post-translational modifications present in conditions including these and other diseases and is now in discussions with various pharmaceutical companies about forming disease-specific partnerships to further explore this data.

The idea underpinning the company's efforts is that "the fundamental biological clock of aging is not the DNA sequence but the stability of the proteome," Grainger said. "Maybe diseases of aging are not triggered by genetic predisposition, but by the accumulation of damage to particular proteins."

"And you might not be able to find out which proteins have been damaged by doing genome-wide association studies or any kind of DNA-based analysis," he added. "Maybe you have to look directly at the proteome in affected individuals."

This basic notion that the proteome provides crucial information about disease and biological function not available at the genomic level is, of course, a common one in proteomic circles. In Methuselah's case, Grainger said, the interest in the proteome stemmed from work on the radiation-resistant bacteria Deinococcus radiodurans by Miroslav Radman, a professor at the French National Institute of Health and Medical Research (INSERM) and scientific founder of the company.

Radman "has been working for decades in the field of aging," Grainger said. "And his studies of [Deinococcus radiodurans] have shown that the death of the organism occurs not when the DNA becomes degraded but when the proteins have accumulated a certain level of damage."

To assess levels of protein damage, Methuselah has developed a mass spec platform that Grainger said is capable of highly quantitative measurements of multiple protein PTMs. The company outsources the actual mass spec work to labs including the Cambridge Center for Proteomics, but uses a proprietary informatics pipeline for analysis of the mass spec data.

With this platform, the company is able to go "protein-by-protein through a sample and get a picture of to what extent every amino acid in it has been modified in particular ways," Grainger said.

Analysis of protein post-translational modifications is notoriously complex due to the many different possible PTMs, which may include multiple modifications on the same protein and/or different combinations of PTMs on different protein isoforms. Adding to the difficulty are the computational challenges involved in searching for multiple modifications in a single analysis. Identifying the diversity of proteins forms present in biological samples requires working through the enormous search space required to capture these many forms, something that is not currently possible on a proteome-wide scale.

In its work, Methuselah typically confines its analyses to the 200 or 300 most abundant proteins in a sample, trading depth of proteomic analysis for a more comprehensive and quantitative look at the modifications on these proteins.

Grainger said that he and his colleagues have found this to be sufficient to identify damaged proteins linked to the diseases they are interested in studying.

The company is particularly interested in what Grainger called hyper-stable danger variants, proteins whose alterations cause them both to lose functions associated with their wild-type versions and to stay present in the body for long periods of time.

"The reason people focus on DNA damage as a central clock of aging is that once you've lost your DNA sequence you are permanently going to produce a dodgy version of the protein, whereas if I just damage a copy of the proteins surely it is going to get replaced in a little while by a perfect copy again coming from the DNA," Grainger said. "And that is what happens nearly all of the time. The problem is that just occasionally [the body] creates a protein that is much more stable than the wild type, and if I have a very long half-life variant, every time I make one of those, I am stuck with it, and it accumulates over time."

He described such proteins as arising due to a combination of genetic and environmental factors. "For example, smoking increases oxidation of proteins, and certain genetic variants will interact with that smoking to create a hyper-stable danger variant more quickly than [would occur] either in someone who didn't have the genetic variant or someone who didn't smoke."

Methuselah believes it can identify PTMs associated with these hyper-stable danger variants and use this information for diagnostic and drug development purposes.

"We imagine opportunities in diagnostics and therapeutics potentially together," he said. "You might want to select for patients you want to treat with drugs [targeting a danger variant]. You might want to monitor the effect of the treatment. I don't really see the two components as separable here."

Methuselah currently has four employees but plans to expand significantly in the coming year, Grainger said. The company is privately held and funded through equity financing from European venture fund Medicxi, of which Grainger was a co-founder. Grainger previously co-founded X01 limited, a biotech firm that developed the anti-thrombin antibody ichorcumab, which was acquired by Janssen Pharmaceuticals in 2015. Grainger was also a venture partner at Index Ventures, which backed X01 and originally founded Medicxi.

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