L1 Inhibitor to Prevent Age-Associated Inflammation and Disease

Overview

One hallmark of aging is the accumulation of senescent cells that contribute to sterile inflammation, which underlies many age-associated diseases such as osteoarthritis, cancer, and neurodegeneration. Nuclear element-1 (L1), which represents approximately 17% of the human genome, plays a key role in this process. We are identifying candidates to develop into inhibitors specific to the L1 endonuclease (EN), as a potential way to prevent these age-related diseases.

Market Opportunity

Though nuclear element-1 (L1) repeats are normally repressed in heterochromatic (genetically inactive) regions of the genome, changes in chromatin organization cause them to become derepressed with age. This allows L1 to copy itself into new genomic loci through the process of retrotransposition. As a result, L1 activity is associated with diseases of aging such as osteoarthritis, cancer, and neurodegeneration. An L1 inhibitor, therefore, could provide an effective way to prevent these diseases.

Innovation and Meaningful Advantages

The design of selective inhibitors for the L1 reverse transcriptase (RT) domain is currently not feasible because of a lack of structural information on the protein domain boundaries that would enable recombinant protein purification. The structure of the L1 EN domain, however, has been solved, allowing for structure-based inhibitor screening and design. We have begun to identify candidates to develop into inhibitors specific to the L1 EN, making the L1 EN a promising target for inhibition of L1 activity.

Commercial Development: Current State and Next Steps

The L1 EN structure allows for virtual screening of large libraries of potential inhibitors to test biochemically. The L1 EN can be easily purified recombinantly and assayed to allow for compound screening in vitro. L1 EN inhibitors can be designed to specifically target the L1 EN based on existing data. In addition, they will not have off-target effects on mitochondrial polymerase γ and can reduce DNA damage resulting from L1 activity. We have also defined biochemical, structural, and cell-culture approaches to further characterize these inhibitors, as well as other candidate compounds.

Going forward, we plan to solve the structures of L1 EN-inhibitor complexes, investigate the role of L1 EN in cytoplasmic L1 cDNA accumulation, develop a fluorescence-based readout for L1 EN activity assay, and test L1 EN inhibitors against inflammatory factors in senescent cells.

Principal Investigator

IP Information

PCT Patent WO2021102423A1, Published May 27, 2021

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