Umlaut.bio: First-in-biology approach for therapies targeting tRNA modifications

Umlaut.bio GmbH (“Umlaut”), a German/Swiss oncology/autoimmunity biotech company, announced the publication of its molecular mode-of-action today. The publication supports its first-in-biology approach to develop small molecules to block pathologically dysregulated tRNA modifications that are associated with aggressive disease progression in cancer. The publication in Cell shows, for the first time, that tRNA modifications act by increasing the stability of protein-coding mRNAs and that this mechanism is upregulated in cancer cells.

Umlaut, an EMBL spin-off, is pioneering the development of small molecules that inhibit enzymes involved in tRNA modifications, addressing the shortcomings of current cancer and autoimmune treatments with the promise of circumventing treatment resistance as well as a favorable side effect profile. Foundational to its approach is its novel, proprietary platform that enables high-throughput screening and mass spectrometry-based validation of the inhibition of such enzymes.

“This publication marks a change in our understanding of how RNA modifications influence posttranscriptional gene regulation” said Bastian Linder, Ph.D., Co-founder, Chief Scientific Officer at Umlaut and first author of the publication. “Our approach showed that modified nucleotides in mRNA and tRNA can functionally interact in vivo and that this interaction serves to regulate gene expression at the level of mRNA decay”.

In the publication, the scientists demonstrated that the mRNA modification N⁶-methyladenosine (m⁶A) leads to a deoptimization of specific codons that ultimately results in the decay of m⁶A-modified mRNAs. The tRNA modification mcm⁵s²U counteracts this process by enhancing the decoding of m⁶A-modified codons and stabilizing m⁶A-modified mRNAs. The expression of both RNA modification pathways is coordinated, but dysregulated in cancer, where increased mcm⁵s²U is responsible for the overactivation of multiple oncogenic pathways.

Karsten Fischer, Ph.D., Chief Executive Officer at Umlaut added: “Addressing such a fundamentally novel biological principle is highly promising, potentially allowing a leap forward in treatment of cancer and autoimmune diseases. Combining these findings with our proven technology suite and classical small molecule development expertise is maximizing the chances of success to do so.”

Umlaut has assembled a world-class executive and corporate advisory team with a century of relevant expertise to maximally leverage the value of this novel field of biological regulation. The company is seed funded by the HTGF and LBBW Venture Capital, supported by L-Bank through the InnoGrowth BW programme. In addition, Umlaut.bio is backed by Ono Pharmaceutical and Eli Lilly through the Mission BioCapital Platinum Program and Abbvie through the Golden Ticket.