Ushering in the era of tRNA medicines

Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs

“…The repressed proliferation associated with tRNA-Tyr depletion is consistent with the growth defect that we have detected in TRMT1-knockout human cell lines as well as the developmental delays observed in human patients with TRMT1-or TRMT1L-deficiency (Blaesius et al, 2018;Davarniya et al, 2015;Dewe et al, 2017;Monies et al, 2017;Najmabadi et al, 2011). By pinpointing specific tRNAs and their mechanism of dysregulation, the results presented here could guide tRNA-based strategies for rescuing phenotypes associated with neurodevelopmental disorders linked to tRNA modification deficiency (Anastassiadis & Kohrer, 2023;Hou et al, 2024).…”

Tuning tRNAs for improved translation

“…These tRNA therapies give rise to unique medical benefits and inhibitions compared to the extensively researched genetic engineering toolbox of various CRISPR- and CRISPR-adjacent platforms ( Terns, 2018 ; Petraitytė et al, 2021 ; Chehelgerdi et al, 2024 ). Certainly, engineering therapeutic suppressor tRNAs for proper efficiency during elongation (or initiation) is a necessity and evidenced by several recent start-up companies developing tRNA therapeutics ( Dolgin, 2022 ; Anastassiadis and Köhrer, 2023 ). Although outside the scope of this review, an excellent recent review is provided which details tRNA therapeutics and delivery ( Ward et al, 2024 ).…”

“…Additionally, nearly 10% and 50% of pathogenic genetic conditions result from aberrant stop codons ( Mort et al, 2008 ) and missense mutations ( Katsonis et al, 2014 ; Stenson et al, 2017 ), respectively. This has led to substantial research aimed towards developing modified tRNAs for efficient, orthogonal, and safe readthrough of improper gene sequences ( Dolgin, 2022 ; Anastassiadis and Köhrer, 2023 ; Coller and Ignatova, 2024 ).…”

Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders

“…Future clinical studies may recruit patients sharing the same PTC across multiple diseases, and adopt the basket trial design in oncology to streamline translation [ 181 , 182 ]. Therefore, sup-tRNA may be a viable gene therapy solution for a large population of patients suffering from diverse CNS pathologies but sharing a common PTC [ 183 , 184 ].…”