Successfully outsmart harmful mutations

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Photo: Pixabay Symbol image of a DNA
Photo: Pixabay Symbol image of a DNA

An international research team led by Zoya Ignatova from the University of Hamburg has developed a novel strategy to suppress genetic mutations using artificially engineered transfer RNAs (tRNA). These mutations can lead to serious diseases. The tests, which were successfully performed on patient cells and mice, could provide a new approach to combat various and currently incurable diseases. The results of the study were published in the current issue of the journal -Nature-.

In protein synthesis, various vital proteins are produced in the cells of the human body according to a blueprint stored in deoxyribonucleic acid (DNA). In the first step, transcription, the information for the corresponding protein is read out in the cell nucleus and transcribed onto a messenger ribonucleic acid (mRNA). Like DNA, RNA is a nucleic acid, but unlike DNA it can leave the cell nucleus and transport the genetic blueprint for the production of the protein to the ribosomes, the protein biosynthesis machines of the cells.

This is where the second step takes place: translation. The mRNAs are translated into the desired proteins by the ribosomes with the help of the tRNAs. During this process, the functional units of the tRNA, the so-called anticodons, attach themselves to the complementary matching functional units of the mRNA, the so-called codons. In order to mark where the protein to be synthesized starts and where it ends, there are special start and stop markers on the mRNA blueprint, the start and stop codons.

Heritable nonsense mutations convert a normal codon on the mRNA into a stop codon, which has dramatic effects similar to the tearing off of a part of the blueprint, because protein synthesis then stops prematurely and an incomplete protein is produced. Since the necessary protein cannot be produced, affected individuals also lack the associated biological function. The result is devastating and as yet incurable diseases such as spinal muscular atrophy, cystic fibrosis, muscle wasting or even growth hormone deficiency. An estimated eleven percent of all hereditary diseases are caused by nonsense mutations.

Some microorganisms counteract these mutations with so-called suppressor tRNAs, which are created by mutation in the tRNA and enable the cell to completely read out the mRNA despite new mutation-induced stop codons. Human cells do not have such a repair mechanism. However, the international research team led by biochemist and last author Zoya Ignatova from the Department of Chemistry at the University of Hamburg has taken advantage of this approach and developed a novel strategy to convert tRNAs into efficient suppressors of nonsense mutations.

The researchers first generated various suppressor tRNAs on the computer, which they then synthesized and tested extensively. The final result was suppressor tRNAs that function on ribosomes and effectively suppressed mutation-induced stop codons, thereby not interrupting the synthesis process and fully building the protein. -Our goal is to outsmart the premature mutation-induced stop codon while minimally affecting the normal stop signals with our suppressor tRNAs-, says first author Dr. Suki Albers from the Department of Chemistry at the University of Hamburg.

The biggest problem for the scientists, however, is transport, because this involves the tRNAs being degraded in the body, but also in the cells. -That’s why we partnered with U.S.-based Arcturus Therapeutics, a leader in gene therapies and RNA-based vaccines,- Ignatova explains. Arcturus has developed lipid nanoparticles in which the tRNAs can be encapsulated, providing them with good protection while allowing them to exert their full effect. Similar lipid nanoparticles have been used in anti-covid vaccines developed by BioNtech/Pfizer or Moderna.

-In the current study, we demonstrated that our suppressor tRNA encapsulated in lipid nanoparticles showed high clinical benefit in mice and in patient-derived cells and restored disease protein function,- says Ignatova. -This gives us a novel gene therapy approach that corrects genetic diseases at the mRNA level and opens the way to a new class of therapeutics with a high safety profile and no side effects.-.

For the developed tRNA technologies, the scientists at the University of Hamburg already own two granted patents and three new applications, two of which have already been licensed by the company Arcturus.

Original publication

Suki Albers, Elizabeth C. Allen, Nikhil Bharti, Marcos Davyt, Disha Joshi,, Carlos G. Perez-Garcia, Leonardo Santos, Rajesh Mukthavaram, Miguel Angel Delgado-Toscano, Brandon Molina, Kristen Kuakini, Maher Alayyoubi, Kyoung-Joo Jenny Park, Grishma Acharya, Jose A. Gonzalez, Amit Sagi, Susan E. Birket, Guillermo J. Tearney, Steven M. Rowe, Candela Manfredi,, Jeong S. Hong,, Kiyoshi Tachikawa, Priya Karmali, Daiki Matsuda, Eric J. Sorscher, Pad Chivukula, Zoya Ignatova: Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature (2023):­’023 -06133-1