What Is The Role Of Trna In Protein Synthesis – Our relatively new field is growing rapidly, and an exciting new therapeutic RNA modality is now gaining traction. tRNA is essential in protein synthesis and by engineering tRNA molecules, it may be possible to treat disease. In fact, it is believed that a single tRNA therapy could have the potential to treat several different diseases.

Much work has been done to understand the role of mRNA in the disease process and to understand and develop antisense oligonucleotides (ASOs) and siRNA therapeutics to treat disease by interacting with mRNA. It is well understood that as mRNA is translated into proteins, mutations can cause disruptions to this process, including the production of mutant, toxic proteins, or too much or too little of a protein being made, leading to disease which are often debilitating and deadly. .

What Is The Role Of Trna In Protein Synthesis

However, there is another small RNA molecule that is vital for protein synthesis called transfer RNA (tRNA). Each tRNA molecule contains an anticodon region and a region that binds to a specific amino acid.

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As the mRNA is translated in the ribosome, the tRNA is the molecule whose anticodon region base pairs with the complementary sequence on the mRNA. By doing so, its amino acid is transferred to the ribosome and attached to the growing polypeptide chain to form the protein. This process continues until the ribosome reaches a stop codon on the mRNA, which signals that the protein is complete. In a perfect world, the process of protein synthesis would result in perfectly functioning proteins in optimal amounts for a healthy, thriving human.

As we know, this is not always the case. Genetic mutations can cause the correct codon to be changed to another, resulting in the addition of an incorrect amino acid to the protein. An incorrect sequence can also result in a premature termination codon (PTC).

Only 3 of the 64 codons signal the end of translation. These three termination codons are UAA, UAG, and UGA (1, 2). However, a nonsense mutation changes a nucleotide from an amino acid codon to another nucleotide that now creates a premature termination codon.

When this happens, the cell does not make the fully formed protein. The resulting truncated protein will be either non-functional or actively harmful. Either case can lead to dysfunction and disease. In fact, nonsense mutations cause nearly 1,000 serious genetic disorders (1).

A Brief History Of Protein Biosynthesis And Ribosome Research

Therefore, multitudes of scientists are striving to understand the intricacies of the human body and protein synthesis and how to use the knowledge to create solutions to treat disease. As we understand more about how the disease process begins inside the cell, more possible solutions are emerging. tRNA shows promise, with particular therapeutic application in correcting PTCs caused by nonsense mutations.

This is not a new idea. In fact, 40 years ago, Yuet Wai Kan’s lab at the University of California, San Francisco published a paper on using tRNA to restore protein production (3). Other groups have also validated the approach over the years (4). Research into tRNA was not widely pursued, but some scientists continued to research it. Recently, it has shown promising results and companies are now investing in the development of tRNA technologies.

Many have focused on suppressor tRNAs (sup-tRNAs). The purpose of the suppressor tRNA is to bypass the premature termination codon (PTC), caused by a nonsense mutation, and provide the amino acid that should be next in the chain. The nucleotides in the anticodon can be modified to make a synthetic tRNA that will bind to a PTC, which is relatively simple to do. Suppressor tRNAs are supposed to restore protein production from defective genes.

Christopher Ahern and John Lueck have constructed a library of hundreds of anticodon-edited suppressor tRNAs (ACE-tRNAs) that can suppress premature termination codons and incorporate desired amino acids (5), which is being used to develop therapeutic applications.

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Over 10% of all genetic diseases are caused by premature termination codons. Because many different diseases are caused by the same PTC, it is believed that a single suppressor tRNA therapy designed for a specific stop codon could work for any disease caused by the same PTC.

Enhancer tRNAs are another type of therapy that was designed by Tevard Biosciences. Amplifying tRNA increases protein production in people who produce only half the required amount due to haploinsufficiency.

In addition, the ability to control tRNA provides the ability to also control which mRNAs are translated. In this way, it may be possible to control the biological processes that result in disease (6).

TRNA is also involved in cell division, and downregulating tRNA could be a way to slow cancer growth (7). Researchers have also discovered that tRNA has many other functions, such as gene expression, protein degradation, and apoptosis (8, 9, 10).

Researchers Explore How Trnas Evolve In Protein Synthesis

Of course, as research continues and knowledge grows, other ways to treat or prevent disease using tRNAs as clinical therapy may be discovered.

Safety is a concern with tRNA therapy, particularly if it will cause autoimmunity, off-target activity, and toxicity. Will tRNA bind only to premature termination codons or will it bind to normal termination codons (1)? If the suppressor tRNA binds to normal termination codons, other proteins will not end where they should, which could create toxic proteins and likely have serious unwanted effects. Mysteriously, that doesn’t seem to be the case, and Ahern, Lueck and the Cystic Fibrosis Foundation scientists aren’t quite sure why their molecules don’t cause many more stop codons to be skipped than is normal at this point . Additionally, Zoya Ignatova of the University of Hamburg engineered tRNA to preferentially bind to premature termination codons, which alleviates this concern.

TRNA faces delivery challenges similar to other nucleic acid therapies, such as being easily degraded and must be able to reach the desired cell type and penetrate the cell membrane. However, tRNA has the advantage of smaller size and is therefore easier to deliver through multiple delivery options. It is believed that tRNA will be able to be delivered using technologies that are effective in delivering other oligonucleotide and gene therapies (1). These include lipid nanoparticles (LNPs) containing synthetic tRNA or by engineering a virus, in this case an adeno-associated virus (AAV) with DNA to create suppressor tRNA once in the cell.

Another question that needs to be answered is how many tRNAs need to be delivered to achieve therapeutic effect? The therapeutic threshold often differs between different diseases, between individuals with the same disease, as well as in different tissues within a single individual.

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If you want to read an in-depth explanation of tRNA biogenesis, processing, interactions, and therapeutic promises and challenges, check out this article.

At the University of Iowa, Christopher Ahern, PhD, and his team, along with co-investigator Aislinn Williams, MD, PhD, are using engineered suppressor tRNAs to treat a form of autism associated with loss-of-function mutations in

The gene that causes the reduced expression of the Nav1.2 sodium channel (11). tRNAs will be delivered by adeno-associated virus into cortical neurons derived from induced pluripotent stem cells from individuals with nonsense mutations in

. This tRNA therapy aims to repair premature termination codons with the goal of restoring Nav1.2 channel function and neurophysiology.

Emerging Roles Of Trna In Adaptive Translation, Signalling Dynamics And Disease

Alltrna has developed a broad tRNA platform to explore tRNA biology. Alltrna is about “harnessing and understanding the entirety of biology and using the precision of this molecule to treat millions and millions of patients (6).” They built proprietary tools to perform basic methodologies for expressing, quantifying, modifying, and synthesizing tRNAs to “learn the rules of tRNA as a programmable drug.”

TRNA can be modified to modulate activity, stability, selectivity and delivery. Alltrna learns how to modulate how many of each tRNA are in a cell to change the amount and type of protein in a cell.

Another interesting aspect they are exploring involves tRNA fragments that function within and between cells. These fragments have many different novel functions outside of decoding, some of which relate to cell proliferation and cancer metastasis.

Tevard Biosciences is developing both suppressor and enhancer tRNA therapies using AAV for delivery that would potentially allow a single dose with permanent results. Both approaches are highly selective and restore gene expression to normal levels regardless of the position of the mutation in the gene.

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Their main CNS indication is Dravet Syndrome. When caused by heterozygous loss of function mutations in the sodium channel

, Dravet syndrome could be treated with a cocktail of three tRNA enhancers that could double the productivity of the working copy of

In the affected cells. This could provide treatment for a wide range of Dravet patients, regardless of the specific defect in the other copy of a

However, about 25% of people with Dravet also have premature stop mutations in the gene, also allowing the use of the suppressor tRNA.

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Thus, they are exploring a dual approach in partnership with Zogenix, an epilepsy drug company, to promote both enhancer tRNA and suppressor tRNA to treat Dravet syndrome. Tevard is also developing remedies for other genetic epilepsies and both CNS and non-CNS indications caused by haploinsufficiency and/or nonsense mutations.

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