tRNA therapy proposed by Chinese scholar Jian Yuewei 40 years ago is becoming a new outlet for gene therapy

In 1965, American scientist Robert W.
Holley first isolated transfer RNA (tRNA), and elucidated its sequence and approximate structure, and thus won the 1968 Nobel Prize in Physiology or Medicine
.

First isolation of transfer RNA 1968 Nobel Prize in Physiology or Medicine

According to the central dogma, DNA is transcribed into mRNA, and mRNA is translated into protein, which is the flow direction of genetic information.
Gene therapy for DNA, vaccine for mRNA, and targeted degradation of proteins have received a lot of attention in recent years, and Many breakthroughs have been made
.

However, transfer RNA (tRNA), which is very important in this flow of genetic information, seems to have been overlooked.
tRNA is a key executor of mRNA translation into protein.
tRNA recognizes codons on mRNA through its own anticodon and converts it to The amino acid corresponding to the codon is transferred to the polypeptide chain in ribosome synthesis, thereby realizing the translation process of mRNA to protein
.

tRNA structure

tRNA structure tRNA structure

The marginalization of tRNA has been quickly reversed recently, with at least 4 therapeutic tRNA companies completing large financings since 2021
.

In November 2021, Flagship Pioneering, a well-known biotech venture capital firm, invested $50 million in a new company called AlltRNA, which bills itself as "the world's first tRNA platform company
.

" The company aims to treat thousands of genetic diseases and cancers caused by genetic mutations that lead to premature stop codons and halted protein translation by developing engineered tRNA therapies

But in reality, AlltRNA isn't the only company developing tRNA therapies, or even the first
.

Before Alltrna, ReCode Therapeutics, Shape Therapeutics and Tevard Biosciences had all appeared
.

After it, hC Bioscience received $24 million in financing on February 23 this year, adding another major player to the tRNA therapy field

All of these companies are focused, or partially focused, on tRNA therapy, by engineering tRNA to carry the correct amino acid and introduce it in the place of a mutated stop codon, allowing the protein to continue to be translated, thereby achieving the therapeutic effect of the disease.
purpose
.

It is estimated that about 11% of genetic diseases are caused by genetic mutations that lead to premature stop codons and premature termination of protein translation (so-called nonsense mutations)
.

Therefore, in theory, only one such suppressor tRNA (suppressor tRNA) can eliminate the premature interruption of translation caused by this nonsense mutation, thereby curing thousands of different genetic diseases

If this tRNA therapy can be administered safely, it could open a whole new door for gene therapy
.

The history of tRNA therapy

The development of tRNA therapy The development of tRNA therapy

The idea of ​​using suppressor tRNA (suppressor tRNA) to treat human diseases can be traced back to 40 years ago.
In 1982, Professor Yuet Wai Kan of the University of California, San Francisco published a paper in Nature, proposing to suppress tRNA to treat β- Thalassemia method
.

Professor Jian Yuewei, Academician of the National Academy of Sciences and Foreign Academician of the Chinese Academy of Sciences

Professor Jian Yuewei, Academician of the National Academy of Sciences, Foreign Academician of the Chinese Academy of Sciences, Professor Jian Yuewei, Academician of the National Academy of Sciences, Foreign Academician of the Chinese Academy of Sciences

In 2000, Massimo Buvoli et al.
at the University of Colorado Boulder demonstrated the feasibility of tRNA therapy in transgenic mice
.

In 2002, Anton Kiselev et al.

But at that time, other treatments, such as gene replacement therapy and read-through drugs, showed better therapeutic effect and prospects, so the vast majority of people in the field of tRNA therapy abandoned tRNA therapy
.

For quite some time thereafter, research on tRNA therapeutics stalled, and early patents surrounding the therapeutic use of suppressor tRNAs were never licensed or further developed
.

This was largely due to the fact that the technology was not ready at the time, and it was difficult to imagine how to efficiently deliver it into the body and express it in the most adequate amounts in cells

In 2014, Carla Oliveira of the University of Porto in Portugal published a paper revealing that suppressor tRNA (suppressor tRNA) has the potential to treat or prevent familial hereditary cancer caused by nonsense mutations, but this research also did not attract other scientists and investors.
attention
.

But the situation soon turned around
.

The arrival of tRNA tuyere

The arrival of the tRNA tuyere The arrival of the tRNA tuyere

Founded in 2015, ReCode Therapeutics pioneered the use of tRNA to treat cystic fibrosis
.

But the company's R&D focuses on delivering mRNA using organ-specific LNP vectors to treat diseases such as cystic fibrosis, primary ciliary dyskinesia, and more

In 2018, Prashant Mali of the University of California, San Diego founded Shape Therapeutics to begin developing suppressor tRNA-based therapies for Rett syndrome, a neurodevelopmental disorder caused by nonsense mutations in the MECP2 gene.
disease
.

Prashant Mali was a postdoc at George Church and one of the first researchers to study CRISPR gene editing
.

tRNA therapy is just one of the research directions of Shape Therapeutics, which is also investigating adenosine deaminase (ADAR)-based RNA editing and the development of novel AAV delivery vehicles

It's a similar story at Tevard Biosciences, whose two co-founders, Daniel Fischer and Warren Lammert, both have daughters with a rare disease called Dravet syndrome, a developmental disorder that presents with symptoms in infancy.
Sexual and epileptic encephalopathy, the sudden death rate is 10%, and most patients have different degrees of cognitive developmental lag.
Most of the diseases are caused by mutations in the SCN1A gene
.

They set up the company to reverse Dravet syndrome, which is where the company name Tevard comes from (Dravet spelled backwards)
.

Initially, the company wanted to use base-editing technology for treatment, and base-editing technology pioneer David Liu was also the company's scientific advisor

But in 2017, an exchange between Jeff Coller of Johns Hopkins University and Harvey Lodish of the Whitehead Institute changed Tevard Biosciences' mind
.
Jeff Coller had shown at the time that the abundance of codons in the mRNA of a particular gene and the concentration of the corresponding tRNA in the cell can dramatically alter protein expression levels, a concept known as codon optimization
.
They realized that this could be used to develop enhanced tRNA therapy for Dravet syndrome
.

Enhanced tRNA therapy

enhanced tRNA therapy enhanced tRNA therapy

Currently, the company has demonstrated that the expression level of the SCN1A gene can be approximately doubled without significantly affecting the expression of other genes with a cocktail of 3 enhancing tRNAs
.
In addition, about 25% of Dravet syndrome patients are caused by nonsense mutations in the SCN1A gene, and these patients also need to be treated by suppressor tRNA (suppressor tRNA) therapy
.

In November 2021, Flagship Pioneering invested $50 million in a new company called AlltRNA, which bills itself as "the world's first tRNA platform company
.
" The company aims to treat thousands of genetic diseases and cancers caused by genetic mutations that lead to premature stop codons and halted protein translation by developing engineered tRNA therapies
.

AlltRNA says it has successfully applied machine learning to reveal the unique language of tRNA biology, which has more than atoms in the universe, and could turn powerful biology into programmable medicines
.
They also stated that AlltRNA's industry-first platform integrates learning across tRNA biology and modal space to unlock the full therapeutic potential of tRNAs and design tRNA oligonucleotides with desired therapeutic properties
.

On February 23, 2022, hC Bioscience completed a $24 million Series A financing, adding another major player in the field of tRNA therapy
.

In addition to developing tRNA therapies for diseases in which protein translation is prematurely terminated due to nonsense mutations, the company also develops tRNA therapies for diseases caused by unwanted proteins, by tagging the disease-causing protein, thereby destroying the protein, achieving the purpose of treating disease
.

All therapeutic tRNA companies hope to take advantage of advances in other types of genetic medicine, including mRNA vaccines, gene replacement therapies delivered by viral vectors, and CRISPR-based gene editing therapies
.
But they also face the same conundrum as these gene therapy companies—how to safely and effectively deliver therapeutic components into a patient's cells
.
Adeno-associated virus (AAV) and lipid nanoparticles (LNP) are currently the delivery systems of choice for most therapeutic tRNA companies
.

Professor Xia Qing from the School of Pharmacy of Peking University said that compared with other types of gene drugs, tRNA therapy has two distinct advantages.
First, for this nonsense mutation with an early stop codon, tRNA therapy has universality.
A tRNA therapy Thousands of genetic diseases can be treated; secondly, tRNAs are small, so there are no size constraints that exist when using AAV vectors to deliver some complete genes or CRISPR nucleases
.

Professor Xia Qing's team published a paper in the journal Nature Biomedical Engineering in August 2021.
This study was the first to use gene codon expansion technology to restore the full-length expression of endogenous Dystrophin protein in muscle stem cells and PylRS/mdx mouse disease models.
The above systematically reviewed the safety, efficacy and feasibility of this method for the treatment of Duchenne muscular dystrophy (DMD), and completed the safety and therapeutic effect evaluation of the AAV-PylRS-tRNAPyl system delivered in different ways, for DMD and Rare disease treatment with nonsense mutations provides a new strategy
.

Based on the results of this research, Professor Xia Qing became QiXia Decode Therapeutics in September 2021.
It is reported that QiXia Decode Therapeutics has completed financing of about 16 million US dollars.
The company is currently promoting muscular dystrophy diseases and colorectal insufficiency.
Research and development of sense mutant tumors
.

So far, no tRNA therapy has entered clinical trials, and it is unknown whether tRNA therapy is better than existing gene replacement therapy, read-through drugs or gene editing therapy
.
But what is certain is that the versatility of tRNA therapy, once proven to be safe and effective, will open a whole new door to gene therapy
.

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