The 2024 Nobel Prize in Physiology or Medicine has finally been announced, and surprisingly, the previously highly requested GLP-1 target and alphafold system have not been awarded, and the award-winning fields are similar to last year, which are pioneers in the field of RNA. Last year it was mRNA, this year it is microRNA.

On October 7 at 5:30 p.m., the Sweden Carolinska Institutet announced that the 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun · · for their "discovery of microRNAs and their role in post-transcriptional gene regulation." It is reported that the two are professors at the University of Massachusetts Medical School and Harvard Medical School, respectively.

As we all know, the winner of the Nobel Prize needs to go through a long time from making relevant achievements to winning the Nobel Prize: the Nobel Prize needs time to test its value to society, and any scientific breakthrough from discovery to mass production and the beginning of the process of changing society is long and has many stakes. For example, it has been 31 years since Victor · Ambrose discovered the first microRNA, lin-4, in a nematode in 1993.

Born in 1953, Victor · Ambrose received his bachelor's and doctorate degrees in biology from the Massachusetts Institute of Technology, and was only 26 years old when he completed his doctorate. During his Ph.D., he was supervised by another genetic, David · Baltimore, who won the 1975 Nobel Prize in Physiology or Medicine for his discovery of reverse transcriptase, and made outstanding contributions to the study of viral genes. To some extent, the inheritance of teachers plays a considerable role in cutting-edge academics.

Interestingly, he became an assistant professor at Harvard in 1984, and in the United States, an assistant professor is roughly equivalent to a lecturer in a Chinese university, and he can only stay for tenure after 5-6 years of service. His achievement in 1993 came during his time at Dartmouth College. Later, he came to Massachusetts State University, where he remains to this day.

In fact, Victor has gained the fame he deserves by becoming more widely recognized for the effects of microRNAs. In 2006, he received the Order of the United States Genetics Society, and in 2007, he became a member of the United States National Academy of Sciences. In 2015, he won the Breakthrough Prize in Life Sciences, which was founded by Silicon Valley entrepreneurs such as Google's Sergey · Brin, Meta's Zuckerberg, etc., and began to be awarded annually in 2013, with a prize of $3 million per person, the highest prize in the field of physiology or medicine to date.

The well-known RNAs are mRNA (messenger RNA), tRNA (transport RNA) and rRNA (ribosomal RNA), DNA is obtained through the process of transcription, then translated into polypeptide chains, and then through folding and other processes to obtain three-dimensional structures into proteins. In addition to these three major RNAs, there are many RNAs that play a crucial regulatory role in transcription and translation, such as microRNAs (miRNAs). In terms of mechanism, at the earliest, Nobel laureate Victor published the first miRNA molecule lin-4 discovered in CELL, which is a single-stranded small RNA molecule that inhibits the expression of the protein LIN-14 in an unknown form in Caenorhabditis elegans, and larvae lacking "lin-4" will continue to express high levels of LIN-14. Later, it was discovered that this RNA does not have the coding function of mRNA, and mainly interferes with the translation process of molecules. In 2000, Let-7, the first mammalian miRNA, was reported, demonstrating that this small nucleic acid also plays an extremely important regulatory role in human cells.

To date, multiple research groups have identified hundreds of miRNAs in a variety of biological species, including humans, fruit flies, and plants. It is estimated that miRNA-coding genes account for 1%-5% of mammalian genes, and more than 60% of human protein-coding genes are regulated by miRNAs.

In terms of mechanism of action, there are various mechanisms of action of miRNA in animals, and the two mainstream mechanisms found so far are: 1. miRNA binds to the 3'UTR region of mRNA through its own "seed sequence", which leads to the inhibition of mRNA translation, thereby affecting gene expression. 2. Blocking the advance of ribosomes during the translation extension phase, leading to the termination of translation. Both mechanisms of action are achieved by inhibiting the translation process. In the process of inhibiting translation, the stability of mRNA is also constantly weakened, which eventually leads to the degradation of mRNA. In addition to degrading mRNA, miRNAs have also been found to degrade long non-coding RNAs (lnc RNAs).

It is important to note that although both are short-stranded non-coding RNAs, there are significant differences between siRNAs and miRNAs. The pairing of siRNA to mRNA is fully complementary and has strong specificity, whereas the pairing of miRNA to mRNA is not completely complementary and therefore has a wider range of effects and less specificity. The process of mRNA degradation in the former is more direct, while the role of the latter is achieved through the translation process, and the regulatory mechanism is more complex.

The former has strong specificity, in other words, if considered from the perspective of druggability, the former has a clearer target. The difference in the mechanism of action between the two also lays the groundwork for the gap in the progress of the development of the latter therapy. The release of a blockbuster technology news will certainly cause an uproar in the secondary market. However, it seems that many foreign investors and public opinion publishers have a certain misunderstanding, and use the concept of miRNA to transfer the flowers to siRNA companies to build momentum for major biotech companies that do small nucleic acid interference therapy.

This is inappropriate, and there is a very obvious gap between the current development progress of the two. In terms of siRNAs, Alnylam Pharmaceuticals, the originator of the mountain, has completed the commercialization of five single products, while Arrowhead is also accelerating its catch-up, and currently has three siRNA pipelines entering the Phase III clinical stage. In addition, this year, China's biotech Bowang Pharmaceutical has also completed a huge BD of small nucleic acid with Novartis, and as a pharmaceutical company that has just raised to the A round, the potential total amount of its license out has reached 4.165 billion US dollars.

According to the data of pharmacologics, the current domestic oligonucleotide treatment drug pipeline with high clinical progress is mainly focused on the indications of cardiovascular and cerebrovascular diseases, metabolic diseases and liver diseases. In general, although there is a gap between the progress and foreign countries, it will soon enter the stage of commercialization. But miRNAs are not. As mentioned above, miRNAs are not as specific in terms of drug-specific compared to siRNAs, so there is still some distance from large-scale commercialization of therapeutics, and the fastest advancing therapies are only advancing to Phase II clinical trials.

One of the more notable developments in this segment this year was Novo Nordisk's announcement in March of the acquisition of Cardior Pharmaceuticals, a biotech deeply engaged in RNA therapeutics for heart diseases. Its core pipeline is CDR132L: a miRNA inhibitor targeting miR-132, which can also be grouped under the category of ASO therapeutics. When patients are under cardiomyocyte stress conditions, the expression of miR-132 in cardiomyocytes will be upregulated, and high expression of miR-132 in cardiac tissue will lead to progressive adverse cardiac remodeling, which will lead to heart failure. The CDR132L can selectively block the abnormal level of miR-132 molecule, thereby inhibiting the occurrence of cardiac remodeling. At present, the dosing cycle is not much different from the first generation of siRNA commercialization, with an interval of about one month.

At present, most of the therapies exist in the form of ASO, which regulates miRNA expression by inhibiting miRNA by antisense oligonucleotides, thereby affecting the expression of related genes. However, due to the mechanism of miRNA itself, it can regulate a wide range of genes, and the long-term safety of the efficacy needs to be verified by registrational clinical trials.

In addition to miRNA therapeutics in the form of ASO, miRNA mimetic therapies are also being developed, which can be widely used in cancer treatment in the future by introducing artificially synthesized miRNAs into the human body to regulate overexpressed genes. However, there is also a lot of resistance to therapeutics, with the most typical failure case being MRX34, which had five cases of serious treatment-related side effects and four deaths in the Phase I clinical trial, and the clinical study was closed. This is the current status of miRNA R&D, which has not yet entered the clinical phase III pipeline, and its commercialization value is far less certain than that of siRNA. Therefore, it is not objective to use the information of this Nobel Prize too much to speculate on the concept.

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