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How the first iRNA therapy developed (Part Two)

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But after the passion faded, the problem gradually emerged. Among them, a major problem that researchers cannot solve is how to start the RNAi process only in the cells that are needed. To make things worse, many people were in hurry to undergo a series of therapies that have just rushed into human trials with only preliminary verification in the laboratory.

"Many early clinical trials are very unwise, and many people want to be the first to do clinical trials," said Professor Mark Kay, a gene therapy expert at Stanford University. He knew these tests will not succeed.

The seeds of disaster, which were buried from the beginning, quickly bear bad fruit. Soon after, RNAi therapies in some studies showed unexpectedly dangerous side effects in the human body. These therapies are either ineffective or harmful to the body because they cannot be delivered to the correct cells in the body.

The entire RNAi field fell to the bottom in an instant, and many biopharmaceutical companies including Roche, Pfizer, and Merck have decided to exit. In 2014, Merck sold its RNAi technology company Sirna at a discount. It was bought by a biotechnology company called Alnylam.

The rise of bright star

Alnylam was founded in 2002, right at the midpoint of RNAi's scientific breakthrough (1998) to the Nobel Prize (2006). Its name is a bit difficult to read, but there is an interesting story behind it-it is derived from the word "Alnilam".

Like the stars, more than 10 years ago, cutting-edge companies developing RNAi technology can be seen everywhere, and Alnylam seems to be no different from them. But when RNAi therapy fell into a trough, Alnylam was one of the few lucky ones to survive. This does not mean that it has never experienced pain. On the company's official website, Alnylam wrote that in the early days of its establishment, it had also encountered many challenges: the departure of its partners and the loss of confidence in the technology by the outside world had brought a big blow to Alnylam. Only within the company can we see the belief and optimism that make RNAi therapy a reality.

Of course, countless cases prove that faith and optimism alone are not enough. What really drives Alnylam forward is a key technology he invented during the "darkest moment" of RNAi therapy. In 2010, the company published a paper that impacted the entire field of RNAi therapy-they found that using ligand-based technology, people could finally deliver targeted RNAi therapies. Yokohama's biggest obstacle to scientists' progress was removed. In front of them is a bright road to the approval of first RNAi therapy.

First RNAi therapy

After finding the key to solving the problem, Alnylam quickly established a series of research and development pipelines to address a variety of rare genetic diseases. Among them, its leading RNAi therapy, patisiran, treats a disease called hATTR amyloidosis. The root cause of this disease is mutations in the gene encoding thyroxine transporter, which causes the abnormal accumulation of amyloid in the human body and causes damage to organs and tissues. It is a severe and fatal rare disease. The life expectancy of a patient is only 2-15 years from the onset of symptoms.

Patisiran can exert the "silencing" effect of RNAi on genes. By inhibiting the expression of specific mRNAs, this therapy can effectively prevent the generation of mutated thyroxin, clear the amyloid deposits in tissues, and restore tissue function.

In September 2017, Alnylam and his partner Sanofi announced the positive top-line results of patisiran in a phase 3 clinical trial. Studies have shown that the new drug has reached the primary clinical endpoint, as well as all secondary clinical endpoints. At the 18-month node, patisiran significantly reduced patients' neurological lesions and improved their quality of life compared to placebo.

Two months later, Alnylam submitted a rolling listing application to reduce the time required for listing. The US FDA has also granted patisiran breakthrough therapy designation and orphan drug status, accelerating its introduction. On August 3, the UK granted patisiran "Early Access" status, allowing patients to get treatment before the treatment is officially launched. Today, humans finally ushered in the approval of the first RNAi therapy.

Some personal opinions

As we know, the  even research and development of new drugs is not easy, even with Nobel Prize support. Even if they can finally leave the laboratory and come to the patient's bed, these new therapies often go through a long research and development journey. Monoclonal antibodies, for example, have gone through a long journey, as are RNAi therapies today.

And perhaps only the bravest fighters can open up a path of benefit for the patients from the thorns of doubt.


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