Alnylam’s journey from laboratory discoveries to life-changing treatments

The journey from research discoveries to impactful new treatments

Alnylam Pharmaceuticals, of which he is the founder MYTH professors and former postdoctoral fellows, has developed five FDA-approved RNAi drugs that are making a significant impact on patients’ lives. The company continues to innovate in the field of RNAi delivery, with the goal of treating a variety of diseases, including neurological disorders.

Before a research discovery becomes a life-changing treatment for patients, many hurdles must be overcome. This is especially true when the treatments being developed represent an entirely new class of drugs. However, overcoming these obstacles could revolutionize our ability to treat disease.

Few companies exemplify this process better than Alnylam Pharmaceuticals. Alnylam was founded by a group of MIT-affiliated researchers who believed in the promise of technology… RNA interference or RNAi.

Creation and early development

Researchers have done fundamental work to understand how RNAi, which is a natural process, works to silence genes through the degradation of messenger RNA. But their decision to found Alnylam in 2002 attracted the funding and expertise needed to turn their discoveries into a new class of drugs. Since this decision, Alnylam has made significant progress, moving RNAi from an exciting scientific discovery to an influential new therapeutic pathway.

Today, Alnylam has five drugs approved by the US Food and Drug Administration (the RNAi treatment discovered by Alnylam is licensed from Novartis) and a rapidly expanding clinical offering. The company’s approved drugs are designed to treat debilitating, sometimes life-threatening diseases that many patients have struggled with for decades and have few other options.

The company estimates that its treatments have helped more than 5,000 patients in 2023 alone. Behind that number are patient stories that show how Alnylam has changed lives. The mother-of-three says Alnylam treatments have helped her regain control of her life after being bedridden by seizures associated with acute intermittent porphyria (AIP), a rare genetic disorder. Another patient reported that one of the company’s treatments helped her attend her daughter’s wedding. A third patient, who dropped out of college because of frequent AIP attacks, was able to return to school.

Today, Alnylam is not the only company developing drugs based on RNAi. But it remains a pioneer in the field, and the company’s founders – Professor Phil Sharp from the MIT Institute, Professor David Bartel, Professor Emeritus Paul Schimmel and former MIT postdocs Thomas Tuschl and Phillip Zamore – consider Alnylam a champion in the field in the broadest sense. .

“Alnylam has published more than 250 scientific articles over 20 years,” says Sharp, who currently chairs Alnylam’s scientific advisory board. “Not only did we do science, not only did we translate it for the benefit of patients, but we also described every step. We have established this as a treatment modality for patients and I am very proud of this record.

Pioneering development of RNAi

MIT’s involvement in RNAi dates back to its discovery. Before Andrew Fire PhD ’83 shared the Nobel Prize for the discovery of RNAi in 1998, he worked to understand how DNA was transcribed into RNA while he was a graduate student in Sharp’s lab.

After leaving MIT, Fire and his colleagues showed that double-stranded RNA could be used to silence specific genes in worms. But the biochemical mechanisms that made double-stranded RNA work were unknown until Professors Sharp, Bartel, and Ruth Lehmann of MIT, along with Zamore and Tuschl, published seminal papers explaining the process. The researchers developed a system to study RNAi and showed how RNAi can be controlled using different genetic sequences. Shortly after Tuschl left MIT, he showed that a similar process could also be used to silence specific genes in human cells, opening a new frontier in the study of genes and, ultimately, in the treatment of disease.

Transformative discoveries

“Tom showed that you can synthesize these small RNAs, transfect them into cells, and get a very specific gene knockout that matches that of the small RNAs,” explains Bartel. “This discovery transformed biological research. The ability to specifically inhibit mammalian genes was enormous. You could suddenly study the function of any gene you’re interested in by knocking it out and seeing what happens. …The research community immediately began using this approach to study the function of their favorite genes in mammalian cells.

Besides elucidating gene function, another application came to mind.

“Since almost all diseases are linked to genes, can we use these small RNAs and silence genes to treat patients? Sharp remembers wondering.

To answer that question, the researchers founded Alnylam in 2002. (They hired Schimmel, a biotech veteran, around the same time.) But there was a lot of work before the technology could be tested on patients. The main challenge was to bring RNAi into the cytoplasm of the patients’ cells.

“Through work in the lab of Dave Bartel and Phil Sharp, among others, it became clear that to translate RNAi into therapy, there are three problems that need to be solved: delivery, delivery and delivery,” said Kevin Fitzgerald, Alnylam’s chief scientific officer. in the company since 2005.

Alnylam has collaborated with MIT drug delivery expert and institute professor Bob Langer from the start. Eventually, Alnylam developed the first lipid nanoparticles (LNPs) that could be used to encapsulate RNA and deliver it to patient cells. LNPs were later used in mRNA vaccines against Covid-19.

“Alnylam has invested more than 20 years and more than $4 billion in RNAi to develop these new treatments,” says Sharp. “It is a means by which innovation can be translated to the benefit of society. »

From scientific discovery to bed

In 2018, Alnylam received its first FDA approval for the treatment of transthyretin-mediated hereditary polyneuropathy amyloidosis, a rare and fatal disease. It is also the first RNAi drug to reach the market and the first drug approved to treat this disease in the United States.

“What I keep in mind is that at the end of the day, for some patients, it’s two months,” says Fitzgerald. “The diseases we try to treat progress month by month, day by day, and patients can reach a point where nothing helps them. If you can advance their disease one stage, that’s huge.

Since that first treatment, Alnylam has updated its RNAi delivery system—including the conjugation of small interfering RNAs to molecules that help them enter cells—and won approval to treat other rare genetic diseases as well as hypercholesterolemia (a treatment approved by Novartis). All of these treatments work primarily by silencing the genes that code for protein production in the liver, which has proven to be the easiest site for delivering RNAi molecules. But the Alnylam team is confident it could deliver RNAi to other areas of the body, opening the door to a new world of treatment possibilities. The company has reported promising early results in the central nervous system and says a Phase I study last year was the first RNAi therapy to show gene silencing in the human brain.

Future prospects and goals

“A lot of work is being done at Alnylam and other companies to deliver these RNAs to other tissues: muscle, immune cells, lung cells, etc.,” explains Sharp. “But for me the most interesting application is delivery to the brain. We believe that we have a therapeutic modality that can very specifically control the activity of certain genes in the nervous system. I think it is extremely important, for caused diseases Alzheimer’s disease to schizophrenia and depression.

Working on the central nervous system is especially important to Fitzgerald, who watched his father battle Parkinson’s disease.

“Our goal is to be present in every organ of the human body, then in combinations of organs, then in combinations of targets within individual organs, then in combinations of targets within multiple organs,” explains Fitzgerald. “We’re really at the very beginning of what this technology will do for human health. »

This is an exciting time for the RNAi scientific community, including many of those who continue to study it at MIT. However, Alnylam will need to continue its drug development efforts to deliver on this promise and help more and more patients.

“I think that’s the real limit,” says Sharp. “There is a huge therapeutic need and I think this technology could have a huge impact. But we have to prove it. That’s why Alnylam exists: to deal with new science that opens up new possibilities and find out if they can be applied. Of course, that’s why MIT is here: to improve lives.