Alnylam scientists harnessed RNA interference to build a platform that has delivered a proven class of medicines — and is now poised to reach new heights.
An Alnylam scientist at work in the lab. Credit: Alnylam Pharmaceuticals, Inc.
In drug discovery, very little of what’s learned from one project can typically be carried over to the next. “For every new target you go after with a small molecule, you basically start from scratch,” says Steve Dowdy, professor of cellular and molecular medicine at the University of California, San Diego. With small molecules, which make up an estimated 90% of approved medicines1, each new medicine requires in-depth knowledge of the structure of the protein the gene makes so the drug can be made to precisely fit the appropriate binding pocket. It’s a costly process that often takes years of trial and error, with success far from certain2.
Development programmes that leverage an approach called RNA interference (RNAi) are breaking this mould, accelerating the design process for new drug candidates while also improving the odds of success in clinical trials. RNAi therapeutics are inspired by a mechanism that exists in all cells to regulate gene expression, using specially-designed small interfering RNA (siRNA) that is complementary to specific human messenger RNA (mRNA) to target and degrade it. RNAi therapeutics have the potential to effectively ‘silence’ the function of any gene associated with disease. Targeting RNA rather than proteins is at the heart of RNAi-based medicines’ therapeutic effect, as well as the advantages of their development over traditional methods.
“The difference is pretty profound,” says Dowdy.
The power of a platform
Developing a new RNAi drug requires two key pieces of knowledge: the sequence of the target gene to programme a complementary siRNA, and a way to deliver it to the appropriate cell type. With these components in place, companies like Alnylam, which pioneered RNAi therapeutic technology, can use their RNAi platforms to quickly discover, design, and test new medicines as soon as target genes are identified. At Alnylam researchers can move from discovering a target gene to identifying and testing an investigational drug in as little as 18 months, a fraction of the time it typically takes for small-molecule drugs. And breakthroughs in one area can accelerate progress in others.
“Once you have figured out how to design an siRNA and deliver it, you can take that know-how and apply it to gene A, B or C,” says Vasant Jadhav, Alnylam’s chief technology officer.
In this way, the RNAi therapeutic platform is analogous to a computer operating system like iOS or Android; scientists can use the platform to quickly create new investigational medicines in the way a software developer uses iOS as a base on which to build new apps. This RNAi ‘operating system’ has already been used to create six FDA-approved drugs – five of them discovered by Alnylam.
RNAi-based drugs have been well tolerated in tens of thousands of people. And they are already helping patients, says Kausik Ray, a cardiologist at Imperial College London who has worked on the development and testing of RNAi drugs. Standard first-line treatments for many common and rare conditions must be taken daily. In contrast, RNAi therapeutics have the ability to be administered infrequently.
“Among other benefits, RNA-based drugs overcome a key problem: patient adherence to medications for chronic conditions,” says Ray. “Instead of relying on the patient to take more than 300 pills a year, you can give a couple of injections.”
The delivery dilemma
The development of Alnylam’s RNAi operating system, and the first few drugs based on it, was not an easy process, however. Just over a decade ago, many large pharmaceutical companies had begun to lose interest in the platform as researchers struggled to overcome the biggest challenge for RNA-based drugs: delivering them to the right tissues.
As a molecule, siRNA goes against just about every rule in the traditional drug discovery book. Compared with small molecules, siRNA is large, covered in negative charges, and doesn’t easily cross cell membranes. It’s also easily degraded, and can trigger an immune response. Getting siRNA into the cell where it can target, bind to and disrupt mRNA is difficult.
Scientists at Alnylam worked for more than 15 years to overcome these challenges, says Jadhav, first using lipid nanoparticles to encapsulate the siRNA and deliver it to the cell — an approach that was later used in the mRNA-based COVID-19 vaccines — and then via conjugates: molecules that link to siRNAs and guide them to target cells. A sugar molecule called GalNAc has proven effective at binding to a receptor on the surface of liver cells, and new delivery routes are now opening for other tissues.
Genes expressed in the liver were Alnylam’s initial focus, as that organ’s ability to take up large molecules made it the natural first target. But new C16 conjugates — which see siRNAs attached to specially designed chains of carbon molecules — have now allowed researchers to target more inaccessible cells in the central nervous system (CNS) and beyond. For example, Alnylam has a drug candidate that targets the CNS in phase I clinical trials for early-onset Alzheimer’s disease, and the company is working to systematically unlock additional tissues. It has already seen promising preclinical data in adipose tissue and muscle.
Once inside the cell, siRNA has key features that aid drug development. Small-molecule drugs rely on the unique shape of a biological target to recognize it. In contrast, siRNA reads and recognizes a short stretch of genetic sequence within an mRNA target. The sequence recognized by siRNA is generally selected to be identical between species, which increases the relevance of preclinical studies, says Jadhav.
“We’re using the shared properties of the molecules to improve our odds of success,” he says. In addition, the siRNA component of RNAi therapeutics has standard physical and chemical properties that enable researchers to take lessons from one programme and apply them to the next.
With RNAi’s therapeutic platform established, the applications for RNAi are coming thick and fast. As the field continues scaling across rare and common diseases, this therapeutic approach has the potential to positively impact the lives of millions of people with some of humanity’s most challenging-to-treat conditions, including cardiovascular disease, neurological disease and cancer.
“Once I know I can deliver to a given cell type, I know I can hit every target gene in that cell,” says Dowdy. “It’s really what the world of pharma has wanted for decades.”
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References
Govardhanagiri, S., Bethi, S. & Nagaraju, G.P. in Breaking Tolerance to Pancreatic Cancer Unresponsiveness to Chemotherapy (ed Nagaraju, G.P.) Ch. 8 (Academic, 2019)
Mullard, A. Nature Rev Drug Discov 15, 447 (2016).
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