Our Science

OUR SCIENCE

Pioneering RNA interference (RNAi) Therapeutics

RNAi therapeutics are an innovative class of gene silencing medicines based on RNA interference (RNAi)—a breakthrough discovery in understanding how genes are regulated naturally within cells. The significance of the discovery of RNAi was recognized with the 2006 Nobel Prize in Medicine or Physiology.

Since our founding in 2002, Alnylam has pioneered RNAi-based medicines through sustained research and development (R&D) efforts that have yielded the critical breakthroughs and innovations that make RNAi therapeutics possible. Nearly 15 years of work by Alnylam delivered the world’s first approved RNAi therapeutic—ONPATTRO® (patisiran)—in 2018 and, subsequently, GIVLAARI® (givosiran), OXLUMO® (lumasiran), Leqvio® (inclisiran)*, AMVUTTRA® (vutrisiran) and Qfitlia™ (fitusiran)*.

Our robust pipeline of investigational RNAi therapeutics is currently focused on disease areas including transthyretin amyloidosis, rare diseases, cardiovascular diseases, metabolic diseases, and neurological diseases—and we are actively exploring other disease areas.

How RNAi Therapeutics Work

What is RNA interference (RNAi)?

RNA interference (RNAi) is a natural biological process that regulates gene expression (how your body makes proteins) by "interfering" with messenger RNA (mRNA) which carry DNA's instructions for making new proteins.

How do RNA interference (RNAi) Therapeutics Work?

Our medicines use RNA interference to "silence" gene expression for specific proteins that have been found to cause or contribute to diseases. RNAi therapeutics mimic the RNA interference gene silencing process using specially designed small interfering RNA (siRNA) which are delivered to cells where they function like a pair of molecular scissors. They join with a protein complex already in the cell called RISC (RNA-induced silencing complex) to target and degrade specific mRNA before they can deliver their instructions.

RNA interference (RNAi) pathway diagram – how RNAi therapeutics use siRNAs to target and degrade mRNA

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Different from other types of medicines?

Our RNAi therapeutics act before unwanted proteins are made compared to many other classes of medicines which target proteins after they've been made. Additionally, RNAi therapeutics can be administered infrequently — every three or six months for example. We believe that acting "upstream" in this manner provides important therapeutic benefits.

Key Features of RNAi Therapeutics

RNAi therapeutics have several unique features and benefits. They:

Act “upstream” of other classes of medicines, preventing unwanted proteins from being made. Other therapeutic approaches seek to stabilize or reduce these proteins after they’ve been made
Are long-lasting meaning that dosing can be done infrequently, every 3-6 months for example, which can aid adherence and potentially improve the patient experience by reducing the burden of taking daily or weekly medication
Don’t permanently alter genes (DNA) within cells, which is a key safety feature compared to some other types of genetic medicines. Because dosing can be stopped, the treatment effect is reversible if necessary
Can target potentially any gene in the genome, including targets that are “undruggable” by other classes of medicines
Can be delivered to various organs and tissues such as the liver, CNS and muscle using multiple approaches including subcutaneous, intravenous (IV) and intrathecal
Have streamlined the drug development process, leading to more medicines, faster with greater predictability – this has been possible because RNAi therapeutics utilize a “platform approach” with similar basic chemistry and genetically tailored small interfering RNA (siRNA) specific to the disease to be treated

The Role of mRNA and siRNA

Gene expression is the process by which a set of instructions in DNA are converted into proteins. Proteins are the “workers” in the biochemistry of life and are responsible for almost all body functions. They build and repair tissues; are critical to the development of the brain, heart, lung, liver, bones, muscles, cartilage, blood, and skin; and make up many body chemicals including enzymes and hormones. The genetic code for making proteins contained in the DNA directs the synthesis of a version of RNA called messenger RNA, or mRNA, which transports these instructions out of the nucleus of the cell (where DNA resides) into the cytoplasm of the cell where it is used by ribosomes to make new proteins.

Sometimes, errors in the DNA, known as “mutations,” result in faulty mRNA that produce proteins that cause diseases. In these instances, our RNAi therapeutic approach leverages small interfering RNA (siRNA) to target and degrade these specific mRNA. In other instances, our approach delivers therapeutic benefit by using siRNA to target and improve the levels of other, non–disease-causing proteins that are implicated in the disease pathway (ie, those that are not caused by a single genetic mutation). This second approach allows for the RNAi therapeutics to be used in a broader base of human diseases, such as hypercholesterolemia and hypertension.

We believe that siRNA can be designed to target essentially any gene in the genome

Our ability to synthesize siRNA, combined with our R&D product engine that features technology that makes our RNAi therapeutics highly reproducible and modular, opens up possibilities to address a wide variety of diseases, both rare and more common.

How siRNA Work

When the siRNA duplex is delivered into the cell, it is recognized by a protein complex known as the RNA-induced silencing complex (RISC), which already resides in the cell as a primary component of the natural RNAi pathway. Our siRNA duplex is recognized by and loaded into RISC, which removes one of the two strands (the “passenger” strand). This functional RISC now has only the complementary (or “guide”) strand that stays bound to the RISC, helping it find and pair with its matching (or “complementary”) mRNA before it is converted into a protein by a ribosome. Once the match is found, like a pair of molecular scissors, the siRNA together with RISC cleaves the “unwanted” target mRNA, causing it to be degraded. This process is catalytic, meaning that a single siRNA-loaded RISC can degrade many copies of the target mRNA. As a result, the production of the specific “unwanted” protein that corresponds to that mRNA is reduced or “silenced.”

Additionally, we believe that siRNA can be developed to address infectious diseases by directly targeting viral RNA or their host factors for destruction such that the virus is unable make copies of itself or to get inside cells in the first place.

OUR RNAi THERAPEUTICS DELIVERY PLATFORMS

In order for siRNA to target and disable mRNA involved in the cause or “pathway” of disease, they must be specifically and efficiently delivered to the tissue where the production of proteins encoded by a specific gene takes place. Solving for delivery was one of the primary obstacles that Alnylam scientists had to overcome in pioneering this new class of medicines.

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LEVERAGING GENETICS TO ACCELERATE DRUG DEVELOPMENT

The Alnylam Human Genetics group is leveraging large sets of genetic data, the latest analytical and computational technologies, the expertise of a multi-disciplinary team and strategic partnerships, to disrupt the traditional drug discovery and development process. We believe that our approach, investments and commitment to genetically validated targets has the potential to increase our success rate, streamline clinical trials and speed the development of precision medicines for patients with both rare and common diseases.

Our Partnerships: