Is RNA Interference Therapy (RNAi) the Next Big Thing in Healthcare?

Have you ever wondered how it would feel to have a treatment for all ailments?

More than twenty years ago, scientists Andrew Fire and Craig Mello had the same questions. They figured out how to use RNA, one of the key molecules in our cells, to search for and control specific genes. This discovery, called RNA interference, or RNAi for short, earned them the Nobel Prize in 2006.

“Okay, Google, explain RNAi to me”

Imagine your DNA is a massive library with billions of books. Somewhere in that library, there is a tiny error, just one page in one book, that is responsible for a disease. The challenge? Finding it.

That’s where RNAi comes in. It acts like the cell’s very own Google search. It scans through all that genetic information using a guide, looking for specific sequences, just like searching for a phrase online.

Once RNAi finds the genetic “mistake,” it doesn’t stop there. It can actually silence that faulty gene, preventing it from doing harm. Scientists have been so excited about it because RNAi could be a powerful way to treat diseases caused by genetic errors.

Let’s break it down.

You are probably already familiar with DNA(Deoxyribonucleic acid), which contains our genetic code, the blueprint of life. RNA, or ribonucleic acid, is structurally similar to DNA and is found in every living cell. While DNA stores the instructions, RNA is the part that actually gets things done. Think of DNA as the architect, and RNA as the builder who takes the plans and makes them happen.

Here’s how it works - your DNA stays safely tucked away, and when your body needs to use a part of that blueprint, it unzips the double helix to copy a section. That copy is made into messenger RNA (mrna) - a mobile version of the genetic instructions that cells can read and act on.

This is where things get more interesting. RNA interference, or RNAi, is a natural, built-in system in many organisms that is used to silence specific genes. Yes, silence is like pressing the mute button on a noisy gene, which is causing trouble.

Eureka moments in science are rare but when they happen, they can completely flip the entire field on its head. One of the most exciting examples? The discovery of RNA interference, or RNAi.

Like many great breakthroughs, this one started with a bit of curiosity and something that didn’t quite make sense. Scientists Andrew Fire and Craig Mello were studying tiny worms called C. elegans, a common model organism, when they noticed something strange - a mutant strain of the worm displayed an unusual twitching behaviour.

They were trying to understand how genes are turned on and off, and this twitchy behaviour made them pause. What was going on?

To get there, let’s take a quick detour into how DNA makes proteins. Our DNA is like a cookbook, made up of two strands twisted together.

When the body needs to “read” a recipe, it unzips the strands and copies one side into a single strand of messenger RNA (mrna). That mrna then travels to the cell’s protein-making machinery, where it’s read and translated into a protein.

Fire and Mello wondered - what if they could block this message using RNA itself? Would that stop the protein from being made, and cause the twitching behavior they saw?

First, they tried using single-stranded RNA that matched the message for a muscle protein. Nothing happened - the worms stayed completely normal.

Then they tried something different. They paired the RNA with its matching strand, creating double-stranded RNA, and injected that into the worms. And that’s when things got interesting - the worms began to twitch, just like before. It meant that the protein had been shut down.

This unexpected result launched a series of experiments and ultimately led to the discovery of RNA interference - a natural process where cells recognise double-stranded RNA as a signal to silence matching messages, preventing the production of specific proteins.

Their findings, published in 1998, earned them the Nobel Prize in 2006. But more importantly, they opened the door to a whole new way of understanding and controlling genes.

Today, scientists use RNAi as a research tool to better understand genes. By using small fragments called siRNAs, they can “switch off” specific genes and watch what happens. It’s like turning off the lights in a room to see what stops working.

And perhaps most excitingly, RNAi has become a new form of medicine.

In 2018, a drug called Patisiran became the first RNAi-based treatment to be approved. It was designed to treat a rare and serious condition called hereditary transthyretin-mediated amyloidosis (hATTR) - a disease where the body makes too much of a certain protein, which then builds up in the nerves and causes problems with movement, digestion, and heart function.

Patisiran works by targeting the RNA that makes this problematic protein, effectively turning it off. In clinical trials, patients who received Patisiran showed significant improvements in muscle strength and mobility compared to those who didn’t.

The path from the discovery of RNA interference (RNAi) to developing therapies has been a long, exciting, and sometimes challenging journey. RNAi has unlocked the ability to create treatments that target genes with incredible precision.

This means doctors can now use RNAi to treat diseases in a much more targeted way, minimising side effects and improving outcomes.

Several RNAi-based therapies have already been approved by the FDA, and they're making a big difference for patients with rare and serious diseases. These include:

• Patisiran (Onpattro): Treats hATTR

• Givosiran (Givlaari): Used for acute hepatic porphyria

• Lumasiran (Oxlumo): A treatment for primary hyperoxaluria type 1

• Inclisiran (Leqvio): A treatment for high cholesterol

• Vutrisiran (Amvuttra): Another therapy for hattr

• Nedosiran (Rivfloza): Treats primary hyperoxaluria type 1

These treatments work by using small RNA molecules to target specific messenger RNAS (mRNAs), stopping them from making the proteins that cause disease.

It’s a huge leap forward in the world of medicine, offering a much more tailored approach to treatment.

One exciting example of an RNAi therapy still in clinical trials is Zilebesiran, which has shown promise in treating hypertension (high blood pressure). Zilebesiran works by targeting angiotensinogen, a protein made in the liver that plays a big role in regulating blood pressure.

There are also other promising RNAi-based therapies in development for a range of diseases, including:

• Fitusiran (Sanofi): Under testing for haemophilia A and B, genetic conditions where the blood doesn’t clot properly.

• Teprasiran (Quark Pharmaceuticals): Developed as a treatment to prevent acute kidney injury in people undergoing surgery or organ transplantation.

• Cosdosiran (Quark Pharmaceuticals): Aimed at treating eye conditions like non-arteritic anterior ischemic optic neuropathy and primary angle glaucoma.

• Tivanisiran (Sylentis): Helps with ocular pain and dry eye disease.

The potential for RNAi therapies is broad. In oncology, for example, RNAi can be used to target genes that are driving cancer, offering a new way to treat tumours by turning off the genes that allow them to grow. In genetic disorders, RNAi can directly target the faulty genes causing disease, offering the possibility of correcting these problems at the molecular level.

RNAi is also a powerful tool for treating infectious diseases. It can target the RNA of viruses, preventing them from replicating and spreading. This adaptability makes RNAi a game-changer in precision medicine, where treatments are tailored to an individual’s genetic makeup.

Despite its huge promise, there are still hurdles to overcome. For example, delivering RNAi therapies into the right cells without causing unwanted side effects is a tricky business.

Researchers are also working to make sure that these therapies don’t trigger immune responses or affect genes they shouldn’t. And of course, testing the long-term safety and effectiveness of RNAi treatments is crucial before they can be widely used.

But the future looks bright. With continued research and clinical trials, scientists are making strides toward personalised RNAi therapies—ones that can be fine-tuned to target a person’s specific genetic variations. This could lead to even more precise and effective treatments in the future.

The potential of RNAi therapies is just beginning to be fully realised, and as our understanding of genetics grows, we’ll likely see even more groundbreaking applications. It’s an exciting time in the world of medicine, and RNAi is proving to be a major player in reshaping the future of healthcare.

RNAi therapies are transforming modern medicine by allowing doctors to target genes directly for treatment. This approach promises personalised, precise treatments that can address a wide range of diseases with fewer side effects.

As research progresses, RNAi offers exciting potential for genetic medicine, ushering in a new era of precision and efficacy in healthcare. It’s just the beginning, and the future of RNAi holds incredible promise for more effective treatments and better patient outcomes.

Q. What is RNAi?

A. RNA interference (RNAi) is a natural process where small RNA molecules target and “silence” specific genes, preventing the production of certain proteins.

Q. How does RNAi work?

A. RNAi works by introducing double-stranded RNA into cells, which triggers a molecular process that breaks down the matching messenger RNA (mrna) and stops protein production.

Q. What are RNAi therapies used for?

A. RNAi therapies are used to treat various diseases, including genetic disorders, cancers, and viral infections, by targeting specific genes that cause these conditions.

Q. Is RNAi used in medicine?

A. Yes, FDA-approved RNAi-based drugs, like Patisiran and Givosiran, are already used to treat conditions such as hereditary amyloidosis and acute hepatic porphyria.

Q. What are the challenges of RNAi therapies?

A. Key challenges include ensuring effective delivery to target cells, minimising off-target effects, and ensuring long-term safety and efficacy.