The Future of Medicine Is RNA

F. Perry Wilson, MD, MSCE


November 13, 2023

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson of the Yale School of Medicine.

Every once in a while, medicine changes in a fundamental way, and we may not realize it while it's happening. I wasn't around in 1928 when Fleming discovered penicillin; or in 1953 when Watson, Crick, and Franklin characterized the double-helical structure of DNA.

But looking at medicine today, there are essentially two places where I think we will see, in retrospect, that we were at a fundamental turning point. One is artificial intelligence, which gets so much attention and hype that I will simply say yes, this will change things, stay tuned.

The other is a bit more obscure, but I suspect it may be just as impactful. That other thing is RNA therapeutics — the medicines of the future.

I want to start with the idea that many diseases are, fundamentally, a problem of proteins. In some cases, like hypercholesterolemia, the body produces too much protein; in others, like hemophilia, too little.

When you think about disease this way, you realize that our current medications take effect late in the disease game. We have these molecules that try to block a protein from its receptor, prevent a protein from cleaving another protein, or increase the rate that a protein is broken down. It's all distal to the fundamental problem: the production of the bad protein in the first place.

Enter small inhibitory RNAs, or siRNAs for short, discovered in 1998 by Andrew Fire and Craig Mello at UMass Worcester. The two won the Nobel prize in medicine just 8 years later; that's a really short time, highlighting just how important this discovery was. In contrast, Karikó and Weissman won the Nobel for mRNA vaccines this year, after inventing them 18 years ago.

siRNAs are the body's way of targeting proteins for destruction before they are ever created. About 20 base pairs long, siRNAs seek out a complementary target mRNA, attached to it, and call in a group of proteins to destroy it. With the target mRNA gone, no protein can be created.

You see where this is going, right? How does high cholesterol kill you? Proteins. How does Staphylococcus aureus kill you? Proteins. Even viruses can't replicate if their RNA is prevented from being turned into proteins.

So, how do we use siRNAs? A new paper appearing in JAMA this week describes a fairly impressive use case.

The background here is that higher levels of lipoprotein(a), an LDL-like protein, are associated with cardiovascular disease, heart attack, and stroke. But unfortunately, statins really don't have any effect on lipoprotein(a) levels. Neither does diet. Your lipoprotein(a) level seems to be more or less hard-coded genetically.

So, what if we stop the genetic machinery from working? Enter lepodisiran, a drug from Eli Lilly. Unlike so many other medications, which are usually found in nature, purified, and synthesized, lepodisiran was created from scratch. It's not hard. Thanks to the Human Genome Project, we know the genetic code for lipoprotein(a), so inventing an siRNA to target it specifically is trivial. That's one of the key features of siRNA — you don't have to find a chemical that binds strongly to some protein receptor, and worry about the off-target effects and all that nonsense. You just pick a protein you want to suppress and you suppress it.

Okay, it's not that simple. siRNA is broken down very quickly by the body, so it needs to be targeted to the organ of interest — in this case, the liver, since that is where lipoprotein(a) is synthesized. Lepodisiran is targeted to the liver by this special targeting label here.

The report is a standard dose-escalation trial. Six patients, all with elevated lipoprotein(a) levels, were started with a 4-mg dose (two additional individuals got placebo). They were intensely monitored, spending 3 days in a research unit for multiple blood draws followed by weekly, and then biweekly outpatient visits. Once they had done well, the next group of six people received a higher dose (two more got placebo), and the process was repeated — six times total — until the highest dose, 608 mg, was reached.

This is an injection, of course; siRNA wouldn't withstand the harshness of the digestive system. And it's only one injection. You can see from the blood concentration curves that within about 48 hours, circulating lepodisiran was not detectable.

But check out these results. Remember, this is from a single injection of lepodisiran.

Lipoprotein(a) levels start to drop within a week of administration, and they stay down. In the higher-dose groups, levels are nearly undetectable a year after that injection.

It was this graph that made me sit back and think that there might be something new under the sun. A single injection that can suppress protein synthesis for an entire year? If it really works, it changes the game.

Of course, this study wasn't powered to look at important outcomes like heart attacks and strokes. It was primarily designed to assess safety, and the drug was pretty well tolerated, with similar rates of adverse events in the drug and placebo groups.

As crazy as it sounds, the real concern here might be that this drug is too good; is it safe to drop your lipoprotein(a) levels to zero for a year? I don't know. But lower doses don't have quite as strong an effect.

Trust me, these drugs are going to change things. They already are. In July, The New England Journal published a study of zilebesiran, an siRNA that inhibits the production of angiotensinogen, to control blood pressure. Similar story: One injection led to a basically complete suppression of angiotensinogen and a sustained decrease in blood pressure.

I'm not exaggerating when I say that there may come a time when you go to your doctor once a year, get your RNA shots, and don't have to take any other medication from that point on. And that time may be, like, 5 years from now. It's wild.

Seems to me that that rapid Nobel Prize was very well deserved.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his new book, How Medicine Works and When It Doesn't, is available now.

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