Gene Editing to Prevent Heart Disease
GENE THERAPIES AND THE FUTURE OF MEDICINE WITH KIRAN MUSUNURU
We all know someone who has died of a heart attack. That’s because heart disease is the number one killer on our planet today.
At the Perelman Center for Advanced Medicine, a cutting-edge facility at the University of Pennsylvania, Dr Kiran Musunuru is developing something truly extraordinary, a ‘one and done’ gene therapy to prevent heart disease. Because heart disease kills so many, I’m calling this the most important gene therapy in the world.
MEETING DR MUSUNURU
I visited Kiran at his office in Philadelphia. It was an exciting time to be there, as two of his colleagues had just won the Nobel Prize in Physiology and Medicine that very morning! It was also much anticipated, as I’ve wanted to interview him about his ground-breaking work since we met at a MIT conference more than a year ago. We discussed his journey so far, the Stage 1 human trials currently underway, his BIG future goals to tackle cardiovascular disease planet-wide, and finally, how his ‘programmable medicine’ toolkit will be repurposed to tackle all kinds of genetic diseases. Kiran is an exceptionally engaging and positive person. He explained the mechanisms behind his therapies with wonderful clarity. The future implications of his work are profound. As you will hear, I got pretty excited about them at multiple points in our conversation. Enjoy the podcast!
CHECK OUT THE PODCAST TRANSCRIPT →
NEEDLE IN A HAYSTACK
Dr Musunuro built on pioneering science, chased down cell samples, and ultimately identified the critical genes from just two ‘outlier’ patients – talk about finding the proverbial needle in the haystack! It’s an outstanding story of dedication to solving a problem, and a reminder of how each small incremental improvement in our biological knowledge – in this case the early studies of those two patients apparently naturally protected against heart disease – can be so powerful in opening up new medical opportunities in future. Right now we are making considerable and rapid knowledge gains across a whole spread of biological disciplines (neuroscience, genetics, cancer pathology, etc, etc) which is one of the reasons I am so optimistic about the next 20 years in medicine.
COMBINING 2 NOBEL PRIZE WINNING TECHNOLOGIES
Kiran combined two Nobel prize-winning technologies (mRNA and CRISPR) to invent his therapy. How it works is even more astonishing. I’ll try to condense the series of steps that take place in a few lines:
Lipid nanoparticles carrying mRNA molecules are infused intravenously into the patient’s bloodstream. The procedure takes about an hour.
The infusion goes straight to the liver and is taken up by all the liver cells because that is the liver's purpose – to clean things out of the blood. The dose hits every single liver cell, and delivers the RNA encoding CRISPR into every cell, which then teaches the cell’s machinery to produce the CRISPR protein.
The CRISPR protein then edits the DNA of those same cells, scanning the entire genome (all 20,000 genes) until if finds the correct gene, then changes precisely one letter out of the three billion letters in the genome and … Presto! The liver produces less cholesterol.
Within a week (if we use the results so far in mice as a guide) the patient’s overall cholesterol levels are down — and stay down. Job done!
And here’s my one-sentence version of the above: “lipids deliver mRNA into cells, to teach those cells to make CRISPR, which edits the DNA of those same cells to turn off precisely the right genes to protect the patient for the rest of their life.”
‘ONE AND DONE’ THERAPY
In case you missed it above, Kiran’s therapy is for life — ‘one and done.’
Today’s therapies, the only options to try to control high cholesterol, are repeat therapies (like taking statins daily) that go on forever.
The future is one hospital visit and one infusion that permanently reduces cholesterol levels and protects the patient thenceforth. Think of ALL the lifestyle and cost and adherence advantages this will bring for the patient.
Kiran was careful to emphasize the multiple genetic, lifestyle and demographic contributing factors to the incidence of cardiovascular disease, and which factors we can and cannot control. His therapy can only attack the genetic factors. But these make up roughly 50% of the total, which is massive, and given it’s the half we cannot control, it’s doubly massive! As he puts it, “it's the difference between dying of a heart attack at age 60, still in the prime of life, still a lot to live for, versus dying peacefully in your sleep from a heart attack at age 100 when you've lived your full life.”
MOVING THE BELL CURVE FOR HUMANITY
Kiran’s initial target is hypercholesterolemia sufferers, for which it will obviously be a more immediate lifesaver. But where it goes next is truly mind-blowing:
Making it available to all heart attack victims. Anytime a patient leaves the hospital after heart attack, instead of taking a statin every day for the rest of their life, they get the one-time treatment.
Then Kiran wants to offer it to people identified as at high risk of having heart disease in their lifetime.
Then he wants to offer it as a preventative to … everybody.
In short, he wants to “move the bell curve” for cardiovascular disease across ALL of humanity.
Big enough? Impressive enough? Any doubts that the future of medicine is an exciting place? Through the application of CRISPR, AI, mRNA and more, we are truly, right now, entering a golden age of medicine.
PATIENT #1
If you’ve attended one of my future of healthcare keynotes you’ll know I often talk about “Patient #1” and tell their stories to illustrate how real therapies start with one patient, then save the lives of dozens, thousands, and then hundreds of thousands around the world. I love doing this progression because its an emotional and powerful way to show not only what the future looks like but also the likely timeframes for getting there. I spotted the announcement of Kiran’s Patient #1 (on the other side of the planet in New Zealand in his Phase I trial) more than a year ago. From our conversation it sounds like we are at 5-10 patients. Stay tuned :-)
TARGET: AVAILABILITY BY 2030
It’s always a tough question, and Kiran was extremely sporting when I pressed him on possible and probable timeframes. Based on our discussion of the timetable achieved thus far from first mouse edit to the Phase I human trial, coupled with his measured expectations for Phases II and III, there is a good possibility this drug will be approved and available to high-risk patients by 2030. Of course that’s a target, not a guarantee, but it seems realistic. And his thinking on a realistic date for approval and availability to anyone who wants it? 2040. That is NOT far away.
THE BEGINNINGS OF REPROGRAMMABLE MEDICINE
It was wonderful to hear at the end of our discussion how excited Kiran was about the ‘re-programmability’ of his platform to treat a range of rare genetic diseases, such as PKU, that are also centred on the liver, and further, and how astonishingly easy the reprogramming is! As he put it: “I can take the same exact therapy, lipid nanoparticles, messenger RNA for CRISPR, and just change that ‘GPS’ I mentioned — 20 letters that say where in the genome should CRISPR go to make a change, go to gene A versus gene B — all I need to do is change 20 letters, everything keep it exactly the same, change 20 letters, and it would cure patients with PKU. Totally different disease, totally different circumstances.”
This is huge.
So many more people with disorders, people who are waiting (and dying) for a liver transplant will in future have a ‘one and done’ editing therapy as well. No more transplant. No more dying while waiting. And this applies even for the rarest disorders. As Kiran put it, he’ll be able to do it “even if that patient has a unique mutation, that they're the only person in the world who's ever been found to have that mutation.”
Reprogrammable medicine. The game-changer of game-changers.
FUTURE NOBEL LAUREATE?
You can hear Dr Musunuru’s passion and optimism throughout our discussion. I’ve already included his story in my future of healthcare keynotes to illustrate the exponential game-changers coming in medicine, and the boundless new opportunities for proactive and preventative interventions. I’m looking forward to adding to the story. If Nobel prizes are awarded on positive impacts to humanity, then on scale alone I expect he will join the greats. Dr Musunuru IS rewriting the future of medicine. What an inspiration, and what a privilege it was to interview him!