Prof Stephen Nicholls:

My name's Steve Nicholls. I'm Professor of Cardiology at Monash University in Melbourne, Australia and the Director of the Victorian Heart Institute.

Can you explain the rationale behind targeting the ANGPTL3 gene for patients with lipid disorders?

ANGPTL3 plays a really important role in lipid metabolism. It inhibits a factor called lipoprotein lipase that breaks down triglyceride-rich lipoproteins. We know from genetic studies that people who have less ANGPTL3 tend to have more lipoprotein lipase, their triglyceride levels are lower, in fact, their LDL cholesterol levels are lower, and what we see in the genetic studies is that they're at a lower risk of having cardiovascular events. So there's a lot of interest in developing therapeutics that inhibit ANGPTL3.

How does this CRISPR-Cas9 therapy differ from existing treatments?

CRISPR Cas9 is a technology that's evolved really quickly, won the Nobel Prize a few years ago. It's fundamentally gene editing. And what it enables us to do is to deliver a specific therapeutic into the hepatocyte, where we go into and find the specific gene of interest and find one specific base pair where we can make a very targeted, permanent change in that gene at that specific site, leading to a reduction in protein production.

So in this case, what we want to do is target the ANGPTL3 gene, leads to a permanent reduction in ANGPTL3 production. And what's really exciting about CRISPR-Cas9 technology is it has the potential to be a one-and-done, once in a lifetime treatment.

What was the study design and patient population?

We presented the findings here of a phase-one clinical trial with 15 participants. They could either have high cholesterol or high triglyceride levels. To get in, baseline LDL cholesterol was about 155, triglycerides, 192 milligrams per deciliter.

They received a single infusion of this agent at different doses ranging from 0.1 to 0.8 milligrams per kilogram. And then we looked at primarily safety, but also we looked at biochemical results in terms of reduction in LDL cholesterol and triglycerides.

What were the key findings?

Well, the first thing we found was it was very well tolerated. We saw a few infusion reactions, but we could temporarily pause the infusion, give some medications and then continue with the infusion. So that was really good. We saw a good knockdown of ANGPTL3 and that resulted in a reduction in LDL cholesterol by about 50% and triglyceride levels by about 55%. We see those changes emerge within two to four weeks, which is really good. And then what we've seen so far in a relatively small and short study is then the durability of that effect. The longer we follow those people, the results have just persisted.

Now what we'll do is go on and do bigger and longer studies and try to understand, can this truly be the once in a lifetime therapeutic that we would all hope it would be?

What are the take-home messages, and what further research is required?

The take-home messages are, one: gene editing is here. We can now effectively treat cholesterol and triglyceride with therapies targeting ANGPTL3 and there will be others that will be coming into the clinical development landscape.

The next stage here is going to have to be bigger and longer studies. Let's make sure that we really understand how effective this is. Let's understand how well it is tolerated when we get into bigger clinical trials, and then once we're able to do that, then hopefully we can then bring a new therapeutic to the clinic.