Gene therapy for haemophilia

People with haemophilia don’t produce enough of a critical factor that helps blood to clot. As a result, they have to inject themselves regularly with a replacement form of the factor to avoid suffering lethal bleeds into their joints and organs. But, within a year or two, it should be possible to offer patients with haemophilia a long-term solution using a gene therapy technique that enables cells in the liver to produce the missing blood clotting factor. Sandy Macrae is the CEO of the US-based company Sangamo therapeutics that’s developing and conducting clinical trials on the new technique. Speaking with him at the recent Biotechnology Innovation Organisation (BIO) meeting in Philadelphia, Chris Smith asked Sandy about the therapies the company are exploring...

桑迪,我想人们谈论most is for haemophilia, which is the blood disorder that the Royal Family suffered from in Victorian times. And now there are two or three companies, including mine, that have medicines that will be on the market in the next 3 to 4 years and provide an option for these patients that they won't have to take factor every day or two, but will have one injection and be done for 5 to 10 years.

Chris - Are you saying then that you've got a way of genetically modifying a haemophiliac so they can make the thing they don't have?

Sandy - We need to be careful how we describe that. In gene therapy you park a version of the gene in the cell. So it's not stitched in, and it's not forever, and it may only last 5 to 10 years. But for these patients, 5 to 10 years is a long time compared to having to inject yourself every day.

Chris - What's the strategy then? What do you actually do to get that gene into them and where do you park it?

Sandy - That's a good question. We borrow a virus and the virus goes to the liver where it infects the liver cells. Once it infects the liver cells it releases the bit of DNA that then produces the factor that the patient was missing, and the liver acts like a factory releasing a little amount of factor each day.

Chris - What's the virus that you use to get the gene into the liver cells?

Sandy - It's called an adeno-associated virus, so it's related somewhat to the cold virus.

Chris - And how does the liver tolerate that? Is it quite comfortable to have this virus going in there?

Sandy - Mostly. Most patients tolerate it very well. Occasionally, patients will get a slight inflammation of their liver and that's something that we need to monitor carefully, and so for the first 3 to 6 months of the patient's treatment they'll be having their liver enzymes measured on a weekly basis. Very few have had any trouble with this course of treatment.

Chris - And how much virus do you actually have to administer to the person in order to treat them? Because you've got to presumably hit a lot of cells in order to get them making enough of the factor, and that means you're going to need a lot of virus?

Sandy - You need to hit a sufficient number of cells to produce the protein. You give a very large number of virus particles: E to the 11, E to the 12, E to the 13. These are more than grains of sand on the beach.

Chris - That’s a hundred billion plus, isn't it?

Sandy - Yes. It's a huge amount.

Chris - Can you make that much easily in the lab? Because that's been one of the problems that’s held back this field in the past is actually scaling up the amount of virus you need to do it in a way that's going to be deliverable for the numbers of patients that we need to treat.

Sandy - Absolutely right. One of the most important things in this field is having reliable manufacturing. It's possible to do this, you make large vats of virus - a bit like homebrew - and you create virus in the billions, as you describe. It needs to be done with quality because patient safety is the most important thing.

Chris - The liver cells aren't long-lived like a nerve cell though are they? They turnover, they die off, and they’re replaced. So that means, presumably, you're going to have to keep doing this to keep the levels topped up in the person?

Sandy - Our liver replaces about 1/7 of its cells every year, so over the course of 10 years you'll be replacing a lot of the cells. Gene therapy doesn't pass it on to the daughter cells, to the next generation. We need to follow these patients out for a period of time to see how long it lasts, what's the durability. But if I was a patient, if I could get 5 to 10 years of benefit from it, I think that's a good balance of benefit and risk.

Chris - So where are you in the trials process now with this?

Sandy - We're in the proof of concept trial. We've seen some really powerful results from our virus and our construct, and then we're at the stage of handing it over to our partner Pfizer, who'll take it into phase three and then to registration.

Chris - One problem that people who have to inject factor VIII for haemophilia experience from time to time is, because they're putting into their body something that their body doesn't naturally make, the immune system regards it as hostile and you get an immune response against it. And that means that actually they then don't get any therapeutic benefit through injecting it. Is there a risk - because you're putting in something that some of these haemophiliacs aren't naturally making with your virus - you're going to have the same problem?

Sandy - A great question. And there's a cohort of patients with antibodies to the factor that mean that they would be excluded from the current trials, and there's other medicines that other companies are developing for them. Nobody has yet seen that reaction from patients with gene therapy, and it's perhaps because it's given chronically in low levels and perhaps something to do with the liver that we can avoid that. But of course we need to follow these patients long-term to make sure they get continued benefit from it.

Chris - How do you actually get the virus just into the liver?

Sandy - We infuse it into a vein. It's a very unremarkable process where the patient waits for an hour or two while the drip slowly drops the virus into the vein and it manages to find its way there.