Gene-silencing: 'New class' of medicine reverses disease porphyria
13 April 2019
Doctors have used a new type of medicine called "gene silencing" to reverse a disease that leaves people in crippling pain. The condition, acute intermittent porphyria, also causes paralysis and is fatal in some cases. The novel approach fine-tunes the genetic instructions locked in our DNA. Doctors say they are "genuinely surprised" how successful it is and that the same approach could be used in previously untreatable diseases. Sue Burrell, from Norfolk, has endured pain few could imagine and needed to take strong opioid painkillers every day. At one point her porphyria was causing severe attacks every couple of weeks and needed hospital treatment. But even then morphine did not stop the pain. She told the BBC it was worse than child-birth, saying: "It's so intense - so strong it's in your legs, in your back, and it just resonates everywhere. It's really, really unbearable." Her sister was affected even more severely and was completely paralysed in hospital for two years. There are several types of porphyria, but each is caused by the body being unable to produce enough of a substance called haem. Haem is a key component of the haemoglobin in red blood cells that transport oxygen around the body. Problems in the body's haem manufacturing process can lead to a build up of toxic proteins. These cause the attacks of physical pain in Sue's form of the disease. In other porphyrias the proteins can cause skin problems. There is some speculation King George III had porphyria. Sue was one of the patients on the trial and is now taking the drug. She says her life has been transformed. "I've had pain for 10 years, I didn't expect that could go away. I'm seeing friends and they're [asking] 'you're not taking any painkillers?' and I was [saying] 'no!'." A clinical trial on 94 people across 18 countries was presented at the International Liver Congress in Vienna. The therapy cut the number of severe attacks by 74%. And 50% of patients were completely clear of attacks that needed hospital treatment, compared to 16% given a dummy treatment. One person dropped out of the study due to side effects. The treatment uses an approach called gene silencing. A gene is part of our DNA that contains the blueprint for making proteins, such as hormones, enzymes or raw building materials. But our DNA is locked away inside a cell's nucleus and kept apart from a cell's protein-making factories. So our bodies use a short strand of genetic code, called messenger RNA, to bridge the gap and carry the instructions. This drug, called givosiran, kills the messenger in a process known as RNA interference. In acute intermittent porphyria it lowers the levels of an enzyme involved in haem production and prevents the build-up of toxic proteins. Prof David Rees, from King's College London, treated patients taking part in the trial in the UK. He told the BBC: "This is a really important treatment - it's innovative. Porphyria is one of the first conditions it has been used in successfully. "I'm genuinely surprised how well it works in this condition and I think it offers a lot of hope for the future." Potentially yes, but it is still very early days. Gene silencing has been used to treat a genetic disease that causes nerve damage and the US Food and Drug Administration said such medicines "have the potential to transform medicine". A similar approach is also being investigated in Huntington's disease, which is caused by a toxic protein that kills brain cells. Researchers are also looking into it as an alternative to statins for lowering cholesterol. Barry Greene, the president of Alnylam, which developed the porphyria drug, told the BBC the latest findings were "heralding a brand new class of medicine". The field of gene silencing has been around for a long time. The Nobel Prize in Physiology or Medicine in 2006 went to the researchers who discovered RNA interference, which occurs naturally in our cells. But the field is now getting to the point where it can be harnessed to help some patients. Dr Alena Pance, from the Wellcome Sanger Institute, told the BBC News website: "I get excited about this, because targeting the messenger RNA allows the fine-tuning of the proteins that are involved in certain diseases. "And therefore, perhaps for the first time, [it can] offer a tool to be able to control those diseases to very accurate levels. "There are diseases that are very difficult to find treatment for, that with this technology might be possible to tackle." Kind of. Gene therapy permanently alters the hard copy of the genetic instructions in DNA. This can be beneficial as it means you need treatment only once, but could also be more risky. If anything goes wrong, such as accidentally editing the wrong part of the genetic code, it cannot be undone. Gene silencing leaves the original DNA alone, but targets the instructions that it sends out into the cell. The downside is you need to keep taking the treatment for the therapy to work. The two approaches are likely to have roles in different diseases. Gene therapy has greater potential in diseases like Duchenne muscular dystrophy where a vital protein for keeping muscles intact is missing. Gene silencing has more potential where tweaking levels of a protein will affect the course of a disease. This is the million dollar question, almost literally, as so far genetic medicines have been expensive. A recent gene therapy for a rare form of blindness was priced at $850,000 (PS650,000) for the one-off treatment. How much the monthly injections of givosiran will be is still unknown. The hope will be that as the field develops, the costs will eventually come down. 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Sue Burrell, from Norfolk, has endured pain few could imagine and needed to take strong opioid painkillers every day. At one point her porphyria was causing severe attacks every couple of weeks and needed hospital treatment. But even then morphine did not stop the pain. She told the BBC it was worse than child-birth, saying: "It's so intense - so strong it's in your legs, in your back, and it just resonates everywhere. It's really, really unbearable." Her sister was affected even more severely and was completely paralysed in hospital for two years.
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How bad is porphyria?
There are several types of porphyria, but each is caused by the body being unable to produce enough of a substance called haem. Haem is a key component of the haemoglobin in red blood cells that transport oxygen around the body. Problems in the body's haem manufacturing process can lead to a build up of toxic proteins. These cause the attacks of physical pain in Sue's form of the disease. In other porphyrias the proteins can cause skin problems. There is some speculation King George III had porphyria.
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What is porphyria?
Sue was one of the patients on the trial and is now taking the drug. She says her life has been transformed. "I've had pain for 10 years, I didn't expect that could go away. I'm seeing friends and they're [asking] 'you're not taking any painkillers?' and I was [saying] 'no!'." A clinical trial on 94 people across 18 countries was presented at the International Liver Congress in Vienna. The therapy cut the number of severe attacks by 74%. And 50% of patients were completely clear of attacks that needed hospital treatment, compared to 16% given a dummy treatment. One person dropped out of the study due to side effects.
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But the new treatment worked?
The treatment uses an approach called gene silencing. A gene is part of our DNA that contains the blueprint for making proteins, such as hormones, enzymes or raw building materials. But our DNA is locked away inside a cell's nucleus and kept apart from a cell's protein-making factories. So our bodies use a short strand of genetic code, called messenger RNA, to bridge the gap and carry the instructions. This drug, called givosiran, kills the messenger in a process known as RNA interference. In acute intermittent porphyria it lowers the levels of an enzyme involved in haem production and prevents the build-up of toxic proteins.
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So how does it work?
Prof David Rees, from King's College London, treated patients taking part in the trial in the UK. He told the BBC: "This is a really important treatment - it's innovative. Porphyria is one of the first conditions it has been used in successfully. "I'm genuinely surprised how well it works in this condition and I think it offers a lot of hope for the future."
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Is this a big deal?
Potentially yes, but it is still very early days. Gene silencing has been used to treat a genetic disease that causes nerve damage and the US Food and Drug Administration said such medicines "have the potential to transform medicine". A similar approach is also being investigated in Huntington's disease, which is caused by a toxic protein that kills brain cells. Researchers are also looking into it as an alternative to statins for lowering cholesterol. Barry Greene, the president of Alnylam, which developed the porphyria drug, told the BBC the latest findings were "heralding a brand new class of medicine".
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Could this treat other diseases?
The field of gene silencing has been around for a long time. The Nobel Prize in Physiology or Medicine in 2006 went to the researchers who discovered RNA interference, which occurs naturally in our cells. But the field is now getting to the point where it can be harnessed to help some patients. Dr Alena Pance, from the Wellcome Sanger Institute, told the BBC News website: "I get excited about this, because targeting the messenger RNA allows the fine-tuning of the proteins that are involved in certain diseases. "And therefore, perhaps for the first time, [it can] offer a tool to be able to control those diseases to very accurate levels. "There are diseases that are very difficult to find treatment for, that with this technology might be possible to tackle."
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Are people excited?
Kind of. Gene therapy permanently alters the hard copy of the genetic instructions in DNA. This can be beneficial as it means you need treatment only once, but could also be more risky. If anything goes wrong, such as accidentally editing the wrong part of the genetic code, it cannot be undone. Gene silencing leaves the original DNA alone, but targets the instructions that it sends out into the cell. The downside is you need to keep taking the treatment for the therapy to work. The two approaches are likely to have roles in different diseases. Gene therapy has greater potential in diseases like Duchenne muscular dystrophy where a vital protein for keeping muscles intact is missing. Gene silencing has more potential where tweaking levels of a protein will affect the course of a disease.
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Is this like gene therapy?
This is the million dollar question, almost literally, as so far genetic medicines have been expensive. A recent gene therapy for a rare form of blindness was priced at $850,000 (PS650,000) for the one-off treatment. How much the monthly injections of givosiran will be is still unknown. The hope will be that as the field develops, the costs will eventually come down. Follow James on Twitter.
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Will anybody be able to afford it?