Huntington's Disease trial success
A DNA-based drug that can penetrate brain cells might be about to revolutionise the treatment of the degenerative condition Huntington’s Disease. The success of a small initial trial of the agent, currently called IONIS-HTTRx, has prompted the pharmaceutical company Roche to license the drug and take it forward. Chris Smith spoke with UCL researcher Ed Wild, one of the team testing the new agent…
Ed - For the first time we have the results of a clinical trial that is aimed at tackling the cause of Huntington's disease, which is a protein called “huntingtin.” We have injected a drug into the spinal fluid of patients with early Huntington's disease and shown that we have successfully been able to reduce the amount of the toxic protein that is present in the nervous system.
Chris - People with Huntington's; what systems to they display; how does it affect them?
Ed - It’s a relentlessly progressive disease. In early adult life, typically in a patient's thirties or fourties. They will develop subtle personality changes: things like being more irritable, having problems concentrating at work, having a shorter fuse, anxiety, depression, and then a bit of fidgetiness. The symptoms will then slowly progress over ten or twenty years until the person loses the ability to walk, to control their limbs. Loses the ability to speak and swallow and, unfortunately, eventually all patients with Huntington’s disease become completely disabled and it is always fatal.
Chris - Who gets it?
Ed - It is a genetic disease. Many people with Huntington’s disease know that the illness runs in their family. Each person with the disease has a 50% chance of giving it to each of their children. Somewhere between 5 and 10% of patients we see in our clinic though didn’t know that Huntington’s disease existed in their family until they’re diagnosed after clinical investigations and a genetic test.
Chris - What is the abnormal gene doing to these people to make them have this disease?
Ed - Everyone has two copies of the gene behind Huntington’s disease, but in someone who’s not going to get it both genes are normal length. At the beginning of the gene there’s a sequence of genetic letters CAG, CAG, CAG, and so on. If there are to many CAGs at the beginning of that gene, that is what results in a positive genetic test for Huntington’s disease, and that gene is a recipe for a protein called “huntingtin”.
If you have too many CAGs in your gene, the protein ends up a little bit too long, and with too many building blocks called “glutamine” the beginning of it. Essentially, that protein is poisonous to your neurons in the brain and it builds up, it interferes with the functioning of neurons and, at some point, it becomes too much and the neurons start to die.
Chris - The new therapy that you’ve trialled, how does that work?
Ed - The drug is called an “antisense oligonucleotide” or ASO, and it is a synthetic DNA molecule. What happens is that this synthetic DNA molecule is injected into the spinal fluid and from there it enters neurons. It sticks to the ‘message’ molecule that is intermediate between the gene and the protein. So the gene is a recipe for the protein but, before it makes the protein, the cell essentially makes a working copy of the gene and that molecule, that so-called message molecule is the one that is directly used to build the protein. So the drug molecule sticks to the message molecule and the cell has built-in machinery for detecting when something has stuck to its message molecule, and when that happens, the cell’s immediate reaction is to get rid of it. It essentially deletes the message molecule and if you do that then much less of the protein gets made.
Chris - Over what period of time was this given to the patients?
Ed - This was a pretty short trial, so four injections were given over a four month period. It was principally designed to ask the question of whether the injection of the drug was safe, was it well tolerated, and did any short term safety issues arise? The good news on that front is that in the 46 people in the trial, there were no significant safety issues identified from either the injection procedure or from the drug.
Chris - Did it make a difference to the levels of the huntingtin, the abnormal protein that would be there in these people?
Ed - It did, and that is why people in the Huntington’s field and beyond are so excited about this preliminary announcement. What we found was that there were significant decreases in the level of the mutant Huntingtin protein. This is not a cure for Huntington’s disease. At the moment we have no idea what this drug will do clinically. Will it slow the progression of Huntington’s disease or not? We are going to need a much longer trail to test whether giving this drug in the long term slows the progression of Huntington’s disease.