KMO inhibitor drug improves lifespan of Huntington's disease mice
Positive results from tests of a new 'KMO inhibiting' drug in Huntington's disease mice
An enzyme called KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins, which alters the balance of harmful and protective brain chemicals, has been a focus of research into possible Huntington’s disease treatments for several years. Now, the first positive results of a KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins inhibiting drug have been published in the scientific journal Cell. HDBuzz investigates…
Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them and Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation – a classic tale of good versus evil
The story of KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins began in 1983, a decade before the discovery of the gene that causes Huntington’s disease. Dr Robbie Schwarcz noticed that injecting a toxin called quinolinic acidquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them, or Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them, into the brains of mice produced damage similar to that in HD patients’ brains. Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them causes damage by overstimulating neuronsneuron Brain cells that store and transmit information until they die – that’s called excitotoxicexcitotoxic the death of neurons due to overstimulation death.
Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them isn’t just a poison in a jar – it’s actually produced naturally in the brain as a by-product of the breakdown of proteins. Several different chemical machines called enzymes break down proteins in a series of sequential steps, like a disassembly line. A couple of steps back from the production of Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them sits the enzyme at the heart of this story: kynureninekynurenine a chemical similar to kynurenic acid (Kyna) mono-oxygenase – KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins, to its friends.
The activity of KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins determines which way the protein breakdown pipeline flows. If KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins is more active, the poisonous chemical Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them is produced. If KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins is less active, kynurenic acidkynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation, or Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation, is made instead.
Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation’s effects are opposite to Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them’s – Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation actually protects the brain against the damage caused by chemicals like Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them.
To recap – Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation is the ‘good guy’ and Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them is harmful. KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins tips the balance towards more Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them and less Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation. So, reducing the activity of KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins might be one way of protecting neuronsneuron Brain cells that store and transmit information from excitotoxicexcitotoxic the death of neurons due to overstimulation damage.
Is KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins involved in Huntington’s disease?
KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins sounds important, but is there any evidence that it’s actually involved in Huntington’s disease? Well, yes. In 2005, a group of researchers led by Dr Paul Muchowski studied yeast cells with the HD genetic mutation, and found that switching off the KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins gene protected the cells against the mutation’s harmful effects.
The case for KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins in Huntington’s disease was strengthened just this week, when Dr Flavio Giorgini‘s team at Leicester University announced that they’d confirmed that KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins had similar effects in a fruit-fly model of HD.
Meanwhile, measurements have shown that levels of Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them in the brains of HD patients are abnormally high, while Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation levels are low – a situation that could cause excitotoxicexcitotoxic the death of neurons due to overstimulation damage, unless the balance can be restored.
The drug
Muchowski’s team at University of California, San Francisco, set out to make a drug to block, or ‘inhibit’ KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins, in the hope that it would protect neuronsneuron Brain cells that store and transmit information. The results of Muchowski’s five-year efforts have just been published in the scientific journal Cell.
A drug that inhibits KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins was already available – it’s called Ro 61-8048Ro 61-8048 an experimental drug that inhibits the enzyme KMO, but we’ll stick with Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO. Muchowski knew that Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO would be broken down too rapidly in the body, so he set about modifying Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO into a new molecule that would last longer. He called the new drug JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO, and hoped that the body would convert it gradually into the active KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins inhibitor, Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO.
The trial
Muchowski’s team decided to test JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO in a Huntington’s disease genetic mouse model, called the R6/2R6/2 a mouse model of Huntington's disease. R6/2 mice have been genetically altered with an abnormal gene that makes them produce a harmful fragment of the mutant huntingtin protein mouse. These mice develop symptoms rapidly, after only a month or so, and usually die after 3-4 months.
When the mice were given JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO in their food, their lifespans increased significantly. Half the untreated mice died within 13 weeks, whereas it took two weeks longer for half the JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO-treated animals to die – a 15% improvement.
“It seems that JM6 can protect the brains of HD mice – by an unusual, round-about route”
Muchowski’s team then examined the brains of the JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO-treated mice under the microscope. Surprisingly, they found no change in the build-up of the mutant huntingtin proteinhuntingtin protein The protein produced by the HD gene.. Two important differences were seen, though: first, the connections between neuronsneuron Brain cells that store and transmit information – called synapses – appeared healthier; and second, there was less evidence of activation of the brain’s immune cells, called microgliamicroglia the brain's immune cells.
Behind the scenes: how and why?
It’s always crucial to look behind the scenes of a positive result like this, to find out how the drug is working and why it produced the effects it did. Muchowski’s team did just that, and the results were quite surprising.
When mice were given a single dose of JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO, levels of the drug rose as expected in the blood. Levels of Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO also rose in the blood, as a result of the body converting JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO to Ro-61Ro 61-8048 an experimental drug that inhibits the enzyme KMO. What was surprising was that neither drug reached the brain at all – both chemicals had been blocked by the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream, a defensive shield that prevents many molecules from crossing into the brain from the blood.
But if the drug doesn’t reach the brain, how could it cause the brain improvements seen under the microscope in JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO-treated mice?
Bearing in mind that many of the same chemical pathways are present inside and outside the brain, Muchowski wondered whether the drug might be inhibiting KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins in white blood cells, causing production of a chemical called kynureninekynurenine a chemical similar to kynurenic acid (Kyna), which is similar to Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation – the ‘good guy’ that protects the brain.
We know that kynureninekynurenine a chemical similar to kynurenic acid (Kyna) can cross the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream, and once in the brain, it is converted to Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation. Could that be how the drug protects the brain?
To test the idea, the team performed some additional studies using a technique called microdialysismicrodialysis a technique that enables researchers to measure the levels of chemicals in the living brain. Microdialysismicrodialysis a technique that enables researchers to measure the levels of chemicals in the living brain enables researchers to measure the levels of chemicals in the living brain.
Using microdialysismicrodialysis a technique that enables researchers to measure the levels of chemicals in the living brain, Muchowski confirmed that Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation levels in the brain rose rapidly after the JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO was injected into the bloodstream, and that the Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation was coming from the conversion of kynureninekynurenine a chemical similar to kynurenic acid (Kyna) within the brain.
Time for another recap
So, it seems that JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO can protect the brains of HD mice, but it’s by quite a round-about route. First JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO in the blood is converted to Ro-16, then Ro-16 inhibits KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins in blood cells, causing the production of kynureninekynurenine a chemical similar to kynurenic acid (Kyna). The kynureninekynurenine a chemical similar to kynurenic acid (Kyna) then crosses the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream into the brain, where it is finally converted to Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation.
To complicate things further, Muchowski points out in his article that Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation could protect the brain in several different ways – from altering electrical and chemical signaling, to suppressing the brain’s immune system or improving energy production inside cells.
JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO for Alzheimer’s disease too?
Because changes in the balance between Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation and Quinquinolinic acid quinolinic acid, a chemical produced naturally in the brain that can harm neurons by over-stimulating them are also seen in Alzheimer’s disease, Muchowski decided to test JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO in a genetic mouse model of Alzheimer’s, too – with positive results.
Like in the HD mice, JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO didn’t affect the buildup of harmful proteins but did prevent disease damage to synapses. The Alzheimer’s mice treated with JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO also did better then untreated mice on maze tests of memory and anxiety. Again, these improvements happened alongside increases in Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation levels in the brain.
Definitely good news
Whichever way you look at it, this is exciting research that confirms that KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins inhibiting drugs – a whole new class of HD treatments – can protect against some of the damage occurring in Huntington’s disease. The improvement in survival shown in the R6/2R6/2 a mouse model of Huntington's disease. R6/2 mice have been genetically altered with an abnormal gene that makes them produce a harmful fragment of the mutant huntingtin protein Huntington’s mice is definitely good news.
Muchowski is optimistic that JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO will be suitable for testing in human trials in a relatively short time. The positive results from the Alzheimer’s mouse trial are likely to increase the chance that the drug will be taken forward rapidly, giving a boost to the potential benefits for HD patients.
And whether or not JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO turns into a successful treatment for patients, the idea that it can alter the disease within the brain by acting on cells outside the brain, represents quite a shift in our thinking about what drugs might be candidates for HD. Being unable to cross the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream might not be the deal-breaker we’ve always assumed it to be.
What’s the catch?
Good news like this should be celebrated. At the same time, HDBuzz believes it’s always healthy to be a bit skeptical. HD patients and families are all too familiar with hearing about exciting discoveries that don’t translate into treatments. It’s very early days for KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins inhibitors – so, what are the possible pitfalls here?
One note of caution is that the JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO-treated HD mice lived longer but didn’t show any improvement in symptoms. That might be because the R6/2R6/2 a mouse model of Huntington's disease. R6/2 mice have been genetically altered with an abnormal gene that makes them produce a harmful fragment of the mutant huntingtin protein mice have very rapidly progressive disease. But it’s difficult to predict for sure what might be seen in human HD patients – would they, too, live longer, if given JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO? And would they feel better and function better along the way? At the moment, we just don’t know.
Another thing worth pondering is the very indirect way that JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO is acting. There are a lot of steps between swallowing the drug and the protective effects of Kynakynurenic acid kynurenic acid, a chemical produced naturally in the brain that can protect neurons from harmful over-stimulation. That might have its advantages – as Muchowski points out, it might make the drug safer by evening out the effects of the drug. On the other hand, each extra step could be something that might not work so well in human patients.
The only way to settle these issues for sure is to test JM6JM6 an experimental drug that is converted by the body into Ro-61, which inhibits the enzyme KMO in humans. Human clinical trials will take several years to set up, recruit and run. In the meantime, we should be able to get more information from studying the drug in other animal models of HD.
The last word
We’ve been looking forward to hearing the results from this KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins inhibitor research for a while and this positive report, in a well-respected journal, gives a big boost to the work of Muchowski and other researchers working on the KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins angle. You can bet there’ll be more news about KMOKMO kynurenine mono-oxygenase, an enzyme that controls the balance of harmful and protective chemicals resulting from the breakdown of proteins soon, and HDBuzz will be there to bring you the lowdown.
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