What are the prospects of stamping out Huntington’s disease?

Huntington’s disease (HD) is, without doubt, one of the most dreaded neurological disorders. It is named after George Huntington, but the first description is probably by Charles Oscar Waters in 1842. It is dominantly inherited, each child carrying a 50% chance of acquiring the faulty gene. The genetics is slightly tricky because HD is also a tricnucleotide repeat expansion disorder, similar to some other neurological diseases such as Friedreich’s ataxia (FA), Kennedy disease, myotonic dystrophyspinocerebellar ataxia (SCA), and oculopharyngeal muscular dystrophy (OPMD). In these diseases, a section of the genetic code duplicates itself repeatedly, producing abnormally long segments; worse still, these segments get longer which each transmission down the family line. This is called genetic anticipation, and it leads to later generations of the family developing the disease at an earlier age, and manifesting it more severely.

By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354
By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354

HD is not a nice disease. It is accompanied by chorea, probably the most distressing abnormal movement to torment the human body. This is a continuous, writhing muscle activity which involves all the body, and generating very grotesque and painful postures. As if this wasn’t enough, dementia eventually sets in, as does almost every other neurological symptom one could imagine. HD is a problem neurology needs to solve. And thankfully there is some activity in that direction. Here are 4 recent hope-raising developments.

1. Gene silencing with ISIS-HTTRx

RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722
RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722

The manufacturers of ISIS-HTTRx must surely be rueing the unfortunate choice of name for their gene silencing drug. But they will take comfort in its promise to crush HD. It is the first trial of a new drug for HD, and it is touted as probably ‘one of the most important developments since the gene for Huntington’s disease was discovered‘. ISIS-HTTRx neutralises huntingtin, the toxic product which accumulates in, and damages, the nerves of people with HD. The only snag…it has to be delivered directly into the spinal fluid. I’m sure an oral tablet will eventually follow, but ISIS-HTTRx is still a long way off; it has to be tested in human volunteers first. One eye then on Sarah Tabrizi, the trial lead, and the other eye on the drug’s name; ISIS pharmaceuticals is now IONIS.

2. Suppressing Huntingtin by enhancing PPAR-δ

By Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973
By EmwOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973

PPAR-δ stands for peroxisome proliferator-activated receptor delta, and it is a good guy. Researchers have shown that enhancing the activity of PPAR-δ in mouse models of HD has a beneficial effect on mitochondrial function, motor activity, neurodegeneration, and survivalHuntingtin, the infamous bad protein in HD, suppresses PPAR-δ activity. But the wily researchers found a way to reverse this suppression by using an agent called KD3010. They announced their findings in Nature Medicine under the refreshingly self-explanatory title, PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. (OK, it could be a little shorter). The question now is whether this can be translated to humans. We don’t have too long to wait to find out because the Food and Drug Administration (FDA) has just approved KD3010 human trials

3. Removing cholesterol by boosting CYP46A1

By Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275
By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275

CYP46A1 is an enzyme which regulates the breakdown of cholesterol. And what has cholesterol got to do with HD? Well…wait for this…cholesterol accumulates in the nerve cells of people with HD, and may contribute to nerve damage. The good news is that CYP46A1 helps to get rid of cholesterol, and some researchers postulate that medicines which enhance the activity of CYP46A1 will improve HD. This all comes from a paper in the journal Brain titled CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease. We are still at the proof of concept stages, but it will help if the CYP46A1-enhancing drugs come as handy pills! 

4. Controlling chorea with deutetrabenazine

By (bencbartlett (talk)) - I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647
By (bencbartlett (talk)) – I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647

Neurologists are familiar with tetrabenazine, the best treatment for chorea. And Star Trek fans are familiar with the heavy hydrogen atom, deuterium. Put the two together and, voila, you get deutetrabenazine (SD809). The heavy hydrogen of deuterium makes deutetrabenazine a more stable drug. This should make it last longer in the body, and also cause less side effects. Considering that the adverse effects of tetrabenazine include depression and parkinsonism, this is not an insignificant advantage (pardon the double negative…I couldn’t help it).

How well does deutetrabenazine translate to clinical practice? Sufficiently well enough it seems, going by the trial published in JAMA Neurology titled Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease. The authors compared the drug to placebo and showed that deutetrabenazine effectively improved chorea at 12 weeks. It is not surprising that the trial compared deutetrabenazine to placebo rather than the existing alternative; head-to-head drug trials are as rare as hen’s teeth in medicine (I wonder why that is). Anyway, deutetrabenazine may be coming to a pharmacy near you soon…we hope. 

Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682
Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682

There is still a long way to go yet, but each  small step is a glimmer of hope for a neurodegenerative disease such as HD.

Remember, you can have everything HD at your fingertips with neurochecklists (and pardon the shameless pitch).

Addendum

Shortly after posting this blog I came across these articles on HD prospects

  • From Huntington’s Disease News comes Pridopidine. One more to add to the hope for neuroprotection against HD.
  • From the Hazard Gazette comes SIRT2 as a future treatment target for HD

Standing up to the challenge of refractory epilepsy

In neurology, the word ‘refractory‘ is almost exclusively used in relation seizures. It may apply to drug-resistant epilepsy (DRE), or to rampaging status epilepticus.’Refractory’ doesn’t sound good in whatever context it is used, typically connoting a situation beyond redemption. But this is not the case with epilepsy. Rather than a bell tolling in despair, refractory is used in epilepsy as a bugle calling to arms.

Ask Not For Whom the Bell Tolls...Vicky Vinch ON/OFF on FLikr https://www.flickr.com/photos/91593630@N08/28095933065
Ask Not For Whom the Bell Tolls…Vicky Vinch ON/OFF on Flikr https://www.flickr.com/photos/91593630@N08/28095933065
 

Refractory epilepsy

If anyone was asked to imagine refractory epilepsy, they would surely picture a case that has failed to respond to the heavy arsenal of anti-epileptic drugs (AEDs). They would visualise a patient who has failed Lamotrigine, Carbamazepine, Valproate, and Levetiracetam. They would envisage subsequent failures with Zonisamide, Eslicarbazepine, Oxcarbazepine, and Lacosamide. They would clearly see a neurologist desperately hoping that the seizures would respond to the new AEDs on the block such as PerampanelBrivaracetam or Retigabine.

Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173
Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173

They would be very wrong. Rather than a failure of all AEDs, refractory epilepsy is defined by the International League Against Epilepsy (ILEA) as the failure of two well-chosen and tolerated AEDs. The chances of achieving seizure freedom in this situation are slim, and the sooner non-drug interventions are considered, the better. ‘Refractory’, in the context of epilepsy, is therefore a red flag for the neurologist to prevent years of juggling partially effective drugs. It is an early warning system to consider non-drug interventions such as surgery and neuromodulation. This point was strongly made in an article in European Neurological Review titled Treating Drug-resistant Epilepsy – Why are we Waiting? Well worth a read!

Red Flags on the Railway Line. Evelyn Simak on geograph. http://www.geograph.org.uk/photo/1572393
Red Flags on the Railway Line. Evelyn Simak on Geograph. http://www.geograph.org.uk/photo/1572393

Refractory status epilepticus

Refractory is also used in the context of status epilepticus where it describes the failure of two different anti-status medications. In this case, ‘refractory’ tells us that it’s time to use anaesthetic agents to put the patient to sleep, and essentially wait for things to settle. The real challenge comes when this strategy fails. What name do we give this conundrum that goes beyond refractory, and is there anything we can do about it?

By Vaikoovery - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242
By Vaikoovery – Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242

The experts ingeniously named this scenario super-refractory status epilepticus! And this super duper name doesn’t scare them from trying to treat it. In their enlightening and hope-raising critical review of super refractory status epilepticus, published in the journal Brain, epilepsy experts Simon Shorvon and Monica Ferlisi offer a surprisingly long list of interventions for super refractory status epilepticus. These include magnesium, steroids, IVIg, plasma exchange, hypothermia, the ketogenic diet, and Rufinamide. The review is a must-read for anyone who manages status epilepticus (or they could look up the condensed version in neurochecklists!)

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What is the startling research unsettling the treatment of myasthenia gravis?

The long-term treatment of myasthenia gravis (MG) relies on drugs which suppress the immune system. I listed some of these in my previous post titled How is innovative neurology research energising myasthenia? Steroids are the established first line immune suppressing treatment for MG but because of their many nasty side effects, they cannot be used at effective doses for long periods. This is why neurologists treating MG use so-called steroid-sparing agents to reduce, or eliminate, the need for steroids.

Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845
Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845

Azathioprine has the best evidence of effectiveness as a steroid-sparing drug, and it is the acknowledged favourite of neurologists. Azathioprine may however fail or cause unacceptable side effects. It is also unsuitable for people who lack TPMT, the enzyme that breaks it down. It is in these situations that things become slightly tricky for the neurologist.

By NLM - NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931
By NLM – NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931

In theory, neurologists are spoilt for choice when they can’t use Azathioprine. Methotrexate is my favourite option in such cases because it has an easy weekly dosing regime and it is fairly well-tolerated. Alas, a recent paper in Neurology titled A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis has unsettled me by suggesting that methotrexate is not living up to its top billing. The authors of the paper studied 50 people with myasthenia gravis who were already taking steroids. They put some of them on methotrexate, and the others on placebo. The outcome was surprising; methotrexate did very little to reduce the requirement for steroids, and it did nothing to improve the symptoms of MG.

By Fdardel - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576
By Fdardel – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576

 

This is clearly disappointing. Whilst waiting for further studies to confirm or refute this finding, I wonder how reliable the other steroid-sparing MG drugs are. How good are mycophenolate, ciclosporin, cyclophosphamide, tacrolimus, and rituximab? What really works in MG? To the rescue comes the International consensus guidance for management of myasthenia gravis, just hot off the press! Alas, the experts who drafted this guidance only compounded my woes. They made many treatment recommendations, but these came with as many caveats. They said the evidence for mycophenolate and tacrolimus in MG is rather thin, and the evidence-based ciclosporine and cyclophosphamide have potentially serious side effects. And they couldn’t agree on how promising rituximab, the new kid on the block, really is.

By Oguenther at de.wikipedia - Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243
By Oguenther at de.wikipedia – Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243

We are therefore back to the question, what to do when Azathioprine fails? The experts tell us to stick to the usual suspects, but they urge caution. Perhaps what we need are newer and safer alternatives such as Lefluonamide, so new to the MG arena that it did not get a mention in the expert guidance.