Synthetic DNA-Based Drug Is First To Slow Progress of Huntington's Disease (theguardian.com)

John.Banister writes: The Guardian reports of early success in the trial of a synthetic DNA based drug, Ionis-HTTRx, at University College London's Huntington's Disease Center. Bionews explains that this gene silencing drug binds to the RNA transcript of the faulty huntingtin gene, triggering its destruction before it can go on to make the huntingtin protein. There's much excited speculation that the same technique could be used for Alzheimer's and Parkinson's disease, once people know which genes to target. "The trial involved 46 men and women with early stage Huntington's disease in the UK, Germany and Canada," reports The Guardian. "The patients were given four spinal injections one month apart and the drug dose was increased at each session; roughly a quarter of participants had a placebo injection. After being given the drug, the concentration of harmful protein in the spinal cord fluid dropped significantly and in proportion with the strength of the dose. This kind of closely matched relationship normally indicates a drug is having a powerful effect."

Comments

Could it "fix" future generations?

[charliemerritt03]

A single shot, or treatment. If it goes thru the bloodstream seeking copies of a gene wouldn't it find those genes in the testes/ovaries?

Re:Could it "fix" future generations?

[charliemerritt03]

I should have said "If given thru bloodstream"

Re:Could it "fix" future generations?

[AvitarX]

I don't think so, I think it's a monthly does in perpetuity, not a permanent fix for even the current generation.

Re:Could it "fix" future generations?

[damn_registrars]

A single shot, or treatment. If it goes thru the bloodstream seeking copies of a gene wouldn't it find those genes in the testes/ovaries?

No. The drug - which is actually RNA based not DNA based - only interferes with messenger RNA. It essentially stops production of the Huntingtin protein (not a typo, the gene is Huntington and the protein is Huntingtin) in cells that are expressing the gene. We understand that expression of this later in life - particularly expression of the mutant form of the gene - is a direct cause of Huntington's Disease. While the function of the protein in its wild state is not fully understood, it does seem to have an important role in development. Hence we wouldn't want to shut down its expression completely in generations to come.

As for reproductive tissue, it should be unaffected as the drug is injected into the Cerebro Spinal Fluid (CSF) which usually does not reach testes and ovaries.

The treatment for future generations would probably come by way of gene editing; this is gene silencing. If you want to look up the techniques this is based on RNA interference while gene editing is more often done by CRISPR.

Re:Could it "fix" future generations?

[Anonymous Coward]

I don't think so, I think it's a monthly does

Great! So what's it do?

Re: Could it "fix" future generations?

[AvitarX]

Prevents a terrible disease from spreading, maybe even reverses it some?

Seems pretty straightforward.

Re:Could it "fix" future generations?

[Anonymous Coward]

No. This is a RNA chunk which muffles the in-brain RNA chunk which says "make mutant protein"; it's a (potential) treatment not a cure.

Re:Could it "fix" future generations?

[Anonymous Coward]

Assuming it works as a treatment, it stops a fatal neurodegenerative disease from munching away at someone's brain. As a person with the HD gene, who saw relatives go down the "twitching loony and then dead" route, I'd say that's pretty sweet.

Re:Could it "fix" future generations?

[Anonymous Coward]

You seem to have a decent understanding of the disease and treatment. Could this also prevent the onset of olivopontocerebellar atrophy? The symptoms appear to be similar, but I don't know if the mechanism which is blocked by this treatment would also prevent OPCA.

Re:Could it "fix" future generations?

[coldandcalculating]

I would add that there are a couple of advantages of the antisense oligonucleotide therapies developed by Ionis and other companies over CRISPR:

1. Delivery. CRISPR currently requires a viral vector to deliver Cas9 protein as well as guide RNA molecules. Antisense oligos (ASOs) have already demonstrated clinical efficacy in delivery to motor neurons to treat spinal muscular atrophy (nusinersen).

2. CRISPR gene editing generates permanent changes in the genome and while accuracy is improving, off-target cutting is still a hurdle. It will be a while before permanent edits make their way into patients' brains, but the CRISPR hype machine may have the momentum to do it. There are RNA targeting varieties of CRISPR, but they face the delivery barrier and don't offer a significant advantage over ASOs.

The story of ASO drugs is actually really inspiring for anyone hoping to develop a brand new class of drugs that target formerly "undruggable" proteins like Huntingin. Ionis (formerly Isis) has been on the brink of collapse many times and had a few clinical flops before finally seeing some success. I think it's amazing that a devastating disease like Huntington's might actually turn into a manageable condition.

Of course, one of the "cheapest" ways to eliminate this disease from future generations is in vitro fertilization followed by genetic screening. Tens of thousands of dollars to ensure your offspring lack the offending gene vs. what will likely amount to hundreds of thousands per year for ASO (or $1 million+ for a one-off CRISPR viral therapy). Still, using genetic disease to understand and master the technology of gene-based drugs (CRISPR, ASOs etc) can help us to better treat genetic disease that arises de novo, especially cancer.

Re:Could it "fix" future generations?

[slick7]

A single shot, or treatment. If it goes thru the bloodstream seeking copies of a gene wouldn't it find those genes in the testes/ovaries?

A single shot, or treatment. If it goes thru the bloodstream seeking copies of a gene wouldn't it find those genes in the testes/ovaries?

Yeah just like the politicians "fixed" the debt issue. First it will go through the pharmacies ( big money ), then it will have to go through the FDA, (bigger money) and then, when it gets so expensive, the politicians will get involved ( obscene money). The real question is will Medicare/aid cover the expense?

Re:Could it "fix" future generations?

[damn_registrars]

You seem to have a decent understanding of the disease and treatment. Could this also prevent the onset of olivopontocerebellar atrophy? The symptoms appear to be similar, but I don't know if the mechanism which is blocked by this treatment would also prevent OPCA.

My initial inclination would be to say no.

I'll be brutally honest and admit I had never heard of OPCA before you mentioned it, so I had to look it up. When reading the description on wikipedia it sounded to me a lot like CJD (aka Kuru, aka Prion disease, aka human madcow) and it says it can be brought on by prions. It sounds like there are some with genetic traits as well but the genes are not understood, which would make it impossible to target their expression currently.

By comparison Huntington's Disease is better understood on the molecular level. While we don't fully understand the function of the Huntingtin protein (beyond the role of mutant forms of it in Huntington's Disease), it is a fairly clear target.

GMO

[Anonymous Coward]

No thanks. I'll take disease. It's natural therefore can't hurt me.

Re: GMO

[Anonymous Coward]

If I had mod points I would hesitate between funny and insightful.

Re:GMO

[Maritz]

Gwyneth, you should roll an account. Don't post AC.

Probably not

[Okian Warrior]

A single shot, or treatment. If it goes thru the bloodstream seeking copies of a gene wouldn't it find those genes in the testes/ovaries?

Probably not, although I'm not a biologist.

The cell encodes instructions for making proteins in DNA, and these are "copied" onto RNA and taken to the ribosomes where the protein is made. The DNA is kept in the nucleus, and the RNA travels to the ribosome outside the nucleus.

The current treatment binds to the RNA while in transit on its way to the ribosome. The original DNA copy is unchanged, and so when the treatment wears off (RNA binding molecules get used up) the original disease comes back.

However, pre-natal testing can determine whether a child has inherited the defective gene, giving the parents the option to abort said fetus and try for another child.

Re: Probably not

[Anonymous Coward]

Instead of aborting they could fix it using CRISPR or other gene editing technology.

Thirteen will be happy...

[Anonymous Coward]

Does anyone get the reference?

Re: Thirteen will be happy...

[Anonymous Coward]

Yes, but she'd be dead by now.

The time travel cure

[Jesus H Rolle]

If only someone would travel back in time and kill Huntington as a baby.

Re:The time travel cure

[Anonymous Coward]

Then not only would I not have Huntington's, but I wouldn't be alive. :(

Still probably not

[Okian Warrior]

Instead of aborting they could fix it using CRISPR or other gene editing technology.

We don't have that capability yet, and as far as I am aware there are no such treatments on the horizon. That's at least 10 years out, more likely 20 with testing and regulation. (Note that the treatment in the OP was done in Canada, Germany, and the UK. Notably, *not* the US.)

For the next decade or two, abortion (or not) is the only choice.

Re:Still probably not

[DigiShaman]

*If* adhering to western morals and values... While in other parts of the world, specifically Asia, don't discount those with money and the willingness to take a risk. If possible, we could be seeing CRISPR methods being used today. Now, whether or not the medical community will get proper science out of the results (one way or another) is another matter entirely.

Just to put it into perspective; guess how much medical science we've gained throughout WW2 via inhumane treatment. Obviously the ends don't justify the means, but the point still stands. Money, means, willing to take a risk, and difference in ethics will always play a major role in which nations advance in medical progress and which one's hobble behind.

I believe dogs have such treatments available

[Anonymous Coward]

So this is just a first for humans.
DNA therapy for dogs, and rich millionaires getting treatments in China.

I wish we weren't so afraid of genetic engineering

[Baron_Yam]

This is something that should be corrected with germ line alterations. Rather than fix the symptom, the gene itself needs to be corrected, and corrected in the reproductive system so the defect isn't passed on to children.

I'm seeing a day when everyone's taking a cocktail of defect-masking pills on a daily basis because we've allowed these genes to spread through the population and everyone has a dozen debilitating / fatal conditions.

More importantly

[Anonymous Coward]

Why is ALS called Lou Gehrig's Disease but Huntington's is not called Woody Guthrie's Disease?

fairness considered harmful

[epine]

Huntington's disease: the new gene therapy that sufferers cannot afford

I simply looked up "Michael R. Hayden" and the name of the drug in question and quality reporting landed right at the top of my search results.

Hayden is the most cited author in the world for HD and ABCA1, and has authored over 830 peer-reviewed publications and invited submissions (h-index 105).

Hayden is active against genetic discrimination.

The House GOP is pushing a bill that would let employers demand workers' genetic test results — March 2017

Here's Ron Paul, wearing his mechanical heart on his sleeve:

Uniform Federal mandates are a clumsy and ineffective way to deal with problems such as employers making hiring decisions on the basis of a potential employee's genetic profile. Imposing Federal mandates on private businesses merely raises the costs of doing business and thus reduces the employment opportunities for all citizens. (src)

Health insurance and 'genetic discrimination': Are rules needed? — January 2012

Others disagree, noting that genetic discrimination was deemed significant enough to spur the United States and many countries in Europe to enact legislation. The question of what information genetic testing may reveal and how it can be used shouldn't be left up to insurance companies, said Bev Heim-Myers, chair of the Canadian Coalition for Genetic Fairness.

The problem is, if society imposes nothing, business tends to devolve into a crass race to the bottom with real human casualties.

So I'm generally in favour of the government foreclosing on the worst of the worst, while leaving plenty of scope for businesses to morally disgrace themselves (or not).