Gene Editing Offers Hope For Treating Duchenne Muscular Dystrophy (nytimes.com)

schwit1 writes with news that scientists have used a new gene-editing technique called CRISPR to treat mice with defective dystrophin genes. This is the first time that such a method has successfully treated a genetic disease inside a living mammal. The Times reports: "Three research groups, working independently of one another, reported in the journal Science that they had used the Crispr-Cas9 technique to treat mice with a defective dystrophin gene. Each group loaded the DNA-cutting system onto a virus that infected the mice's muscle cells, and excised from the gene a defective stretch of DNA known as an exon. Without the defective exon, the muscle cells made a shortened dystrophin protein that was nonetheless functional, giving all of the mice more strength."

Comments

Doping

[nospam007]

It will be only months until it will be used for some athlete's "Muscular Dystrophy", then we'll know if it's safe.

Re:Doping

[Anonymous Coward]

Actually, no.
It helps sick people by removing faulty part of the DNA. If you aren't sick, in best case, it'll make your scores worse.

Re:Doping

[fuzzyfuzzyfungus]

The trouble with athelete-research is that it is nominally wicked and immoral, so everybody carefully avoids keeping useful records about the experiments.

It's a real pity, there would probably be some very interesting stuff there if the dataset were available. At least the Purity of Sport remains unsullied, so there's that.

Quirks and Quarks

[lazarus]

Quirks and Quarks did a podcast very recently about this technology and its application on a particular strain of MD. This work was done (by Dr. Ronald Cohn from the Hospital for Sick Children in Toronto) on living cells however, not live mammals. The podcast does go into a high level and easily understood description of how the technology works. Fascinating stuff.

Re:Quirks and Quarks

[The-Ixian]

Radiolab also did a netcast on this.

Re:Quirks and Quarks

[coastwalker]

I would have like to have up-voted the link to more information, both podcasts are interesting.

There are many lectures on YouTube requiring varying degrees of expertise to understand but this one seems comprehensible to anyone with a STEM background and I recommend you take a look. Jennifer Doudna. The CRISPR-Cas 9 Genome Engineering Revolution, UC Berkeley Events channel (one of many excellent primary sources on YouTube)

https://www.youtube.com/watch?...

I appreciate that many people with an interest will use a search engine to investigate this interesting topic but YouTube has a high noise to signal ratio so you might not have thought to look there.

Hope is good

[rmdingler]

1)Have a little faith. The FDA, a persecuted entity that withholds miracles from the condemned, is at the very least a science-based bureaucracy that attempts to keep untested cures out of the hands of the desperate. FWIW, promising solutions to fateful childhood diseases such as this will be allowed to proceed much sooner than your estimations in medical trials.

2)Remember the religious furor over stem cell research? The same God didn't make it mantra faded quickly when the technology began to pan out. Turns out, a potential cure in the hand for a loved one wins out over some message interpreted from a thousand-year-old-tome.

Re:Hope is good

[Anonymous Coward]

No, the FDA SHOULD spend the time and make sure any treatment doesn't cause harm. Remember thalidomide.

Many molecular biologists seem to have this hubris that they completely understand the mechanics of DNA and genes. They are so specialized, they do not know what their tinkering may do to an organism down the road and long after they have been published or even dead. The scientific method, although quite rational, can take many many years to ferret out issues that have never even been thought of - and like I pointed out before, these guys are focuses exclusively on their field and outcomes. This technique may for instance cause sever cardiovascular issues. The heart is a muscle and when they get too muscular you get diseases like cardiomyopathy.

And lastly, the Bible is a few thousand years old - not a thousand - and was written by stone age goat herders who thought the world was flat.

Re:Hope is good

[Anonymous Coward]

Christians do not have a problem with science or medicine. We have a problem with killing babies and using their body parts. There are now ways to produce stem cells without killing babies and so stem cell research is no longer an issue. The only Christians that have a problem with at least some medical technology (such as blood transfusions) are the Jehovah's Witnesses. They are a small minority Christian denomination.

Re:Hope is good

[Grishnakh]

No, but most of them in the USA *are* anti-science and do believe the earth is 6500 years old.

Re:Hope is good

[muecksteiner]

This technique may for instance cause sever cardiovascular issues

I suspect you have never seen someone actually dying from Duchenne. Getting cardiovascular disease a decade or two down the road would be something that sufferers would probably all be quite ok with, if they could breathe on their own again for a couple of years.

Of course, the optimal thing would be a cure that does not screw up the cardiovascular system in the process. Or cause cancer. But if you are suffocating because your lung muscles are no longer functional, you will gladly take sub-optimal remedies like this one.

Re:Hope is good

[fuzzyfuzzyfungus]

So long as it isn't a germline modification there will probably be some enthusiasm for even high risk treatments. DMD reliably cripples and then kills you in a time long enough to be an agonizing ordeal and short enough that you can be said to have died tragically young. When Plan A sucks just that much, even serious side effects start to look pretty good.

If it is a germline modification, or if somebody can't keep their genetic engineering virus from hopping around, a lot more caution will be warranted because removing a change committed to the wild will be a real problem; but this is a nasty disease with a lousy prognosis so if the risks are confined to the patients they will likely be tolerated pretty well.

That's actually what ended up happening to thalidomide. The FDA's refusal to approve a zesty teratogen for marketing to pregnant women was roundly vindicated in hindsight; but it has some niche applications in situations where the risks are lower and the diseases more serious.

Re:Hope is good

[tburkhol]

The practical application of this form of treatment will (as all three papers do) use systemic, viral delivery, meaning all cells will be affected. You can modulate the probability a little by selecting a virus with affinity for particular tissues, but there will still be germline modifications. If you're really worried about that, you make vasectomy a required co-treatment.

It's still a long way from useful. All three papers report similar results: 2-5% changes in the DNA pool; 40-60% changes in the mRNA pool; 20-30% reduction in functional deficits. In a mouse model with a homogeneous genetic defect and without severe pathology

The results are pretty comparable to targeted exon skipping treatments, which started around 15 years ago and have made small human trials without serious adverse results. It's exciting to see research starting to make progress on fixing diseases where the root cause has been known for 40+ years, but the science (nevermind the FDA) is still 10+ years away.

Re:Hope is good

[ArmoredDragon]

And you base that on what? Let me guess, Answers in Genesis website? In case you haven't noticed, they aren't primarily in the USA, and furthermore, most well known "bible has all answers" types aren't even in the USA. For example, remember the banana guy? Try New Zealand.

Anyways the continent I suspect would be most opposed to this would be Europe. Why? Well nobody else (besides Africa) has outright bans on known safe genetic modification of plant and livestock.

In fact the USA has been leading the way in this area since the 80's, which began with the creation of humulin, which requires genetically modified e. coli to produce, and has been a huge life saver for diabetics ever since.

Re:Hope is good

[Anonymous Cow Ward]

Many molecular biologists seem to have this hubris that they completely understand the mechanics of DNA and genes. They are so specialized, they do not know what their tinkering may do to an organism down the road and long after they have been published or even dead.

As a molecular biologist, most of us know that we don't completely understand the mechanics of DNA and genes. We do, however, know a lot more than the average person, and we know a lot about the dystrophin gene, as we've been studying it for a long time. We also know that even if we do screw something up, it's unlikely that it'll cause something worse than DMD already is. Furthermore, this cure - and indeed, any gene therapy cure that could go to clinical trials at the moment - is not passed on in the germ line, meaning it's not heritable.

This technique may for instance cause sever cardiovascular issues. The heart is a muscle and when they get too muscular you get diseases like cardiomyopathy.

Do you really think this is something they haven't considered? Yes, the heart is made of muscle, but cardiomyocytes are different from skeletal myocytes. Furthermore, the gene delivery treatments used to target skeletal muscle are generally different than what you'd use to target the heart, and of course they aren't going to ignore the heart, they aren't idiots. They aren't so focused on "their field" that they'd ignore an organ that's affected by DMD in their analyses.

Re:Hope is good

[Anonymous Cow Ward]

Actually, systemic viral delivery doesn't work well to skeletal muscle in larger animals. Isolated limb transvenular administration is the best way at the moment, but it's unclear whether you could modify the technique enough to effectively target the diaphragm/heart. Furthermore, you can also use tissue-specific promoters and/or miRNA to confine your effects to particular tissues or eliminate them from others.

I agree this technique is still a long way from useful, though.

Re:Hope is good

[Blaskowicz]

In fact Earth was known not to be flat before there were christians.

Re:Hope is good

[jedidiah]

> And lastly, the Bible is a few thousand years old - not a thousand - and was written by stone age goat herders who thought the world was flat.

That more accurately describes your own ancestors. The Jews not so much.

They had a sophisticated society with universal literacy when your ancestors were living in caves and eating other.

Re:Hope is good

[jedidiah]

How about actually BEING a patient?

It's one thing to "merely watch". It's quite another to be the one with his ass on the line. As such, I agree with those that advise actually following the scientific method and obeying the usual regulatory controls.

Validating these cures requires scientific rigor, not wishful thinking.

Only 1 in 10 "miracle cures" actually make the cut. None of this is simple, easy, or certain.

Re:Hope is good

[Grishnakh]

I base it on being an American and looking at the people around me. This place is full of fundies. Just go to any "non-denominational" Christian megachurch and listen to what they preach about. And keep in mind, these churches are *growing*, while the "mainstream" liberal sects are literally dying out.

Secondly, look at who we elect. The GOP controls most state governments plus Congress. One of its more popular candidates is a young-earth Creationist (and many of the others are likely Creationists too).

Re:Hope is good

[Grishnakh]

The number is growing: evangelicals' numbers are on the rise, as people from other, more "mainstream" denominations convert. Also, one of those YECs is running for President and is very popular.

Re:Hope is good

[ArmoredDragon]

I base it on being an American and looking at the people around me. This place is full of fundies. Just go to any "non-denominational" Christian megachurch and listen to what they preach about.

So? According to this only 18% of them are young earth creationists:

http://ncse.com/rncse/30/3/ame...

Secondly, look at who we elect. The GOP controls most state governments plus Congress. One of its more popular candidates is a young-earth Creationist (and many of the others are likely Creationists too).

Just for perspective, in the last election in France, 28% of the vote typically goes to the official Fascist party, (Front National, source) which is quite higher than the confirmed number of young earth creationists in the US. Denmark also pushes similar numbers, and about 10 other European countries sit somewhere around 18%. That's JUST the fascist party, and doesn't include any other right leaning groups, or even the strong Muslim population out there which tends to be even more fundamentalist than US Christians. Seriously, you can repeat your comment with one word substituted and say about Europe "this place is full of fascists" and it would be more accurate.

That said, all of the hoopla you hear about the US being far right compared to Europe isn't exactly true, as in fact, a big portion of Europe is much further right. (And as a side note, in spite of Europeans constantly accusing the US of being the most racist country in the world, they actually have known racist people holding political office, and the US can't even claim that.)

The fact is, you have your own personal bubble (everybody does) where you typically only get exposed to the views that you want to acknowledge, and that includes views that you want to acknowledge in a negative way. It doesn't necessarily mean that represents the overall population.

That said, much like the EU, there are different demographics depending on the region you go to, and in the case of the internet, the websites you visit and your social media circle. Maybe there are megachurches where you live, however there aren't any (or at least, I'm not aware of any) in the particular region I live in, which is pretty well populated.

Re:Hope is good

[morgauxo]

It's a complicate two-sided situation. Remember thalidomide... sure, remember it. Also remember that while a medicine is in testing, not yet available to the public real people are suffering and even dying. Those people that die waiting for a cure... they aren't coming back... EVER!

Beyond all that the longer and more beurocratic you make the process the more expensive it is. No, I'm not arguing money over lives but that money could be used to save more lives. The cost of testing is either passed on to patients meaning some will not be able to afford treatment or it is pulled out of R&D meaning some other medicine never gets discovered. Either way.. more death and suffering.

What is needed is a proper balance. From the outside it does not appear that there currently is such a thing. Instead it appears that the medical field has gone from a period of overactive optimism jumping on unfounded treatments like thalidomide, lobotomies, leaches, etc... to an overly pessimistic period where everything that might have one day saved your life will instead be bogged down in decades of expensive and unproductive bureaucracy.

You might want to argue that this is untrue and that we do have a good balance today. If so please, do so and explain why you believe that. Simply explaining one side of it though, either side without acknowledging the other isn't very convincing.

Re:Hope

[penguinoid]

3) Cancer.

(Gene editing has a history of being imprecise, keep in mind to treat a genetic disease this also means delivering to each affected cell in the body.)

Let's approach this with caution, NOT phobia...

[jeffb (2.718)]

I know there are concerns around human genetic manipulation, but there are a lot of people suffering in its absence. I'd be willing to take the risk on a therapy like this if I were suffering from a debilitating or fatal genetic illness. Furthermore, I am ready to shoulder my portion of the societal and ethical risks entailed by others testing it.

Effects on progeny?

[DigiShaman]

So would this also effect the male sex cells post gene therapy? Meaning, would the progeny still inherit the defective gene?

Re:Effects on progeny?

[Qzukk]

It would depend on the ability of the virus to infect them. Since viruses tend to destroy the host cells when they replicate (which would make the gene splicing useless since the fixed cell is now dead), I would assume that this particular virus would be engineered to not replicate, preventing it from spreading through the body.

Re:Effects on progeny?

[Anonymous Cow Ward]

At the moment, the FDA prohibits any gene therapy with a significant chance of germ line effects. So, for now, people with DMD who get gene therapy would still pass on their mutation. In principle, we could design something with intentional germ line effects, but that gets a lot trickier and we aren't sure enough about the safety for that yet.

Re:Effects on progeny?

[jeffb (2.718)]

The summary indicates that this virus infects muscle tissue. I don't know how selective a virus can be, so I don't know how effectively you could select one that specifically targeted or refrained from targeting germ cells or their progenitors.

It seems that making a modification that can be carried down the female line would be trickier, since egg cells are all produced long before puberty begins. You'd need to infect those cells directly, I'd think, and I imagine any such therapy would lag well behind the type discussed in this article (because OMG frankenbabies). There's a need for such therapy, though; some conditions prevent successful fetal development, so you don't have the option of treating after birth.

Re:Effects on progeny?

[Anonymous Cow Ward]

This is true - at the moment, there is no significant research using replicating gene therapy vectors for treating genetic diseases. Anti-cancer gene therapy vectors often are replication-competent, but for treating things like DMD or hemophilia the vectors cannot replicate.

Re:Effects on progeny?

[sjames]

I'm not so sure the concern is even valid in this case given that the germline is already compromised.

Adverse selection against hippies

[Applehu Akbar]

CRISPR is about to bring us an avalanche of genetic engineering on the human genome to attack a variety of gene-related diseases. This is our chance to eliminate the anti- science moment the way Darwin intended, by selecting out people who oppose GMO technology. Good riddance!

Re:Adverse selection against hippies

[jedidiah]

Yes. Because releasing a bunch of little frankensteins out into the wild is the same as keeping them confined to a single human host. You are ever so intellectually superior for being willing to completely ignore these distinctions, or consider the trustworthiness of exactly WHO is using a particular technology. Your scientific hubris is simply fabulous.

Re:Adverse selection against hippies

[Applehu Akbar]

When it comes to fighting something like genetic disease, we need more scientific hubris. We need more of the old sense of adventure that once made us first in applying science to real-world problems. If we want society to fund more research, public or private, we need to make more use of the results research provides.

Re:Hope

[Anonymous Cow Ward]

(Gene editing has a history of being imprecise, keep in mind to treat a genetic disease this also means delivering to each affected cell in the body.)

Not true. Most genetic diseases don't require treating every affected cell, and in some cases not even a majority need to be treated. DMD only really affects the muscles, so no non-muscle cells need to be changed. Furthermore, since this is a gene editing strategy, they could probably afford to only (or primarily) target the muscle stem cells.

Re:Hope

[OakDragon]

2) Religious nutcases will lobby for a ban on this. Because God doesn't want you messing with genetics.... he only wants your donations.

Why would this bother religious nutcases in particular? The last I saw, the anti-GMO crowd did not look particularly religious. (Well, not fundamentalist Christian, anyway. They might be new-age Gaia worshipers.)

Re:Hope

[sjames]

If you have a disease that WILL kill you in 5 years, the risk that the cure might give you a disease that might kill you in 6 years probably seems worth while.

Re:Hope

[jedidiah]

A lot of cancer is secondary, induced by the treatments that were used to deal with the previous cancer. Current cancer treatments are quite brutal and tend to do a lot of collateral damage.

Re:Hope can be horrible

[morethanapapercert]

My son has Duchennes Muscular Dystrophy. He's 10 now and we've been waiting for the exon skipping anti-sense therapy trial you referred to for over a year now. Canadian stage 1 trials were just concluding when we got the diagnosis, we've been told he will only be accepted into the stage 2 trial (when it finally opens) if he is still walking. So now we are in the grim race to keep him ambulatory long enough to qualify for the trial whenever that happens to be. Even the researcher himself cannot give us even a loose estimate of how that will take, since stage 2 trials will only get approved after the stage 1 data has been crunched and reviewed and crunched again by Health Canada.

We were told about the CRISPR/CAS9 approach being tested in animals, but as you note, it is even further down the road then anti-sense therapies. Right now we have to hope that our son can get access to the anti-sense therapies in time and that this will buy him the time he needs for the CRISPER/CAS9 approach to get approved.

The part of it that is eating us up every day is that, even our most optimistic guess for when each therapy will become available isn't soon enough for even our most optimistic prognosis for his condition. The most likely outcome is that he will be in the wheelchair full time and require assistance eating before the anti-sense therapy becomes available and that he will be dead just before the CRISPR/CAS9 "cure" gets full approval.