Fixing a Gene in a Fertilized Egg Prevents Muscular Dystrophy (in a Mouse)

Before social media and the ice bucket challenge, there were telethons. And of these televised pleas for money, perhaps the most famous is the one for muscular dystrophy, the one for “Jerry’s kids.” The MDA Show of Strength (as it is now called) has raised something like two billion dollars over the last 50 or 60 years and the money has been used to make great strides in helping people who suffer from this awful set of diseases.

One of the most severe forms of this disease is Duchenne Muscular Dystrophy or DMD.  Each year around one out of every 3500 boys (and a very few girls) is born worldwide with this devastating, muscle wasting disease. By the age of 10, many are already in wheelchairs as their leg muscles begin to give out and until recently, very few lived beyond their teens. Nowadays, with better treatments, they can live into their 30s, 40s and even 50s.

A new study reported in the journal Science gives hope that newer treatments may extend the lives of people with DMD even longer. In this study, Long and coworkers were able to repair the broken gene responsible for causing DMD in a fertilized mouse egg and so prevent the mouse from getting the disease in the first place.

Now DMD won’t be cured in humans in exactly this way any time soon. Because they treated the mouse embryo at the fertilized egg stage, the researchers knew very early on that the broken gene was there. If parents already knew at that stage, then there are better options already available.

For example, a parent who is a carrier could opt for in vitro fertilization, fertilizing the egg in a petri dish, and then using preimplantation genetic diagnosis (PGD) to pick out only girl embryos who won’t develop the disease. Or if they want boys, they could select boy embryos that do not have the broken gene. While PGD is invasive, it is way less invasive than what was done in this study.

So this study isn’t really pointing towards a cure (at least not yet). But what this study does is give people hope that one day gene therapy might work to treat DMD using the same strategy.

It won’t be the typical gene therapy where a working gene is added to do the job of the broken one, though. No, instead scientists would deliver a gene that can repair the broken gene in some but not all the muscle cells. This mouse study suggests that this approach has a shot at working one day.

Dealing with a Giant

A key problem in thinking about gene therapy and DMD is the size of the gene that is broken. This dystrophin gene is so big that it leaves the microscopic world and enters our everyday world.

If we were to stretch it out, the 2.2 million base pairs of this gene would be around 2/3 of a millimeter long. This is something around the length of a small raindrop or a mustard seed. Sounds smallish but this is gigantic for a gene—by far the largest of the human genes.

This is way too big a piece of DNA to stuff into any but the largest of viruses.* And since most gene therapy relies on using a virus to get the DNA to where it needs to go, scientists can’t really treat DMD by adding back a working copy of the gene.

* There is a virus that might accommodate such a big piece of DNA but it doesn’t infect people.)

Since scientists can’t add back a working gene, the authors instead worked on fixing the broken one with the hottest technology out there right now, CRISPR. And for the most part they succeeded. (Click here and here for a couple of KQED articles on CRISPR.)

When Giving 40% is Enough

One of the tricky parts of gene therapy has always been making sure that enough cells get the new DNA. If too few have the new or repaired gene, then there might be no effect.

When the authors looked more deeply, they found that mice with just 40% of their cells having a corrected gene showed no signs of muscular dystrophy. This means that not every broken gene in muscle cells needs to be fixed.  Which is incredibly important for gene therapy.

And not only that, but they also found that as the mice got older, the few muscle fibers showing signs of DMD were replaced by healthy ones. A new set of experiments showed that this probably has something to do with how muscle cells work.

Muscle cells are special in that they are really a fusion of many, many cells. They are very long cells with many nuclei.

Skeletal muscles get stronger when satellite cells fuse with the muscle fiber, adding their DNA to the elongated cell. It could be that having a mix of nuclei with broken and repaired genes makes enough dystrophin to keep muscular dystrophy away. And to even revert cells that are showing signs of DMD back to healthy cells (at least in mice).

So it may be enough to fix the genes in the satellite cells to help a patient. This won’t work for heart cells as they get stronger in a different way but it shows real promise for the rest of a patient’s muscles.

There may be hope in the future for using gene therapy to help deal with DMD. Not necessarily tomorrow, but much sooner than we thought. All of those telethons have definitely paid off.