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Research continues in many areas of MD treatment, but these days, it’s gene therapy that’s generating the most excitement. According to the National Institutes for Health, gene therapy works in one of three ways:

  1. It replaces a mutated gene with a healthy copy.

  2. It inactivates or “knocks out” a mutated gene.

  3. It introduces a new gene into the body that helps fight disease.

Gene therapy has been around for decades. But it suffered huge setbacks in the 1990s, when patients in clinical trials died as a result of the treatment itself. The whole field drew back and reassessed; research became very cautious, optimism guarded. What changed?

For one thing, there were a few big breakthroughs. In 2003, we saw the completion of the human genome project; the complete set of human DNA, including all of its genes (more than 3 billion base pairs), was mapped. And between 2007 and 2013, CRISPR, a remarkably precise tool for genetic engineering, was discovered and developed. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a bacterial defense system engineered by scientists to clip and redesign human DNA.

But most scientists feel that practical gene therapy has been a long time coming and is a result of small, cumulative advances. These led, finally, to a kind of crescendo, with some really impressive successes in 2016 and 2017; even more therapies showing positive results are still in clinical trials.  

In August of 2017, the Food and Drug Administration (FDA) approved the very first ever gene-therapy drug for use in the United States. This means the new treatment was found to be not only effective, but also reasonably safe. Before the close of 2017, the FDA had approved two more gene-therapy drugs. The first two fight cancer by altering the patient’s T-cells to destroy cancer cells; the third treats a kind of congenital blindness by actually replacing the defective gene. 

“It’s a very exciting time for MD research,” says Laura Hagerty, Ph.D., a scientific program officer for the Muscular Dystrophy Association. “There are advances in so many areas.” Gene therapy goes back to “the first cause,” says Hagerty. It’s more than just treating symptoms, which has extended lifespan for MD patients, but not well or long enough. “It’s about going back to the source,” says Hagerty. 

Many new clinical trials with human patients look promising. For example, Dr. Jerry Mendell, Chair of Pediatric Research at Nationwide Children’s Hospital in Columbus Ohio, and his colleagues recently demonstrated stellar results with a new gene-therapy treatment for spinal muscular atrophy (SMA). 

Babies born with SMA, a genetic disorder of motor nerve cells in the spinal cord, have an 8% survival rate by the age of 20 months; Mendell’s study with 15 infants had a 100% survival rate by the same age. While SMA robs babies of the ability to move, eat or breathe, many of the babies treated in Mendell’s study hit normal milestones like sitting up, eating and speaking. Two walked independently.

Mendell is one researcher supported by Parent Project Muscular Dystrophy (PPMD), a grassroots organization similar to the MDA that focuses specifically on finding a cure for Duchenne MD. The organization is helping to fund Mendell’s new trial for a Duchenne MD gene therapy. 

“I’ve been here almost 11 years,” says Will Nolan, spokesperson for PPMD. “In my time, I’ve never seen so much going on. So much potential and promise. These days,” says Nolan, crediting, at least in part, visibility due to the internet as well as scientific advances, “for many companies, from large pharma to small start ups, Duchenne is a priority.”

“Neuromuscular disease has been my focus for the past 49 years,” says Mendell. His group will take what they’ve learned from everything else – previous trials for Duchenne, his latest success with SMA – and put it all together in a new trial to find a successful treatment for Duchenne. “We apply all of these principles to a new trial,” he says. He’s excited about the possibilities. 

“It’s really a layering,” says Mendell. “Breakthroughs in one area help in another area.” Although, explains Mendell, the differences in types of therapy and in target organs can present obstacles, as well. 

For example, the 2017 FDA approved gene-therapy drug Luxturna targets the eye for a type of genetic blindness. But, says Mendell, “the eye is a ‘privileged’ immune site. This was a great achievement, but there are not the same potential obstacles for success as with other [sites],” such as muscle for muscular dystrophy. Significant are “the size of the organ, and how exposed it is to the environment. Muscle includes a large percent of your body; getting a gene into all of the muscles is a big challenge.”

How do you deliver a revised gene to all of the cells of a particular organ? The delivery system, called a “vector,” has been the biggest stumbling block to gene therapy over the past several decades. It wasn’t so much the genetics of gene therapy that killed patients in the 90s; it was more the vectors.

The most common vector is a virus. Viruses are a good choice because viruses naturally infects cells. Some viruses, called “retroviruses,” integrate their genetic material into the cell’s genetic material; some others, like “adenovirsus” add their DNA to a cell’s nucleus without actually integrating it with the existing chromosomes. 

In order to create an effective gene-therapy vector, scientists remove the virus’ harmful DNA and replace it with the therapeutic gene. Then the vector has to be inserted into the body so that it ends up in the right place; in the muscle cells, for example, and not the liver cells. Not only does the successful vector need to deliver genetic material to the right host cells, the gene has to be integrated and “turned on” to actually do its job (for example, to make a correct, necessary protein). Plus, it also has to avoid being attacked by the body’s immune system. And definitely not cause  other toxic or disease reactions.

“Vector safety took a lot of time,” says Dr. Carston Bönnemann, Senior Investigator at the NIH and Gavin Grubbs’ doctor. Bönnemann notes that recent advances in, and the new excitement about, gene therapy are really a result of mostly incremental developments. “There’s a lot of technology behind it.” He alludes to the gene-therapy deaths that took place in the 1990s. “It put the entire field on hold for a decade or so. We’ve improved to a degree now we’re very confident.”

Still, it’s not as simple as it appears on paper. “To process, to make pure vectors in large quantity is hard,” says Bönnemann. “It’s only scalable to a certain degree. We’re using huge doses, trillions of viruses for one patient.”

Right now, the biggest obstacle to research and development of new gene therapies is a shortage in vectors. It’s difficult to manufacture viruses, especially in the needed quantities. Researchers are lining up at the few biotech companies that manufacture them, anticipating delays in terms of years, not weeks or months. Once more treatments are FDA approved, there may be more delays due to vector shortages until the problems are ironed out.

Meanwhile, there are some other vector possibilities on the horizon. Nanotubes, for example. Only one atom thick, a nanotube is a hollow, rolled up molecule made of carbon atoms.  Researchers at UCLA recently developed a version of a nanotube vector they call a “nanospear.” Claiming they can deliver genetic material with pinpoint accuracy, these nanospears are needle-shaped, gold and nickel-coated nanotubes that can be guided magnetically. 

Whatever the area, research around gene therapy and genetically-caused diseases has exploded. “Maybe three companies were dipping their toes into research for Duchenne MD in 1994 when Pat [Pat Furlong, CEO and founder of PPMD] started,” says Will Nolan. “Now there are maybe 40, with 20+ trials going on.” Not as much research targets merosin-deficient MD, but advances in treating Duchenne will contribute to finding treatments for the rarer merosin. 

Duchenne was recognized and genetically identified long before merosin, Evin’s type of MD. These two types of muscular dystrophy differ because the genetic defect that causes each disease differs, which means the specific protein the body fails to manufacture differs. People with Duchenne (named for the 19th century neurologist who first identified it) can’t manufacture the protein dystrophin; merosin is the name of the protein that’s deficient in people with Evin’s type of MD. 

Dr. Bönnemann, who has been researching merosin-deficient MD, explains that the differences in how the two types of MD manifest have everything to do with the different functions of these two proteins in building muscle. Dystrophin builds on the inside of the muscle; merosin is on the outside, more like a glove. 

“It seems that heart fibers need dystrophin more than merosin,” says Bönnemann. Merosin-deficient MD, he says, “affects the heart, but to a much milder degree [than Duchenne]; it’s not as strong a heart, but it doesn’t cause heart failure normally.”

In anticipation of more effective therapies for merosin-deficient MD, Bönnemann has been studying patients like Gavin Grubbs, Evin’s friend, for many years to establish a baseline. 

“There really wasn’t much on the medicine shelf to give these kids,” says Bönnemann. “We treat to optimize function and survival – physical therapy, surgery for breathing.” Survival rates have gone up by a decade, he says, just because doctors are better at medical management.

Seven years ago, with little more to offer, Bönnemann and his colleagues at the NIH in Maryland began a “natural history” study of children with merosin-deficient and matrix congenital MD. Gavin Grubbs was one of those kids included in the study. 

“The families came every summer for an extended weekend,” says Bönnemann. “Each year, we gave them the same battery of tests, measured the same outcomes.” It was the first real look at changes over time, so that when a therapy became available, doctors would know how to measure success.

Back then, says Bönnemann, “we had nothing to offer. We hoped there would be clinical trials. But we understood so little of what we could actually measure.”

These days, it seems Dr. Bönnemann and his patients won’t have much longer to wait. On the other hand, as Evin said, hope was not his friend. People with MD need to live life to the fullest just as it is, taking advantage of whatever opportunities come their way each day … as do the rest of us. 


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