The Mouse That Roars

James Wood and Alex Heil are good friends. They are both 15, and they both have Duchenne muscular dystrophy, a genetic disease that is the most common form of muscular dystrophy in children.

James and Alex have experienced a similar progression of the disease, which has steadily stolen their muscle strength and left them in wheelchairs. But when it comes to finding a medical treatment that might actually improve their condition—not just address their symptoms—James and Alex are very different.

If a number of scientific and regulatory hurdles can be cleared, both James and Alex may benefit from a breakthrough treatment known as antisense or gene skipping. Gene skipping, though still in trials, could turn out to be a stunning medical advance that raises the possibility of creating a genetically targeted drug that functions as a high-tech Band-aid on the specific area of the dystrophin gene that causes Duchenne. There are 72 different elements, called exons, on the dystrophin gene, and in Duchenne any of those 72 can carry mutations that result in the disease.

James is missing exons 44 through 52. For Alex, exon 63 is not functioning. Some medicines that are now available, such as the steroid prednisone, can moderate the symptoms for both boys. But when it comes to gene skipping, if clinical trials prove successful, James and Alex would require different types of Band-aids to treat their disease.

Welcome to the world of personalized medicine, an incredibly expensive but scientifically thrilling adventure that may offer boys such as James and Alex, who once had little chance of living beyond their early 20s, a far longer and higher quality life. It is a complicated journey that will take time. There are no guarantees, but, for now at least, there is hope.

“Cure is too strong a word. It may not be a grand slam, but it is a triple,” says Joel Wood, the father of James and the senior vice president of government affairs for The Council of Insurance Agents & Brokers. “It could turn life expectancy into a good, healthy middle age for many Duchenne kids. There are a lot of base hits out there under development too. When James was diagnosed, the accepted historic mortality tables then would say he would be in his twilight years. Who knows his life expectancy now, but based on all the things we are already doing, he clearly has many, many years of life ahead of him.”

Duchenne is caused by a mutation of a gene on the X chromosome that produces dystrophin, a protein needed for normal muscle function. It almost exclusively affects boys, who receive an X chromosome from their mothers and a Y chromosome from their fathers. Some forms of the disease are the result of spontaneous mutations of the dystrophin gene, but more often, boys get the faulty gene from their mothers, who have the genetic error on one X chromosome but do not suffer from the disease because their other X chromosome overcomes the deficiency. The dystrophin gene is the largest in the human body, which likely explains why it is so easily mutated.

Duchenne affects an estimated 1 in 3,500 newborn boys. At birth, the boys have adequate proteins in their muscles, but as they age the muscles gradually weaken. It is not uncommon for a boy with Duchenne to be in a wheelchair by his 12th birthday.

Joel Wood and his wife, Dana, started the Foundation to Eradicate Duchenne in 2001, after James was diagnosed. The foundation works closely with the Children’s National Medical Center in Washington, D.C., and has provided important funding for work by Eric Hoffman, the director of the Center for Genetic Medicine Research who discovered the gene responsible for Duchenne in 1987, and his colleague Kanneboyina Nagaraju, a principal investigator at the Center for Genetic Medicine Research who runs one of the world’s largest mouse-testing labs for Duchenne.

Research on gene skipping received a huge boost recently when Rep. Mike Michaud, D-Maine, secured a $1.4 million grant from the Defense Department to fund a joint project between the Children’s National Medical Center and The Jackson Laboratory in Bar Harbor, Maine, to enable the creation of better mouse models for testing of new drugs to treat Duchenne.

The Jackson Laboratory is a mouse genetics facility that supplies more than three million mice a year to researchers around the world, including the MDX mouse model used for research on Duchenne. Mice are excellent animals on which to test potential medical advances because they are mammals with the same organ systems and tissues as humans. By working with inbred strains, researchers can manipulate the genetic makeup of the mice to give them the same characteristics of humans with various diseases, including Duchenne.

Greg Cox, an associate professor at The Jackson Laboratory, says the standard mouse model for Duchenne research and testing is the MDX mouse. The word “standard” is key because, if scientists at academic institutions, research laboratories, biotechnology companies, pharmaceutical companies and other commercial facilities conduct tests on mice that are not genetically the same, there is no guarantee that any breakthrough findings will really work.

The standard mouse model “allows us to reproduce their results,” Cox says. “Until somebody can reproduce that result, it doesn’t have very much value, and in the scientific world, it is not really a proven value yet. For the ability to translate these discoveries to humans, we need that scientific rigor. Lots of times, things make the press as big breakthroughs, but nobody can reproduce the results, and people can get frustrated.”

Duchenne patients have a mistake in only one gene of the estimated 25,000 in the body, and some of those mistakes—or mutations—are more serious than others. In the less serious mutations, the body can still produce some protein to repair muscle damage, even if it is not the ideal protein needed. Patients with this sort of condition have a milder form of the disease known as Becker muscular dystrophy.

Although the MDX mouse has the same gene mutations as human patients with the serious form of Duchenne, its outward symptoms are more like human patients with Becker muscular dystrophy. So Cox has been manipulating genes in inbred strains of the MDX mice to develop an improved mouse that better mimics the more serious version of the disease. That will enable researchers at facilities such as the Children’s National Medical Center to get a better idea of how proposed treatments really will work.

Cox and The Jackson Laboratory recently delivered a new strain of mouse models to Children’s National Medical Center. They are hoping these mice will more accurately match the symptoms of clinical test patients in terms of muscle strength, muscle endurance and behavioral characteristics. The researchers at Children’s National will now conduct a series of tests on the new mice, a process expected to take up to a year.

“We are really excited to see how well these mice perform,” Cox says. “We can also continue to make mutations so we can reach our goal of matching the human performance. We are trying our best to make the mouse as good as possible.”

At Children’s National, the goal is to use the MDX mice and, if successful, the next model of mice to show that proposed treatments for Duchenne meet the standards of non-toxicity, safety and efficacy in animals that are necessary to move the treatment to human clinical trials. If the new mouse model is closer to the human manifestations of the disease, it could reduce the need for additional animal testing before moving treatments to clinical testing, thereby saving valuable time and considerable expense.

The gene skipping experiments that Nagaraju and his team have conducted on mice and dogs will not cure the disease, but they could turn a Duchenne Muscular Dystrophy patient into a Becker muscular dystrophy patient, a transformation that could conceivably add 20 or 30 more years to the life of a Duchenne child.

“We make some probes and inject them into the body—intravenous injections,” Nagaraju says. “This is magic, this kind of advance. This is a miracle for me.”

Some of the exon skipping techniques that have been tested on the MDX mice are already in clinical trials, but the initial testing involves only a single mutation in one gene that affects the largest number of Duchenne patients. Many of the boys suffering from Duchenne, however, will get no benefit from that treatment. This is why the medical advance will necessitate a specialized, or personalized, approach.

“The first round of exon skipping trials going on are going to try to treat the biggest percentage of patients they can,” Cox says. “But a huge number of patients won’t have any benefit at all because their mutations are different. The treatment will have to be modified, or personalized. We have to make exon skipping drugs to target different parts of the gene because that is where the mutations will lie.”

One key problem is the huge expense involved, not only for the treatment itself, but also for clinical trials if each genetic Band-aid is treated as an individual drug.

Cost estimates of the genetic Band-aid run as high as $250,000 per injection, and a patient would need repeated treatments for the beneficial effect to continue.

“This is not a one-time treatment,” Nagaraju says. “You have protein that only lives for a certain time. The drug has to be there all the time so there are no mistakes. For example, you might need this every two weeks, and it is a life-long treatment. The costs are huge. To treat just a couple of dogs cost us close to a million dollars.”

Nagaraju is hopeful that the cost for treatment will drop once the gene skipping technique is proven feasible and becomes more widely available, ideally for more diseases than just Duchenne.

“Since we started five or six years back, the costs have come down by half,” Nagaraju says. “When it becomes a medicine, costs will come down significantly because more people will use this technique for more things.”

Clinical drug trials are incredibly expensive, but when you are dealing with an exon skipping drug that has to be modified into different forms to treat individual patients, the cost would be prohibitive if each individual gene skipping treatment was considered a new drug.

“It is wild to contemplate how in the coming decades this is going to revolutionize medicine, but it is incredibly expensive,” Wood says. “We are in human trials and are demonstrating that it works, but there are challenging regulatory problems. Technically, every combination you have to do is a different drug. You cannot go through hundreds of millions of dollars for a thousand different variations.”

In addition, Cox says, there is a problem gathering enough children to participate in the clinical trials.

“You have to get a large number of patients to even have a trial,” he says. “But for patients with rare mutations, you can never collect enough patients for that. We are hoping that the first exon skipping drugs will work well and FDA will approve these as a class of compounds without having to have a huge trial. If there are only a dozen patients in the world with that mutation, it is hard to imagine how you could ever build a trial around that.”

“We are working with FDA and hope to have them approved as one drug,” Wood says. “There is a tremendous amount of urgency for people like us. James is 15 and in a wheelchair.”

The field of genetic testing and personalized medicine has huge implications for the insurance industry. Now that genome mapping and screening for genetic diseases is becoming less expensive, will more parents test their children? If they discover the child has an incurable illness or some horrid disease that will cost a fortune to treat, will they bulk up on health and life insurance? If personalized medicine provides a real but prohibitively expensive option for treatment that could add years to the life of a child, will health insurance policies cover all or part of those costs?

“To be excluded from insurance is a real problem, and it is a big problem,” Nagaraju says. “I understand that insurance companies need to make a profit to survive, but at an ethical level, is it a good thing or a bad thing? As a country, we need to make sure we don’t skew to one side or the other and stay in the middle.”

Cox says insurance companies will need to become actively involved in the discussion so that personalized medicine becomes a feasible option.

“Some people are going to have to be working on reforms and modifications,” he says. “It will affect health insurance, the pharmaceutical industry, even life insurance. If you change the mortality tables they build all their financial models on, you are going to change their financial risk and exposure.

“I think they are all going to be watching very closely over the next five years. Trials are going on right now in a huge number of areas. I think we have the ability to make a big impact. There are going to be failures and successes, and we are going to have to modify our technologies to accommodate this new development.”