There is a genetic muscle disease in humans called limb-girdlemuscular dystrophy (LGMD). In this illness, the affected personhas a gene that does not make "sarcoglycan" correctly. Sarcoglycanis a protein in the muscle that helps muscles to function correctly.In their study, which appears in this issue of Neurology®,Louise Rodino-Klapac and her colleagues (2008;71:240–247)studied a specific gene treatment. They wanted to find out whetherit was possible to inject mice with a gene that contained anew recipe for sarcoglycan. The idea behind their research issimple. Sarcoglycan is an important component of the musclecell, but when it is made incorrectly it causes muscle weakness.Because there is no known treatment for LGMD, researchers havebeen looking for ways to "fix" the "broken" gene. This studyis just one step in the long process that ultimately may resultin the first treatment for this genetic illness. It is considereda translational study.
Translational studies are critical to the development of medicaltreatments. The term translational refers to research that bridgesthe gap between basic research and clinical trials. Basic researchoften indicates studies that are performed on animals or oncells that are grown in a laboratory. Clinical trials are studiesof medical treatment on people. Often there are many steps betweenbasic research studies and clinical trials. However, translationalstudies are needed to chart the course from animals to humans.
In the study, Dr. Rodino-Klapac injected a "correct" copy ofthe sarcoglycan gene into one of the leg muscles of mice. Theyallowed the gene to be incorporated into the mouse muscle foreither 6 or 12 weeks. After this time, they looked at the muscleto determine whether it was making the "correct" sarcoglycanprotein on its own. Using the identical, untreated muscle fromthe other leg as a comparison, they showed that the treatedmuscle was making two to two-and-a-half times the usual amountof sarcoglycan. In other words, the treated muscle was makingthe protein that they wanted it to make.
In addition, they looked at the muscle to see whether therewere signs of inflammation. Prior studies had shown that themouse’s immune system was "fighting" the injected gene.This was important to evaluate because it would mean that thebody was rejecting that treatment. In other words, even thoughthe treatment was not harmful, the body could not be sure, andit was trying to get rid of the injected gene. In Dr. Rodino-Klapac’sstudy, there was no sign of an inflammation. This was probablybecause she used a different way to inject the gene than hadbeen tried in earlier studies.
Finally, Dr. Rodino-Klapac was concerned that the treatmentwould not last. Previous studies had suggested that the sarcoglycanwould be made for only a short period of time. In this study,the researchers chose two independent ways of checking how muchsarcoglycan was made. Both methods showed that it was producedin good quantities, and the production continued for at least12 weeks. Here again, the difference between this study andprevious studies was in the way that the gene was given.
The term muscular dystrophy refers to a group of muscle diseases.There are now more than 30 different kinds of muscular dystrophy.The cause of all of these is genetic. One of many genes canbe affected. This is because many genes are needed to make anintricate structure in muscle cells called dystrophin. In otherwords, muscular dystrophy is a genetic illness due to an errorin one or more of the genes responsible for making this complexcomponent of muscle cells.
Dystrophin is made up of proteins and complex sugars. It hastwo main components: dystroglycan and the sarcoglycan. It ismade and used in muscle cells. The exact role of dystrophinis unclear. However, much has been learned about dystrophin.It seems to connect the cell membrane to the cell’s skeleton(called a cytoskeleton). In many ways, dystrophin is the substancethat anchors the internal structure of the cell, making it strongerand stable.
There are many kinds of muscular dystrophy. Duchenne musculardystrophy is the most common and most severe type, affecting1 in 3,500 boys. It is due to a complete lack of dystrophin.It causes progressive muscle weakness which is usually firstrecognized in early childhood. Most people with Duchenne musculardystrophy are confined to a wheelchair by adolescence. Becausethe muscles of breathing are also affected, they usually dieat a young age (often in their twenties) from breathing problems.
Becker muscular dystrophy is similar to Duchenne. However, itis milder because people with Becker have some dystrophin, asopposed to none at all in Duchenne. As a result, Becker startsto cause problems later in life. The survival is much longerthan in Duchenne. However, people with Becker muscular dystrophyhave the same gradual weakening of the muscles of their body.
Another common form of muscular dystrophy is called limb-girdlemuscular dystrophy (LGMD). It gets it name from the observationthat the illness primarily affects muscles of the shoulder,chest, hip, and thigh. In LGMD, the problem is not that dystrophinis lacking. Instead, the problem is in the gene that controlsthe production of the sarcoglycan component of dystrophin. Becauseone component of dystrophin is made incorrectly, the dystrophincannot work well. It would be like making nuts and bolts, onlythe bolts are too small, so they do not stay together well.
LGMD can start in childhood, adolescence, or adulthood. As withother types of muscular dystrophy, LGMD gradually gets worseover time. In most people, the weakness occurs over a periodof 20 to 30 years before it reaches its most severe stage. InLGMD, because the upper leg muscles are involved, the personmay no longer be able to walk long distances. They may needa scooter or wheelchair to get around. Their thinking and personalityare unaffected by the illness.
LGMD, as with other forms of muscular dystrophy, is diagnosedin the doctor’s office through a careful history and physicalexamination. Medical testing supports the clinical diagnosis.For instance, in LGMD, blood tests can show an elevated muscleprotein called creatine kinase (CK). In LGMD, CK levels canbe 5 to 25 times the normal levels. In many people with LGMD,magnetic resonance imaging (MRI) can show the changes that occurin the muscles. Finally, an electromyogram (EMG) is often usedto confirm the diagnosis. In this test, a small needle is placedin the muscle to record how well it is working. The kinds ofelectrical signals the muscle sends back to the recording machinewill tell the doctor whether the person has LGMD.
WHAT TREATMENTS ARE AVAILABLE FOR MUSCULAR DYSTROPHY?
Currently there are no known treatments for muscular dystrophy.Patients often start a regimen of physical exercises after diagnosis.These are designed to maintain strength and mobility for aslong as possible. The exercises definitely help; however, theydo not change the course of the illness, which is progressive.
To treat muscular dystrophy, the gene needs to be fixed. Sincewe do not yet have a way to fix broken genes, researchers arelooking at ways to send a "good" gene to the muscle cells. Oneway is to inject the affected muscle, giving it the "good" gene.However, if many muscles are affected, as occurs in musculardystrophy, this would mean that many injections would be needed.Another way to get the "good" gene to the cells would be toinject it into the bloodstream. However, there are problemswith getting the "good" gene past our immune systems.
To get the gene into the cell, researchers use viruses. Theviruses have been changed so that they no longer can cause disease.However, some parts of the virus, like the part that allowsit to get into the cell, is kept. The "good" gene is packagedinto these modified viruses. When the virus goes into the cell,it delivers the "good" gene to the cell’s nucleus. The"good" gene is then placed into the gene library. Once there,it can start telling the cell the "correct" recipe for the dystrophinprotein. In this way, a genetic illness can be "cured."
The human body, though, is very smart. It can quickly identifyforeign substances like viruses. It forms antibodies to protectthe body against future viral attacks. When this occurs, whiteblood cells move to the foreign substance and destroy it. Thisprocess is called the inflammatory response.
When a virus is used to deliver a treatment, like a "good" gene,the body might mistake it for the foreign substance it traineditself to recognize and destroy. Since the muscular dystrophygene is sent to muscle cells (whether injected directly or throughthe bloodstream), the body might mount a response against theinfected muscle cells. Instead of making things better, thesituation might get worse because of the body’s naturalresponse. This has been one of the concerns of many scientists.It was the reason why Dr. Rodino-Klapac and colleagues lookedat the response of mouse muscle cells to the injected "good"gene in this translational study.
Although clinical trials may still be some way off, translationalstudies pave the way for further research. Many genetic illnesseshave been identified, but few are treatable. It seems amazingthat the structure of DNA was only just described in 1953 byWatson and Crick. Only 55 years later, we are using that informationto attempt to fix portions of DNA that are incorrectly written.Using viruses to introduce these genes into cells, studies likethat of Dr. Rodino-Klapac show us that it is possible to treatthe cause of genetic illnesses like LGMD. Perhaps in the next50 years, treatment of these illnesses will be as commonplaceas prescribed medications are today.
Top.
WHAT DID THE RESEARCHERS...
WHAT IS A TRANSLATIONAL...
