Genetics

Weighing the Pros and Cons of Gene Therapy



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Gene therapy sounds like a dream come true for those with muscular dystrophy or other diseases. But gene therapy could also turn into gene doping for athletes desiring that extra boost of energy or speed to win. If gene therapy is poised to become a practical medical treatment, gene doping for personal wants is not far behind. In truth, the start of research toward genetically enhancing muscle size and strength was not focused on serving elite athletes. If gene therapy becomes a worldwide medical practice, will it be so commonplace that the world may accept the manipulation of genes to enhance athletic performance?

In the most common and most severe version of MD (Duchenne muscular dystrophy), an inherited gene mutation results in the absence of a protein called dystrophin. Dystrophin protects muscle fibers from injury by the force that they exert during regular movement. Muscles are good at repairing themselves, but their normal regenerative mechanisms cannot keep up with the excessive rate of damage in MD. In aging muscles the rate of damage may be normal, but the repair methods become less responsive. As a result, in both aging and Duchenne MD, muscle fibers die and are replaced by infiltrating fibrous tissue and fat.

Manufacturing new proteins that can repair the outer membrane of existing fibers and plumping their interior with new myofibrils requires the activation of the necessary genes within the muscle cell's nuclei, and when the demand for myofibrils is great, additional nuclei are needed to support the muscle cell's manufacturing capacity. Local satellite cells residing outside the muscle fibers answer this call. First, these muscle-specific stem cells multiply by normal cell division. Then, some of their progeny fuse with the muscle fiber, contributing their nuclei to the cell. Both progrowth and antigrowth factors are implicated in regulating this process. Satellite cells respond to insulinlike growth factor I, or IGF-I, by undergoing a greater number of cell divisions. The key causal question can be formulated: Why is gene alteration or transfer so effective in helping medical cases such as muscle dystrophy?

A few hypotheses were generated to answer this question: Modifying a tiny virus (AAV) with a synthetic gene that would produce IGF-I only in skeletal muscle would strengthen muscles; Overproduction of IGF-I throughout the skeletal muscle would hasten muscle repair.

A major obstacle to gene therapy was figuring out how to get the chosen gene into the desired cell. A virus was chosen as the delivery vehicle, or the vector. Viruses are very successful in sneaking genes into cells because of the way they trick the cells of the host organism into bringing them inside. Once inside the host organism, the virus then proceeds to use cellular machinery to replicate its genes and produce proteins. Knowing this, a synthetic gene was loaded into the virus and any genes the virus itself could use to cause disease or replicate itself were removed. As the first hypothesis stated, a tiny virus called adeno-associated virus (AAV) was selected as the vector because it infects human muscle readily but doesn't cause any known disease.

The virus was modified with a synthetic gene that would produce IGF-I only in skeletal muscle. It was tested out on normal mice. After injecting young mice with that AAV-IGF-I combination, the muscles' overall size and the rate at which they grew were 15 to 30 percent greater than normal, even though the mice were sedentary. Also, when the gene was injected into the muscles of middle-aged mice and then they were allowed to reach old age, their muscles did not get any weaker.

These experiments prove that the first hypothesis is true, and an "If then" statement can thus be created: If modifying a tiny virus called adeno-associated virus (AAV) with a synthetic gene that would produce IGF-I only in skeletal muscle strengthens muscles, and it was injected into normal mice, then the young mice's muscles' overall size and rate at which they grew would be15 to 30 percent greater than normal; (other experiment) and it was injected into the muscles of middle-aged mice and were allowed to reach old age, then their muscles would not get any weaker. And, the young mice's muscles' overall size and rate at which they were was 15 to 30 percent greater than normal, and the muscles of middle-aged mice allowed to reach old age did not grow any weaker. Therefore, the hypothesis was supported, and modifying a tiny virus (AAV) with a synthetic gene that would produce IGF-I only in skeletal muscle does strengthen muscles.

The alternate hypothesis states that the overproduction of IGF-I throughout the skeletal muscle would hasten muscle repair. A few experiments were done to explore the truth of the statement.

A scientist by the name Rosenthal created mice genetically engineered to overproduce IGF-I throughout their skeletal muscle. As a result, they developed normally except their skeletal muscles ranged from 20 to 50 percent larger than those of regular mice. As those transgenic mice aged, their muscles retained a regenerative capacity typical of younger animals. Consecutive experiments showed that IGF-I production hastens muscle repair, even in mice with a severe form of muscular dystrophy.

A second experiment was made. AAV-IGI-I was injected into the muscle of just one leg of each of the lab rats and then the animals were subjected to an eight-week weight-training course. At the end of the training, the muscles that was injected with AAV-IGF-I had gained nearly twice as much strength as the un-injected legs in the same animals. After training stopped, the injected muscles lost strength much more slowly than the un-enhanced muscle. AAV-IGF-I provided a 15 percent strength increase.

These two experiments also prove the second hypothesis to be true, and another "If then" statement can be formed: If overproduction of IGF-I throughout the skeletal muscle would hasten muscle repair, and mice were genetically engineered to overproduce IGF-I throughout their skeletal muscle, then they should develop normally except for a 20 to 50 percent increase in their skeletal muscles and as they aged, their muscles should retain a regenerative capacity typical of younger mice; (other experiment) And AAV-IGI-I was injected into the muscle of just one leg of each lab rat then subjected to an eight-week weight-training protocol, then at the end of the training, the injected muscles should have gained nearly twice as much strength as the un-injected legs, and the injected muscles should lose strength much more slowly than those with un-enhanced muscles. And, the mice did develop normally except for a 20-50 percent increase in their skeletal muscle and retained a regenerative capacity typical of younger mice, and with the lab rats, the injected muscles did gain nearly twice as much strength and lost strength much more slowly than those with un-enhanced muscles. Therefore, the second hypothesis was also supported, and the overproduction of IGF-I throughout the skeletal muscle does hasten muscle repair.

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