In general, genetic disorders are inherited diseases that arise when someone has two dysfunctional copies of a single gene on both of their chromosomes. The result of this is often devastating, resulting in abnormal functioning of specific cells and the development of an often life-threatening condition. In these cases gene therapy is employed to replace the dysfunctional gene with a correct copy and restore the normal functioning of affected cells. In this page we describe some of the most well-known genetic disorders that are being targeted by the gene therapy community.
1. Cystic Fibrosis
Cystic fibrosis (CF) is an inherited disease of your mucus and sweat glands. It affects mostly your lungs, pancreas, liver, intestines, sinuses, and sex organs. Normally, mucus is watery. It keeps the linings of certain organs moist and prevents them from drying out or getting infected. But in CF, an abnormal gene (CFTR) causes mucus to become thick and sticky. The mucus builds up in your lungs and blocks the airways. This makes it easy for bacteria to grow and leads to repeated serious lung infections. Over time, these infections can cause serious damage to your lungs. The thick, sticky mucus can also block tubes, or ducts, in your pancreas. As a result, digestive enzymes that are produced by your pancreas cannot reach your small intestine. These enzymes help break down the food that you eat. Without them, your intestines cannot absorb fats and proteins fully. The abnormal gene also causes your sweat to become extremely salty. As a result, when you perspire, your body loses large amounts of salt. This can upset the balance of minerals in your blood. The imbalance may cause you to have a heat emergency. CF can also cause infertility (mostly in men). The symptoms and severity of CF vary from person to person. Some people with CF have serious lung and digestive problems. Other people have more mild disease that doesn't show up until they are adolescents or young adults. Respiratory failure is the most common cause of death in people with CF. Until the 1980s, most deaths from CF occurred in children and teenagers. Today, with improved treatments, people with CF live, on average, to be more than 35 years old
Gene Therapy Approaches
Only a year after the gene for CF was identified scientists showed in cells in the laboratory that it was possible to correct the CF defect by adding a healthy copy of the gene. These findings have been consistently repeated by other groups using a variety of models and gene transfer agents. Studies in humans followed quickly. Gene therapy for CF has been tested in humans using both viruses and liposomes. These early studies were concerned mainly with safety issues. The amount of gene transfer achieved is similar for both systems and is probably still too small to have any real therapeutic benefit - although it is important to note that none of these trials actually measured therapeutic benefit. Also at present the effect seen (gene expression) only lasts for a few days. The scientific principle of gene therapy for CF is a sound one and the technology already exists to transfer the CF gene into the airway cells in man but there are still challenges ahead of the field. The two main challenges are getting the gene into the cells more efficiently and to make gene expression last longer. However the field is moving forward rapidly and with the development of better new viruses and liposomes these problems are surmountable. After initial encouraging clinical trials most research for CF gene therapy has returned to the laboratory to solve the problems mentioned above.
2. SCID
The body's immune system fights against diseases and infections. The SCID syndromes are inherited disorders that result in severe defects in the immune system. White blood cells (which fight infection) are produced in the bone marrow by stem cells. In people with SCID, the bone marrow stem cells are absent or defective. This leaves the affected person open to any and all germs around him because he has no way to fight them off.
There are several different types of SCID. The most common type is called X-linked SCID because its gene is linked to the X chromosome that a mother provides to her child during reproduction. To break down the genetics simply, males are more likely to develop this type of SCID because they only have one X chromosome--the traits tied to it are more likely to be expressed. Females, on the other hand, have two X chromosomes -- both must carry the SCID gene in order for a girl to have the disease.
The second most common type comes from the lack of the enzyme adenosine deaminase. The disorder is inherited when both parents contribute an abnormal gene to a child during reproduction. This is referred to as autosomal recessive inheritance.
Since a child is born with SCID, the diagnosis is usually made before age 6 months. The child has a high number of infections that are more serious and less responsive to antibiotics than normal. These infections may be ones that are unusual for a child to have, such as Pneumocystis carinii pneumonia (PCP). The child may have persistent diarrhea with weight loss and chronic skin infections.
Since 1968, the treatment of choice has been replacing the defective bone marrow with normal bone marrow through stem cell (bone marrow) transplant. This is a difficult treatment that does not guarantee a cure, but it does work in many cases.
Children with SCID are usually kept isolated from other people, including relatives, and take Bactrim (trimethoprim/sulfamethoxazole) to prevent PCP infection. Without a bone marrow transplant, the child is always at risk for a severe or fatal infection and will have difficulty surviving beyond his first birthday.
Gene Therapy Approaches
In order to treat a child using gene therapy s ome of the child's own marrow stem cells are removed. The "normal" version of the defective gene responsible for SCID (the gamma-receptor) is inserted into the cells. The "corrected" cells are then put back into the child's bone marrow.
Gene therapy for SCID has been tried successfully. On April 3, 2002, physicians in England announced that they had successfully restored the immune system of a boy with X-linked SCID. Eighteen-month-old Rhys Evans appeared to have been "cured" of the disorder, although whether one treatment will last a lifetime is not yet known. Other children have also been treated successfully.
A complication developed with gene therapy trials in France, however, beginning in September 2002. Unfortunately, three boys treated as infants later developed a leukemia-like blood disorder. They have been treated with chemotherapy. Researchers are working on discovering why this happened, and how to ensure that other children with SCID who are treated enjoy the success of gene therapy without the negative consequences.
Based on the French cases, the U.S. Food and Drug Administration (FDA) suspended two similar American studies.
3. Muscular Dystrophy
Muscular dystrophy (MD) is a genetic disorder that weakens the muscles that help the body move. People with MD have incorrect or missing information in their genes, which prevents them from making the proteins they need for healthy muscles. Because MD is genetic, people are born with the problem - it's not contagious and you can't catch it from someone who has it.
MD weakens muscles over time, so children, teens, and adults who have the disease can gradually lose the ability to do the things most people take for granted, like walking or sitting up. Someone with MD might start having muscle problems as a baby or their symptoms might start later. Some people even develop MD as adults.
There are several major forms of muscular dystrophy that affect teens, each of which weakens different muscle groups in various ways.
- Duchenne (pronounced: due-shen) muscular dystrophy (DMD), the most common type of the disease, is caused by a problem with the gene that makes a protein called dystrophin. This protein helps muscle cells keep their shape and strength. Without it, muscles break down and a person gradually becomes weaker. DMD affects boys. Symptoms usually start between ages 2 and 6. By age 10 or 12, kids with DMD often need to use a wheelchair. The heart may also be affected, and people with DMD need to be followed closely by a lung and heart specialist. They can also develop scoliosis (curvature of the spine) and tightness in their joints. Over time, even the muscles that control breathing get weaker, and a person might need a ventilator to breathe. People with DMD usually do not survive beyond their late teens or early adulthood.
- Becker muscular dystrophy (BMD), like DMD, affects boys. The disease is very similar to DMD, but its symptoms may start later and can be less severe. With BMD, symptoms like muscle breakdown and weakness sometimes don't begin until age 10 or even in adulthood. People with BMD can also have breathing, heart, bone, muscle, and joint problems. Many people with BMD can live long, active lives without using a wheelchair. How long a person with BMD can live varies depending on the severity of any breathing and heart problems.
- Emery-Dreifuss (pronounced: em-uh-ree dry-fuss) muscular dystrophy (EDMD) typically starts causing symptoms in late childhood to early teens and sometimes as late as age 25. EDMD is another form of muscular dystrophy that affects mostly boys. It involves muscles in the shoulders, upper arms, and shins, and it often causes joint problems (joints can become tighter in people with EDMD). The heart muscle may also be affected.
- Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper arms and around the hips and thighs. LGMD can begin as early as childhood or as late as mid-adulthood, and it often progresses slowly. Over time, a wheelchair might be necessary to get around. There are many different types of LGMD, each with its own specific features.
- Facioscapulohumeral (pronounced: fa-she-o-skap-you-lo-hyoo-meh-rul) muscular dystrophy (FSHD) can affect both guys and girls, and it usually begins during the teens or early adulthood. FSHD affects muscles in the face and shoulders and sometimes causes weakness in the lower legs. People with this type of MD might have trouble raising their arms, whistling, or tightly closing their eyes. How much a person with this form of muscular dystrophy is affected by the condition varies from person to person. It can be quite mild in some people.
- Myotonic (pronounced: my-uh-tah-nick) dystrophy (MMD) is a form of muscular dystrophy in which the muscles have difficulty relaxing. In teens, it can cause a number of problems, including muscle weakness and wasting (where the muscles shrink over time), cataracts, and heart problems.
- Congenital muscular dystrophy (CMD) is the term for all types of MD that show signs in babies and young children, although the MD isn't always diagnosed right away. Like other forms of MD, CMD involves muscle weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in how severely it affects people and how quickly or slowly it worsens. In rare cases, CMD can cause learning disabilities or mental retardation.
The life expectancy (in other words, how long a person may live) for many of these forms of muscular dystrophy depends on the degree to which a person's muscles are weakened as well as how much the heart and lungs are affected.
Traditionally it was thought that standard gene transfer technology would be best applicable to the treatment of this disease, i.e. the use of gene transfer vectors to deliver a corrected copy of the dysfunctional gene in muscle cells. In this vein, a substantial amount of work has gone into the construction of non-viral and viral systems that deliver various versions of the genes mutated in the variety of dystrophies. In the case of Duchenne's Muscular Dystrophy, where the mutated gene is a few megabases in length, a huge plethora of vectors have been constructed that express shorter functional versions of the full-length dystrophin protein. It has now been realised, however, that this type of replacement gene therapy is not the only way to treat this devastating disease. Recent research has shown that it is possible to 'correct' a patients own copy of the defective genes by a process known as exon skipping.
Exon skipping is achievable for the treatment of DMD due to the repetitive nature of the gene and it has proved possible to prevent expression of the mutated protein by allowing the cell's trancription machinery to skip the mutation that causes the disease to form a slightly shorter functional version of the full-length protein. In this approach it is not strictly speaking the gene that is corrected, but the messenger that actually produces the protein from the DNA code. This approach is now feasible because of a new chemical means of synthesising the short nucleic acids that are required to induce the exon skipping. Using modification to the natural nucleic acids it is possible to synthesise oligonucleotides based on morpholino chemistry to induce exon skipping. These morpholinos are more stable in patients and can enter more muscle cells than traditional oligonucleotides. This imporved technology is now under evaluation in the clinic and the first results from these trials should provide some insight into the potential success of this approach.
