Dr. Mark Haskins
Professor, University of Pennsylvania School of Medicine
Dr. Mark Haskins is a professor of pathobiology at the University of Pennsylvania School of Medicine. He and his colleagues conduct research on metabolic diseases caused by deficient enzyme activity. Such diseases have similar manifestations in animals and in children. Among the techniques Dr. Haskins and colleagues are exploring are use of recombinant DNA and gene therapy. Dr. Haskins has a BS in pre-veterinary sciences from Penn State University, a VMD from the University of Pennsylvania, an MS in biomedical engineering from Drexel University and a PHD in pathology from the University of Pennsylvania. He lives in Philadelphia.
Lysosomal storage diseases (LSDs) are very rare genetic diseases that children get. Tay-Sachs and Fabry disease are examples of the nearly 50 LSDs that have been identified. When we add all the LSDs together, the incidence is about one in every 7,000 live births. A number of LSDs aggregate in certain populations, such as some Jewish populations or the Amish. We also find them in certain breeds of animals. At the University of Pennsylvania veterinary school, we now have 10 of these diseases in dogs and cats that form the basis of our research.
Here’s how the disease works: The body is constantly making big molecules or substrates that are taken into the cells and chopped into smaller pieces by enzymes to be used to make products the body needs. Lysosomes are small bags of enzymes that enable cells to reduce the substrate into the smaller pieces. They do this in a sequential way — enzyme 1 cuts off one piece, enzyme 2 cuts off another piece, enzyme 3 and so on. If one of these enzymes doesn’t work because there has been a mutation, the process stops. In such cases, the substrates enter the cells and instead of being broken down and used, it is stored and the lysosomes become enlarged.
Having cells that are packed with large lysosomes can be a problem, depending on the type of cell. One example of where it’s a problem is in the cells in the cornea of the eye. The large lysosomes cause cloudiness in the cornea, hindering the way light is refracted. This causes a child with an LSD to see as if he or she were looking through ground glass. Children or animals with LSDs are also growth retarded. For instance, puppies in our lab that have an LSD known as MPS VII weigh half as much as normal puppies. Children with MPS I tend to be short in stature, have coarse features and enlarged livers and are severely mentally retarded. In the case of other LSDs such as MPS VI, children who have it are not severely mentally retarded but have other afflictions such as bone disease.
One approach to correcting the problems caused by LSDs is to introduce normal enzymes with mannose 6-phosphate on it that can help the cell begin to break down the substrate that has accumulated in its lysosomes. If we can get this healthy enzyme to be secreted outside of the cells affected by LSDs, it can attach to most of them and be trafficked into the cells where it can begin to work normally.
Where do you get the normal enzyme? One way is to make it in cell cultures, but it has to be genetically engineered. The cost is prohibitive — $300,000 to treat one child for one year and that’s just the cost of the enzyme. In addition, it has to be administered intravenously once a week. So a child would have to go to the hospital to get the treatment one day a week for the rest of his or her life.
Another approach would be to give the child a new organ that would make the enzymes. Two examples are bone marrow and liver transplants. This has been done but has limited possibilities.
The most promising approach is gene therapy where you take a gene, put it into the animal and the animal makes the new enzyme. We have had considerable success with gene therapy in our lab. For example, we took a retrovirus that causes cancer in mice and removed portions of it. Then we put into this virus a promoter which happens to be from a gene in a human liver and also put in the dog’s missing gene. Then we made a lot if this in culture and injected it in animals with LSDs. The result was that our vector infected the dogs’ liver cells, causing them to become factories for producing normal dog enzyme. When administered to puppies at birth, the manufacturing capacity for healthy enzymes is much greater since the liver grows by a factor of 40 times by the time they reach adulthood. We have one dog that manufactures 60 times the normal amount of healthy enzymes that he needs every day and is now 11 years old.
Many of our animals treated with this therapy have body weights that are almost normal, corneas that are now clear, and much improved skeletal features. However, we haven’t been able to improve the neck with gene therapy and at present we don’t know why.
The advantages of this therapy are that it requires only one injection early in life, it is long-lasting and it can be used for other diseases as long as making too much healthy enzyme is not a problem. Its disadvantage is you need to treat very early. At the moment, every child in the U.S. is tested for 15 genetic diseases. The LSDs have generally not been tested for because it hasn’t been a policy to test for diseases we can’t treat. We are now in a situation where, even though enzyme therapy treatment is available, we don’t test for LSDs. That’s a problem because in many cases, we don’t know a child has an LSD until he or she is older and begins to lose language skills and toilet training. The result is that many don’t get diagnosed until they’re two or three years old when the ideal time for intravenous gene therapy has already passed.
We cannot say at this point that gene therapy for LSDs is a cure. For example, the enzyme made in the liver and going into the bloodstream does not pass to the brain. That is because of the blood/brain barrier that is designed to prohibit a variety of substances passing into the brain. This is a big consideration for treating LSDs that cause neurological impairment. There is also the possibility that the therapy, when introduced to a child’s DNA, will result in a tumor. Another problem may be that the body may recognize the normal enzyme as “new” and mount an immune response. That said, gene therapy remains one of the most promising treatments for these profoundly debilitating diseases.
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