Gene Therapy May Defeat Previously Incurable Diseases
Gene therapy is considered the key to combating previously incurable diseases. In contrast to the traditional administration of drugs, a functional gene enables the body to produce the required proteins itself. Researchers are currently pursuing a promising approach for the treatment of hemophilia A, among other diseases.
A little carelessness is all it takes: a small scratch while gardening or cutting yourself while shaving. What is completely harmless for most people can be life-threatening for hemophilia patients. Due to a genetic defect, their blood does not clot and can therefore seep out of a wound for hours. To prevent this, the approximately 320,000 hemophiliacs worldwide must regularly inject themselves with the clotting Factor VIII (FVIII), a protein that their liver cannot produce on its own.
Hemophilia A is a monogenic disease, meaning that only a single gene – a well-researched one in this case – is defective. This makes the hereditary disease an ideal candidate for gene therapy. "The basic concept of this therapy is based on a simple fact: If a gene is missing or defective, a protein with a specific function in the body is also missing," says Professor Hildegard Büning, a biologist and the deputy director of the Institute of Experimental Hematology at Hannover Medical School, Germany. "Therefore, in gene therapy, we introduce a functioning copy of the defective gene into the cell to take over its function."
Instead of administer hemophilia patients repeated injections of the clotting factor throughout their lives, researchers at Bayer want to use a gene to enable the liver to produce FVIII and thus ensure a normal blood clotting function in the body. "We're using gene augmentation to move the production of this protein into the patient's body, to where it occurs in healthy people," says Frank Reetz, PhD, program director at Bayer's Pharmaceuticals Division. Researchers currently believe that this can compensate for FVIII deficiency over many years.
A "taxicab" brings the gene to the defective cell
To ensure that the gene reaches its defined target in the liver, a means of transportation is required. "Transportation is provided by what are known as vectors or gene shuttles. I like to refer to them as taxicabs," says Professor Büning. These "taxicabs" are in fact modified viruses, for example. In this case, they are based on adeno-associated viruses (AAV). Once the cab has reached the vicinity of its target, it makes contact with receptors on the cell membrane. "We can observe this process in the laboratory using techniques developed for this purpose," reports Professor Büning: "It's like knocking on a door. If everything fits together, the vectors are taken up into the cell and transported inside endosomes – small intracellular vesicles – toward the cell nucleus." There, the therapeutically relevant genetic information is introduced.
Really getting to the root of diseases
"Our approach looks very promising," says Frank Reetz, "Phase I/II clinical trials are currently underway in hemophilia A patients." For researchers at Bayer, these could be "truly life-changing therapies." Gene therapy, he says, makes it possible to get to the root of diseases and provide a cure or regeneration. According to Professor Büning, therapies with AAV vectors have great potential in organs where little or no division takes place, such as muscles, the liver, the brain and the eyes, but also in the cardiovascular system: "Often these are rare diseases where we have no way of helping people with conventional medicine."
Seven gene therapies have been approved in Europe to date for use, for example, in a form of immunodeficiency, in a congenital form of blindness, and in hereditary muscular atrophy. For more than a year now, patients who have been out of treatment may be treated with CAR-T cell therapies against aggressive forms of blood cancer. The biologist sees further areas of application in oncology: "There, too, there are changes, a defect that allows the cancer cell to proliferate." With the help of a vector, immune cells can learn to recognize tumor cells. "Numerous other therapies are in development," says Professor Büning. "We expect to see many approvals in the coming decade!"