Hereditary angioedema (HAE) is a rare and serious genetic condition that is caused by mutations in one of two genes that provide instructions for making certain blood proteins. In type 1 or 2 HAE the mutation affects the SERPING1 gene that provides instructions for making the blood protein C1 inhibitor. Type 3 HAE is caused by mutations in the F12 gene that provides instructions for making coagulation factor 12.
Researchers have been working on ways to replace the faulty gene causing the condition by using a so-called gene therapy approach.
Gene transfer using a virus
Researchers at the Weill Medical College of Cornell University, led by Odelya Edith Pagovich, MD are working on developing a gene therapy approach that could permanently restore the amount of functional C1 inhibitor in the blood of type 1 and 2 HAE patients, preventing angioedema attacks.
This approach uses a virus to deliver a healthy copy of the SERPING1 gene inside cells. Viruses are commonly used in gene therapy to deliver genetic material because they are specialized in doing this; they multiply by essentially injecting their genetic material into cells and hijacking the cell’s machinery to make copies of themselves.
Scientists have discovered how to alter viruses so that they retain their ability to introduce genetic material into a cell, but can no longer multiply. These altered viruses can be loaded with the desired genetic material and used as a “vector” to introduce it into cells.
Pagovich’s research is still in the early stages, but the team already has accomplished several steps in the process. First, the researchers have created a variety of mice that are genetically engineered to have similar mutations and symptoms as HAE patients. These mice allow them to test their treatments for HAE before moving to clinical trials in humans.
The team also has developed a virus vector loaded with the SERPING1 gene. When this was injected into the HAE mice, more C1 inhibitor protein was produced and the animals showed reduced symptoms.
The researchers are hoping this approach could be tested in humans.
Focusing on the liver
A group of researchers based in New Zealand and Australia have argued that HAE can be considered a metabolic liver disorder because C1 inhibitor protein is produced primarily in the liver. They have proposed new avenues of research to treat type 1 and 2 HAE that focus on the liver.
First, a gene therapy approach similar to the one described above could be used. Liver cells could be removed from the patient and “given” a healthy SERPING1 gene in the laboratory using a viral vector and then returned to the patient’s liver.
Alternatively, the virus with the healthy SERPING1 gene could be introduced into the patient’s body, but targeted toward liver cells. This approach, however, has a higher risk of triggering an immune response.
The researchers also argue that a liver transplant might cure HAE because the donated liver would have cells with functional SERPING1 genes and would produce sufficient amounts of C1 inhibitor protein to prevent attacks. There have been no documented cases of a liver transplant being performed to treat HAE, but in one case a patient acquired angioedema after receiving a transplant from a donor with the disease, suggesting that curing HAE via liver transplant could work.
Auxiliary partial orthotopic liver transplantation, in which a portion of the liver is donated and grafted on to the recipient’s own liver, also is proposed as a potential treatment for HAE. This might be more feasible because livers have a remarkable ability to regenerate. Donors can donate a portion of their liver, which will then regrow. Another advantage is that the HAE patient’s liver remains intact in case the donor graft is rejected. It is hoped that the donated portion of liver might produce enough C1 inhibitor protein to prevent angioedema attacks.
All of the treatment approaches described above are in the pre-clinical stages of development. But in the future, gene therapy and liver-focused approaches may provide good alternatives to the currently available treatments for HAE, which can be costly and difficult to use.
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