Update on Clinical Trials to Cure Hemophilia
Horizons in Hemophilia, December 2012
By Jeff Cornett, RN MSN, Director of Training, Research, & Advocacy
This past July, Hemophilia of Georgia began funding clinical trial research at two institutions: St. Jude Children's Research Hospital in Memphis, Tennessee ($3,172,401) and the Aflac Cancer and Blood Disorders Center at Emory University, Atlanta ($2,557,979). The $5,730,380 contribution over the next three years is to expand clinical trials to cure hemophilia. The Hemophilia of Georgia funding will enable these institutions to enroll more patients and progress more quickly with their clinical trials. This article focuses on the clinical trials being done on factor IX deficiency (hemophilia B) at St. Jude’s. St. Jude’s has already treated patients and similar clinical trials are starting in other parts of the country.
In order to understand the treatment, you have to start with the most basic elements of human biology. Cells are the building blocks of all living things. The human body is composed of trillions of cells. Within the nucleus of the cell are our chromosomes containing genes – our genetic material. The genes direct the actions of all of the cells of our body. In hemophilia, the gene for factor VIII or for factor IX is flawed – it doesn’t work correctly so the body doesn’t produce enough factor. Researchers are trying to cure hemophilia by putting a new gene into some of the cells of the body. The cells that get the new gene will start making factor.
There are about six times as many people with factor VIII deficiency as factor IX. So why are researchers working on factor IX first? It has to do with the size of the gene. The gene for factor VIII is one of the largest genes in the body. Why does this matter? It’s because of the way the new gene is put into the body.
The new gene is put into the body using an engineered virus. There are many types of viruses, some of which we deal with often, such as cold viruses or the flu. Others are the culprit in severe diseases like AIDS and hepatitis. Some come into our body but don’t cause any symptoms at all. Over the past two decades, researchers have discovered ways to engineer just about all of these viruses to be safe by removing the harmful parts and making room to insert therapeutic genes, which the viruses most efficiently deliver to cells. Other than delivering the gene, or “transgene” as its referred to in gene therapy lingo, these engineered viruses retain none of their normal viral properties and cannot replicate or multiply as would occur in a typical infection.
One of those engineered viruses –adeno-associated virus or “AAV” has been selected for use in hemophilia B gene therapy. Specifically, the researchers are using type 8 of the AAV virus. This is because most people have never been infected with it before. If they had been infected before, the body’s immune system would have antibodies against it. Those antibodies could destroy the virus before the gene therapy had a chance to work. AAV8 has an attraction to cells in the liver. That’s the normal spot in our body where factor IX production occurs, so those are good cells to target. Also, AAV doesn’t seem to mess with our chromosomes – something that could cause later problems, such as cancer.
Researchers take the AAV8 virus, remove the virus's genetic material, and replace it with the factor IX gene. The normal factor VIII gene is too big to fit inside AAV virus. So for the first trials, the researchers are working with factor IX. There are ways to make factor VIII fit (by trimming away nonessential parts of the factor VIII “transgene” and minimizing the remaining viral components), so researchers will be testing AAV-factor VIII gene therapy if the factor IX treatment works and the factor VIII performs equivalently in preliminary laboratory testing. Even if AAV doesn’t prove to be the best strategy for delivery of the factor VIII gene in hemophilia A gene therapy, there are other viral strategies emerging onto the scene that hold significant promise.
The virus with the factor gene inside is called a “viral vector.” Getting the viral vector inside the body is easy. It is injected into a vein in the arm and is carried right to the liver. So far, patients have had no problems with this. They stay overnight at the hospital to make sure everything is okay and go home in the morning.
When the virus gets to a liver cell, it enters the cell and delivers the new gene. The liver cell then starts making factor. A potential problem occurs because pieces of the virus stick to the outside of the cell for weeks. The body’s immune system may recognize this viral protein and destroy the cell. Viruses also leave the body through body fluids like urine. It takes up to 15 days for viruses to disappear from body fluids.
St. Jude is doing this research in partnership with University College London in England. The first six patients were treated in London – the first one about 32 months ago. In the clinical trials, only one patient is treated at a time and then observed for a few months. This lets the researchers observe how well the treatment is working and, most importantly, how safe it is. The first two patients received very low doses of the treatment, the next two a higher dose, and the next two a still higher dose.
The first two patients got the lowest dose. The treatment didn't seem to cause any harm. Their bodies only made small amounts of factor IX (1 to 2%). As they increased the amount of viral vector that was given to patients, the amount of factor the body produced increased also - up to 6%. In England the standard of care for severe hemophilia B is to infuse prophylactically twice a week. Four of the first six patients have been able to stop prophylaxis and have largely been free of spontaneous bleeds -- even when they have done activities that caused them to bleed in the past. They still have to take factor if they have an injury. The other two patients had really bad joints before they received the gene therapy treatment. They have had to continue prophylaxis but infuse less often.
The fifth patient was the first to receive the high dose of the gene therapy. Two weeks after treatment his factor IX level was 7%. The patients have blood drawn regularly to check their factor level and also watch for signs of any effects on the liver or other body systems. At week seven, this patient's blood showed higher than normal levels of liver enzymes. He didn't have any symptoms. His factor IX level dropped to 3%. In earlier studies this was a sign that the body's immune system had destroyed some of the cells that got the new gene. The doctors gave the patient a steroid to suppress his immune system and his liver tests returned to normal. However, his factor level stayed at 3%. The next patient treated had a similar reaction. His liver enzymes went up nine weeks after treatment. His factor IX level dropped from 8 - 11% to 4-6%. He was successfully treated with the same steroid.
In order for most patients to have no joint bleeds at all, we probably need a factor level of at least 13%. The researchers want to get the highest level of factor without provoking the immune system. How can they do that? The first step they are taking is getting rid of "empty" viruses. In the current treatment, over 80% of the viruses given to a patient don't have the factor IX gene inside. This is due to the difficulty of getting the gene inside the virus. Researchers have improved the process and now less than 10% of the genes are "empty." This is very important since empty viruses increase the chance of provoking the immune system with no benefit to factor levels. Another approach is to use a better factor IX gene. This opportunity came about in a very unexpected way.
In 2009, doctors in Padua, Italy, reported the case of a 23 year old man who was seen at the Padua University Hospital. He had a blood clot in his leg that happened after some mild stretching exercises. This was very strange. It became even stranger when the doctors discovered that the young man had a gene mutation that had never been seen before. The mutation caused his body to produce factor IX that was super active.
The technical name for this mutation is "factor IX-R338L" but it is commonly called factor IX Padua. This factor IX is 8 times more active than normal factor IX. That is bad news for this young man but very good news for people with hemophilia B. It opens the possibility of using less factor but getting a greater benefit. Dogs with hemophilia have already been treated with gene therapy using the factor IX Padua gene. The factor level in their blood only went to 4% but acted as if it was at 40%. The dogs didn't experience any problems from the new gene. Trials are now set to begin in humans using the factor IX Padua gene.
There are potential dangers and problems with gene therapy. First, it is not known if there are problems that may show up years from now. The longest any human has been treated is less than three years. There are dogs that were treated eight to ten years ago and they seem fine. However there has been a report that a small number of mice that were treated developed liver cancer.
A second major concern is how long the treatment will last. Liver cells do not live forever. They die after 8 years or so and are replaced. Since the cells with the new factor IX gene do not reproduce, none of the new cells can produce factor. We can expect that the level of factor IX in the blood will drop over time. This also presents a problem with the treatment of children. The current gene therapy approach would not work because of the growth of the liver as the child grows. What would be enough cells producing factor for them at age 3 won't be enough at age 10.
The third concern is the inability to do the treatment twice on the same person. When you get gene therapy using AAV8, your body develops antibodies against the virus. If you were given AAV8 again, your immune system would quickly destroy the virus and the gene therapy wouldn't work. There are other viruses that could be used but they are not currently available.
If you are interested in being part of a clinical trial, your first step is to talk to your hemophilia doctor. Your hematologist is aware of all of the clinical trials that are underway and those that are about to start. None of the trials accept anyone younger than 18. None accept anyone with an inhibitor. Some take people with hepatitis and HIV; others do not. Your hematologist is the person who can best advise you about your situation.
Hemophilia of Georgia is very committed to improving treatment for all bleeding disorders as well as research on a cure. We are still funding researchers that are focused on inhibitors and von Willebrand Disease. The Emory gene therapy program is using a very different approach in an effort to cure hemophilia A, factor VIII deficiency. You can stay informed by reading the HoG newsletter. We will be publishing regular updates on gene therapy research. Finally, you can help us by raising money for research.