Understanding Immune Responses for Hemophilia
Featured in interaction January 2006 (PDF 425KB)
After bone marrow transplants, many patients battle complications from the treatment of their cancer and suffer from illnesses that overwhelm their compromised immune systems.
Dr. Miao was granted an award which will fund her study of the modulation of immune responses for hemophilia following replacement therapy.
When Dr. Carol Miao discusses her nearly eight-year history involving the study of hemophilia, her eyes light up and her manner becomes very direct.
She speaks intently of her early years in the field and of one of her mentors, Earl Davie — "a pioneer in the field of coagulation."
Last September, Dr. Miao was granted an award which will fund her study of the modulation of immune responses for hemophilia following replacement therapy — an ongoing struggle in the treatment of the oldest known hereditary bleeding disorder.
There are two types of hemophilia, A and B. Low levels or complete absence of a blood protein essential for clotting causes the disease. Patients with hemophilia A lack the blood clotting protein, factor VIII, and those with hemophilia B lack factor IX.
There are about 20,000 hemophilia patients in the United States. Each year, about 400 babies are born with this disorder. Approximately 85% have hemophilia A and the remainder have hemophilia B.
It is estimated that most patients on prophylaxis, which is begun in the first few years of life, will easily exceed the common life-time insurance cap of $1,000,000 by the second decade of life. The treatment decisions are not easy.
One course of therapy used in the treatment of hemophilia is protein replacement, which is generally blood-derived.
In the past 10 to 15 years, advances in screening of blood donors, laboratory testing of donated blood and techniques to inactivate viruses in blood and blood products have remarkably increased the safety of blood products used to treat hemophilia.
Although treatment-related infection with the AIDS virus or most of the hepatitis viruses is a thing of the past, these measures do not completely avoid viruses such as hepatitis A and parvo virus.
These infections are rare; nevertheless, they can pose a threat. Researchers are working to improve procedures to destroy these viruses.
To ensure absolute safety from transfusion-transmitted viruses and other agents, hemophiliacs may now be treated with factor VIII which has been produced through biotechnology.
This product, recombinant factor VIII, considered a "non-viral" treatment, is manufactured by a process entirely free of blood products. Thus, it contains only the factor VIII necessary to treat the disease and none of the other components of blood or attendant unwanted agents.
Although the cost of this product exceeds that of the blood-derived product, it is clearly the treatment of choice for those, such as newborns, who have not yet been exposed to blood products.
A factor IX product has also been produced by such a process and is currently in clinical trials.
Another course of therapy available in the treatment of hemophilia is gene therapy, wherein "viral vectors" or "non-viral vectors" serve as the delivery vehicle. Due to safety concerns, Dr. Miao's lab has focused on developing non-viral gene therapy protocols for the treatment of hemophilia.
Currently, patients with severe hemophilia receive frequent, intravenous infusions of manufactured engineered clotting factor.
However, these treatments are expensive and inconvenient, and sometimes stimulate an immune reaction that neutralizes the benefits of treatment. Because a single defective gene causes hemophilia B, gene therapy involves inserting a normal version of the gene, which makes a normal protein — the clotting factor.
It is hoped that gene therapy will lead to patients having fewer bleeding episodes.
Gene therapy might eventually help people with hemophilia begin producing sufficient clotting factor, thereby removing or at least lessening their dependence on weekly infusions.
With this advance, there exists the potential for someone born with severe hemophilia to eventually have significantly milder or no symptoms.
Some gene therapy research trials have been performed in humans with mixed results. The future for gene therapy in hemophilia is continuing albeit at a moderate pace. There are many projects continuing in animal models.
Improved long-term expression of the new genes will require the development of better vectors (the means of delivering the new genes into the cells).
Dr. Miao and colleagues are the first to use non-viral naked DNA delivery to achieve therapeutic levels of factor VIII and factor IX gene expression in a hemophilia A and a hemophilia B mouse model, respectively.
Currently they are investigating safer and more efficient non-viral vectors and delivery methods suitable for clinical applications.
While current treatment has greatly improved the outlook for most hemophiliacs, the development of antibodies (inhibitors) that block the activity of the clotting factors has complicated treatment for some patients.
It is estimated that 25-30% percent of hemophilia A patients and 1-2.5 percent of hemophilia B patients develop such antibodies after exposure to transfused factors.
When inhibitors are present in large amounts, the patient may require very high and expensive quantities of alternative bypassing agents to stem bleeding, which, in some instances, may not even be effective.
The goal of Dr. Miao's study supported by the new grant is to develop strategies to reduce or eliminate these inhibitory antibodies in hemophilia A patients following the repeated factor VIII infusion or gene therapy using mice as models.
"Because it is a single-gene deficiency and the disease is well characterized, hemophilia has long been used as a gene therapy model system," says Dr. Miao. She adds, "This animal model is also an ideal system for developing strategies to ameliorate the immune responses against FVIII."
Approximately 25-30% of hemophilic patients develop anti-FVIII antibodies after repeated infusion of recombinant or pooled FVIII protein.
Following successful transfer of the FVIII gene into the livers of hemophilia A mice, Dr. Miao's team "observed a robust immune response against FVIII within two weeks post-treatment."
The aims of this study are, at once, extensive and exciting.
Of course, Dr. Miao's hope for the long term is that the contributions of her research in this field will have a positive impact on the ability to effectively treat patients with immunological challenges who face this disorder.
At the present time, there are sufficient indications that gene therapy will ultimately be this cure.
The technology for gene therapy is not as simple as was first thought. Yet because of its special characteristics, hemophilia may likely be among the first genetic diseases to be successfully treated.