RxPG News : Hemophilia

Hemophilia a silent killer

Mon, 17 Apr 2006 14:07:37 PST

( from http://www.rxpgnews.com ) Even as the country focuses on headline-grabbing diseases, hemophilia, a little known blood disorder, is turning out to be a silent killer with over 50,000 people affected.

World Hemophilia Day is observed every April 17 to promote a global effort to secure appropriate care and treatment for a disease that is the oldest known inherited bleeding disorder caused by a defect in the genes.

"The disease might affect anyone irrespective of social group," said Ditipriya Ghosh, an official with the Hemophilia Federation of India (HFI).

According to Ghosh, nearly 800 to 1,000 people with hemophilia (PWH) are registered with HFI every year.

Hemophilia normally passes on at birth from an affected father to daughter, who then becomes a carrier of the hemophilia gene having every possibility of passing the defective gene on to her children.

"If the children affected with hemophilia are not treated it might lead to disability and possible death. There is also a high risk of life threatening viral infections like HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) as they are required to take frequent transfusions of blood," said Ghosh.

The disease is not curable, but it can be managed with proper knowledge and treatment, Ghosh told the IANS.

"The only way to reduce hemophilia is through awareness and provision of a life saving drug AHF (Anti Hemophilic Factor)," said Ghosh.

"However AHF is not manufactured in India and has to be imported," said Ghosh, "making treatment extremely costly and impossible at times for a middle class Indian family."

Recombinant products are more safe for people with Bleeding Disorders

Tue, 14 Feb 2006 17:03:37 PST

( from http://www.rxpgnews.com ) An international team of scientists, including a hematologist from Thomas Jefferson University in Philadelphia, has concluded that people with bleeding disorders such as hemophilia remain at risk from emerging infectious agents in plasma and blood transfusions. For this reason, recombinant therapies, that is, those produced in the laboratory, must always be an option.

Writing January 21, 2006 in the journal Lancet, hematologist Jamie Siegel, M.D., clinical associate professor of medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, Christopher A Ludlam, professor of haematology and coagulation medicine at the Royal Infirmary, Edinburgh, Scotland, UK, and colleagues say that coagulation-factor concentrates (CFC) from the blood plasma, used for individuals with bleeding disorders, are now deemed safe from most known infectious agents, such as hepatitis B and C viruses and HIV, in contrast to two decades ago. But challenges from new agents mean plasma-derived products will continue to remain at risk.

The authors point out that an alternative recombinant products, which are made by expressing genes for clotting factors in the laboratory tissue culture dish lessen the likelihood of contamination by infectious agents.

There will always be emerging pathogens and we wont always know what they are, says Dr. Siegel, who is director of the Hemophilia Center at Thomas Jefferson University Hospital. We know that these pathogens may be in the blood supply, and if we have a population dependent on plasma derived products, they are always at risk.

She contends that infectious agents called prions, which are behind diseases such as new variant Creutzfeldt-Jakob disease (Mad Cow disease), may be the most worrisome of all because they are difficult to detect. She is concerned about them affecting mostly young children, and their effects decades later. We dont know if we can get rid of prions, she says. Currently, there is no available method to diagnose and deal with them effectively.

The continued debate about the safety of the blood supply and the use of blood-derived versus artificial products for those with bleeding disorders is under the constant threat of emerging infectious agents. Blood-derived products work better in clotting blood, but carry the caveat of potential exposure to infectious agents in the blood supply. Recombinant clotting products made in the laboratory may not be quite as effective, but are virtually risk-free from contamination.

Up until now, decisions on using blood-derived versus recombinant blood products have been left to patients and physicians. Safety studies have not definitively made the case for either.

But Dr. Siegel is concerned. Today, the doctor reviews treatment options with the patient and together they choose the product to be used. According to Dr. Siegel, Pennsylvania is the first state to have challenged the idea that recombinant products are safer than plasma-derived products for blood clotting disorders. In addition, the state has established a preferred drug list, she says, noting that blood-derived products may cost half the price. For now, all hemophilia drugs are listed as preferred drugs, but she is worried about the long term.

It means you could create a two-tiered system and medical assistance patients may get plasma-derived products, and potentially not get as good as care as those with private insurance, Dr. Siegel says. It means they may have limited access to the safest treatments.

Dr. Siegel says that she is more confident in the safety of recombinant products with respect to infectious agents and doesnt want individuals with hemophilia to again be the victims of unsafe blood products as they were in the beginning of the AIDS epidemic in the early 1980s.

Hybrid baculovirus treats hemophilia in mouse models

Tue, 23 Aug 2005 21:12:38 PST

( from http://www.rxpgnews.com ) A virus that typically infects insects could help with the development of gene therapy treatment for Hemophilia A, a condition in which even a bump on the knee can cause serious internal bleeding in people.

Researchers at the University of Iowa Roy J. and Lucille A. Carver College of Medicine improved a vector -- a vehicle that delivers gene therapy to cells -- in two ways to create a sustained, partial correction to bleeding problems in mice engineered to have Hemophilia A, which is also known as factor VIII deficiency. The findings appear in the Sept. 1 issue of the journal Blood (published Aug. 19 online).

The team adapted the outer layer, or "coat," from a baculovirus, a virus that infects butterflies and moths, onto another modified virus. This hybrid vehicle could more easily attach to certain liver cells and allow the genes within the vehicle to enter the cells. The genes then caused the liver cells to make the protein that prevents bleeding.

The researchers also modified the vehicle so that it would express these therapeutic genes only in liver cells, thus reducing the likelihood of negative side effects.

The laboratory findings have significant potential for developing improved treatment for hemophilia but are not yet applicable to people, cautioned Paul McCray, UI professor of pediatrics and the study's corresponding author. "It's an exciting finding, but we are still many steps away from a possible gene therapy for people with hemophilia," he said.

Hemophilia A is the leading sex-linked bleeding disorder, affecting one in 5,000 to 10,000 males. People with the condition have a genetic mutation that leaves them with little to no factor VIII protein to prevent uncontrolled bleeding. Individuals with the severe form of the disease have less than 1 percent of the normal amount of protein. However, only a relatively small amount of the normal protein level is needed to make the problem milder and, thus, less life threatening.

"Hemophilia is considered an ideal candidate for correction with gene therapy because if you could just raise the factor VIII activity from less than 1 percent of normal to within 5 to 10 percent of normal, the tendency for spontaneous bleeding and need for hospitalization would diminish dramatically," McCray said.

"In the mouse model in our study, we were able to achieve levels of gene expression that converted the hemophilia A in the mouse from a severe to a mild form. The correction lasted 30 weeks -- the duration of the study," he added.

One of the current treatments for hemophilia involves intravenously delivering recombinant (genetically engineered) human factor VIII protein to prevent bleeding episodes. However, the weekly to bi-weekly preventive treatments are extremely expensive, costing up to $500,000 per year. In addition, over time some patients may develop antibodies to the protein, making the treatments less effective.

In earlier studies, McCray's team, which includes Yubin Kang, M.D., at the time a UI assistant research scientist in pediatrics (now a UI resident in internal medicine), targeted the liver because its main functional cells, called hepatocytes, can make the factor VIII protein and secrete it into the bloodstream. However, the investigators recognized the need to target the liver more effectively.

"It has been difficult to conclusively identify the cells that normally make factor VIII," McCray said. "Hepatocytes may not be the main source of this protein, but they are relatively easy to target. So we aimed to find a way to get these cells to make more of it. In effect, we're using the hepatocytes as a factory to make this protein and secrete it into the bloodstream."

To better target the hepatocytes in the mice, the team took the disabled protein coat from the baculovirus Autographa californica and put it on to a modified type of lentivirus called feline immunodeficiency virus (FIV). FIV causes leukemia in cats but no disease in humans.

The hybrid vehicle efficiently bound to receptors on the liver cells because the modified baculovirus coat serves as a "key" that fits into the "lock," or receptor. The percentage of liver cells that took up the virus increased from approximately 5 percent to 20 percent.

The team also modified the part of the FIV that expresses the therapeutic gene so that its promoter that causes gene expression worked only when it was in a liver cell.

"Even if this FIV modified virus goes to other organs of the body, it won't express well because its promoter is liver-specific," McCray said. "This modification helps prevent negative side effects. For example, if the gene were expressed in immune cells instead of liver cells, it could lead to a damaging immune response."

McCray said the team now is studying additional ways to make the hybrid vector express the protein even better.

Hope of an alternative treatment option for haemophilia sufferers

Thu, 11 Aug 2005 03:00:38 PST

( from http://www.rxpgnews.com ) Haemophilia is a hereditary blood disease, primarily affecting males, where the blood fails to clot causing potentially life-threatening 'bleeds'. About one in 6000 Australian males is born with haemophilia in severe, moderate or mild form. People with haemophilia rely on intravenous infusion of recombinant Factor VIII clotting protein.

Professor Denisa Wagner and her Harvard colleagues have made ground-breaking discoveries that provide hope of an alternative treatment option for haemophilia sufferers.

Presenting this research, at the XXth Congress of the International Society on Thrombosis & Haemostasis in Sydney today, Wagner said, "We have demonstrated that a protein called P-selectin is important for blood clotting and altering its levels in the bloodstream by infusion appears to have great therapeutic potential."

Infusion of P-selectin could provide an affordable and more effective means of achieving clotting to stop bleeding incidents in haemophiliacs. Because they carry it naturally in their bodies, patients are highly unlikely to make antibodies against P-selectin. P-selectin also has a longer half-life than clotting factors so treatment is likely to be less frequent.

"This promises to be a much easier and more effective approach for sufferers, particularly children," said Wagner.

Wagner went on to report, "Blood clotting is an intricately balanced process. Blood clots in the heart or brain can result in a heart attack or stroke. Our studies in mouse models have shown that inhibition of P-selectin reduces atherosclerosis (hardening of the arteries) and the work of our collaborators shows that the events leading to deep vein thrombosis are reduced. P-selectin inhibitors have also been shown to be anti-thrombotic in early human trials"

Measurement of P-selectin levels in the blood stream may provide a new diagnostic tool to identify people at risk of heart disease and stroke. Levels above baseline could alert clinicians to potentially fatal events. Several pharmaceutical companies are now searching for compounds that target P-selectin.

"This would represent a major breakthrough in diagnosing and treating cardiovascular disease," she said. "There is still a great deal to be learned about this protein. This research could contribute significantly to effective strategies to inhibit or enhance P-selectin depending on clinical need".

Gene therapy to treat haemophilia

Wed, 10 Aug 2005 21:28:38 PST

( from http://www.rxpgnews.com ) Progress in gene therapy to treat haemophilia has been impressive in the past few years. Gene therapy has been used to successfully treat haemophilia in dogs. A leading researcher from Philadelphia USA, Professor Katherine High, is examining the obstacles to successful gene therapy in human patients with haemophilia. She hopes that the problems may be overcome in the next five years to develop a successful gene transfer approach for sufferers of haemophilia.

"It has taken approximately 5 8 years to move from a cure for haemophilia in mice to a cure in dogs. This has been achieved by multiple gene transfer strategies. Clinical studies have identified which aspects of gene transfer therapy in dogs are directly applicable in humans and have identified potential problems, such as mode of delivery, which must be overcome before applying this approach in humans," said High.

Professor High will review these exciting findings and the steps to achieving a successful outcome in humans at the XXth Congress of the International Society on Thrombosis & Haemostasis in Sydney today.