Spring 2000 - Factor Nine News

 

FACTOR NINE NEWS

From The Coalition for Hemophilia B

Spring 2000

 

Are More Highly Purified Clotting Factor Concentrates Better for Patient Health?

 

In the last issue we mentioned that we have received a number of requests for information on whether more highly purified clotting factor is better for patients, especially patients with hepatitis C or HIV.  Scientifically, this is still an open question although a number of studies have tried to answer it.  Informally, many hemophiliacs will tell you that they feel better on more purified concentrates.  In a 1998 review article, K. Hoots and D. Canty, from the Gulf State Hemophilia Center and New York University, respectively, looked at all of the studies that had been done so far.  They focused mainly on Factor VIII and hemophilia A since very few studies have been done on Factor IX.  Many of the studies, often done on patients with HIV, have shown that parameters associated with good immune system function are decreased in patients using lower purity clotting factors.  These studies all provide evidence that more purified concentrates are better, but no studies have been done to show whether lower purity clotting factor has a negative effect on long-term patient health, the real bottom line.

 

For Factor IX the question concerning immune function is similarly unresolved.  However, lower purity Factor IX concentrates carry another risk that is better understood.  Lower purity Factor IX concentrates contain significant amounts of other clotting factors.  Although the actual cause is still uncertain, it is well known that the presence of these other clotting factors causes a tendency for thrombosis, unwanted blood clots within the blood stream.  This is especially true for patients who use large amounts of factor in a short period of time.  For instance, before more purified concentrates became available in the late ‘80’s, surgery on hemophilia B patients was done only for the most serious conditions because the large amounts of clotting factor needed to control bleeding often produced serious, sometimes fatal, thrombotic complications.  The highly purified concentrates available today appear to have eliminated this problem, and are usually recommended for everyday use as well.

 

Based on these studies, the use of more purified clotting factor concentrates is usually recommended as the lowest risk path.  However, because of the much higher cost of the more purified products, this presents many patients with a dilemma.  Until high purity factor becomes affordable for everyone, our advice is for each patient to work with his physician to determine the best course of treatment for his individual situation.

 

Chimerplasty: a new approach to treatment of genetic disorders

 

At a recent meeting of The American Society of Hematology held in New Orleans this past December, Dr. Michael Blease, Chief Scientific Officer of Kimeragen, Inc. in Newtown, PA gave a speech at our breakfast meeting to discuss Chimeraplasty.  We are happy to share with your Dr. Bleases’ speech:   

 

Genes are the blueprints of life, containing the set of instructions directing the structure and function of all living things.  These instructions are encoded in a long linear strand of DNA which itself is made up of a precise sequence of four similar but distinct components called nucleotides or bases.  The order of these four bases (A,T,G & C) spells out the instruction (or gene) just as the order of letters spell a word.  If we change the spelling we can completely change the meaning of the word or genetic instruction.  Inherited or genetic diseases like Hemophilia B are the result of a misspelling (mutation) in a specific gene like the one for Factor IX.

 

Ever since the genetic code was broken by research during the 1950’s & 60’s, physicians have dreamed of somehow using the instructions encoded in the genes to help treat their patients.  Developing a practical way to correct the spelling of the mutant gene, the “ideal” treatment, proved to be very, very difficult so an alternative strategy was tried.  This involved taking a correctly spelled copy of the gene and trying to insert it into the patient’s cells as a substitute set of instructions (called addition gene therapy).  To assist this process, the correctly spelled gene was often engineered into a virus so that it could be more efficiently delivered to the patient’s cells using the infection mechanism of the virus.  This viral-mediated gene delivery system was first used as a therapeutic in 1990 for two young girls with an otherwise fatal genetic immune system failure.  This treatment involved collecting immune cells from their blood, using a modified virus to deliver the gene to those cells in the lab and then giving these genetically corrected cells back to the girls just like giving a blood transfusion.  I was privileged to be those children’s doctor during that first use of gene therapy and it is thrilling to see them continuing to do so well a decade after we first began treating human disease with genes.

 

Unfortunately, a piece of a patient’s liver cannot be as easily removed and taken to the lab for correction, so that “addition” gene therapy for hemophilia needed a more complex treatment scheme.  Some labs are trying to perfect a “liver-seeking” virus that can be given intravenously (IV) to deliver the correctly spelled Factor IX gene to the liver through the blood stream.  Another approach is to use injections of a Factor IX gene-modified virus to instruct other tissues, such as bone marrow cells or muscle, to produce Factor IX rather than correcting the liver, the normal site of Factor IX production.  A clinical trial testing this later idea is now underway for Hemophilia B. 

 

A decade after virus-mediated gene therapy was first tried, a new technology that is able to repair misspelled genes is nearing clinical trials.  This process, called chimeraplasty, uses a synthetic molecule with both DNA and RNA components (a chimeraplast) that is able to use the cell’s own DNA repair machinery to correct the spelling of a mutant gene within a patient’s cell.  This process does not use viruses for delivery and the chimeraplast molecule is small enough to spread throughout the body more readily than the larger DNA piece needed to carrying an entire gene.  Further, the gene repair process triggered by chimeraplasty seems to be universal because this process works in organisms as diverse as bacteria, yeast, plants, insects, as well as in rodent, dog and human cells.

 

Chimeraplasty has been used in several different animal models of human disease.  In one, Gunn Rats that carry a gene defect in their liver that results in extreme jaundice and ultimately death were given an IV injection of a chimeraplast designed to correct the mutated gene in their liver.  This treatment resulted in genetic correction of a large number of the liver cells (hepatocytes) and marked fall in the degree of jaundice.  When animals were given additional treatment injections, further improvement was seen.  This study clearly showed that genetic disorders affecting liver cells could potentially be treated by a simple intravenous injection of this unique molecule.  In a different study, mice with the genetic defect that causes muscular dystrophy were given an intramuscular injection of a chimeraplast designed to correct the misspelled muscle gene. Six weeks later biopsy of these injected muscles showed correction of the genetic defect. Finally, in a study with direct relevance to Hemophilia B, normal rats were given IV injections of a chimeraplast designed to introduce a change or mutation in the Factor IX gene.  Since there are no rats with a natural genetic defect in the Factor IX gene, this “reverse” experiment was done to prove that intravenous chimeraplasty treatment could change this gene and thus indicate that it could potentially be used as treatment to correct those misspellings in the Factor IX gene that lead to hemophilia B.  Amazingly up to 40% of the hepatocytes contained the mutant Factor IX gene after chimeraplast treatment and this change was stable for over one year.  Even the blood Factor IX levels of these rats fell by about 40% indicating that the genetic change resulted in a direct effect on clotting factor levels in the blood.

 

This chimeraplasty treatment is distinctly different from any other approach to the treatment of clotting factor disorders.  We hope to show that it will provide permanent correction of the genetic defect in Factor IX production in the liver of patients following a simple intravenous administration.  The gene repair process used by chimeraplasty is most efficient when correcting a simple genetic defect involving misspelling of a single base, so initially those relatively more rare Hemophilia B patients who have more complex genetic mutations including large gene deletions or insertions will not be candidates to receive this therapy.  As the initial step in the process of developing this treatment for a wide range of diseases including Hemophilia, Kimeragen plans to first treat a very rare and fatal disease of the liver called Crigler-Najjar syndrome.  This is the human equivalent of the genetic defect found in the Gunn rat, a defect that we already know we can successfully treat.  The pathway to development of this treatment will involve scale-up in manufacturing to produce sufficient quantities of very high quality chimeraplasts, the formulation of those compounds in a delivery system that is safe and effective for use in man, and finally exhaustive pharmacology and toxicology testing to prove to ourselves and FDA regulators that we are now ready to test this exciting treatment in patients.

 

As someone who has been involved from the beginning in the quest to unlock the therapeutic potential found in our genes, progress during the past decade has been exciting and at the same time disappointing.  In the beginning we did not appreciate just how difficult it would be to develop effective treatments for so many diseases that desperately need help. The successes for gene therapy during this decade have been relatively few, but on those clinic days when I see a healthy child who would have otherwise died from her immune system failure or a man still cancer-free 7 years after receiving gene therapy for a recurrent brain tumor, I can’t help but feel some satisfaction that our work has actually had a positive impact on a few people’s lives and renewed excitement at the prospects for better outcomes in the future.  Finally we see that new technologies are being developed to address some of the hurdles that have hindered progress in the past.  I believe that chimeraplasty is one of those new technologies with the potential to help revolutionize medicine in this new millennium.

 

Avigen, Inc. Trials  – an update:

 

In the Summer 1999 issue we spoke of gene therapy trials currently underway.  Phase 1 trials usually collect data on dosage, timing and safety – but not efficacy.  The trials typically involve the gradual escalation of dosage to determine the maximum tolerable level.  Data is also collected on how a drug is absorbed, metabolized and distributed through the body    As reported in Nature Genetics March edition, Dr. Katherine High and colleagues, the authors of the present study, injected adeno-associated vector carrying the gene encoding factor IX into the skeletal muscles of three patients, with severe hemophilia B.  As the first participants in a trial of dose escalation design, the three patients received the lowest dose of the vector.  On the basis of preclinical data from animal models, this dose was not expected to increase the levels of circulating factor IX.  In two of the patients, however, there was evidence of a modest clinical response as measured by a 50% to 80% reduction of episodes of a factor infusion and by changes (although small) in levels of circulating factor IX.  A third patient, who has the least severe phenotype, showed no measurable differences after injection. 

 

Aventis Behring (Formerly known as Centeon)

 

On March 16, the FDA heard testimony from Aventis Behring about one of the latest achievements to help ensure blood safety.  As the only company in the United States to screen plasma for the five of the most feared viruses in the country (HIV, HAV, HBC, HCV and Parvovirus B19), Aventis Behring was asked to present data about their use of investigational PCR (polymerase chain reaction) screening.  PCR may be able to detect viruses earlier than traditional screening methods, which test for response to virus as opposed to the actual presence of virus. PCR, a form of Nucleic Acid Testing (NAT), is designed to detect very low levels of viruses by testing for the presence of viral DNA and RNA.

 

To answer questions of safety, Aventis Behring has launched the largest educational initiative ever conducted about plasma quality and safety.  To learn more about purification and production processes visit their web site at www.AventisBehring.com/na, or call 800 633-1288.

 

L.I.G.H.T (Leadership Institute for Global Hemophilia Training)

 

L.I.G.H.T. (Leadership Institute for Global Hemophilia Training) is a private organization that identifies, motivates, trains and support leaders (grassroots organizations or official national organizations) in developing countries to plan consistently and strategically to improve hemophilia care in their developing country.  L.I.G.H.T. is run by Laurie Kelley, mother of two children with hemophilia and author of many books on hemophilia and popular speaker in the hemophilia community.

 

L.I.G.H.T. works long term to provide leadership training workshops, educational materials, financial assistance for well-defined goals and humanitarian relief. Part of the efforts to give humanitarian relief includes shipment of factor.  All brands and potency are accepted.  We deliver these to hematologists or blood banks, where the factor is tested for potency, and used to save lives and limbs.  In 1999, L.I.G.H.T. shipped over 500,000 units of factor VIII and IX to children who could never afford them. (Most of the donated factor was received from private donations-not companies).  L.I.G.H.T. promotes education and communication through its quarterly publication Hemophilia Leader, and makes on-site visits in various developing countries throughout the year.

   

Starting in 2000 another program called “SOL,” Save One Life, which enables US families to sponsor children with hemophilia overseas.  Families can ship factor or medical ancillaries, or call to volunteer their time.  Organization: Leadership Institute for Global Hemophilia Training,21 Sawmill Way, Georgetown, MA 01833, Tel: (978) 352-7657;  (800) 249-7977  Fax: (978) 352-6254  E-mail: info@kelleycom.com

 

A Farewell Tribute to a Friend of The Hemophilia Community:  SOOZIE COURTER

 

Our thoughts and prayers go out to the family of Soozie Courter.  Soozie passed away suddenly on February 9, of a cerebral aneurysm in Chapel Hill, North Carolina. 

 

Soozie was a clinical research specialist with a 20- year career devoted to hematology and oncology.   Soozie Courter started with Genetics Institute in 1995 as the Clinical Program Director for rFIX (now called BeniFIX).  She led the clinical team to pursuit of licensure of BeneFIX in North America and Europe over a two- year period.  This was the fastest time registration of any product with the FDA.  In the past, Soozie had been with Baxter/Hyland where she was instrumental in the clinical trials of Recombinate (the first Factor VIII made available for hemophilia A).

 

Soozie was always available to answer our concerns and questions.  She had a very personable way about her and you knew that she was a person who had genuine concern for the people.

 

 Soozie Courter, was our friend and dearly loved by many.  We shall miss her, but she remains forever in our hearts  The family of Soozie Courter has asked that all donations be made payable to The National Hemophilia Foundation in memory of Soozie Courter.