Future Prospect

Tremendous progress has been made to reduce the exposure of hemophilia patients to transfusion-transmitted disease through making the blood supply safer. However, concern remains for hemophiliacs still dependent on blood products and the threat of agents which may contaminate the blood supply. It is also known from international studies that crippling joint involvement can be avoided through periodic and regular transfusion.

The expense, danger of indwelling catheters, and inconvenience of the treatment regimen are all negative factors. All of these issues will become less important, even irrelevant, if the disease can be cured. 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 will likely be among the first genetic diseases to be successfully treated.


Many reputable scientists claimed early success in treating with unusual substances. A report in The Lancet in 1936 extolled the virtues of a bromide extract of egg white. As recently as 1966, a report in the esteemed scientific journal Nature claimed that peanut flour was also effective for the treatment of hemophilia.

The first hint of success came with the report from R.G. Macfarlane in 1934 that snake venoms could accelerate the clotting of hemophilic blood, and he reported success in controlling superficial bleeds in PWH after topical application. Blood transfusion However, the major advances came from developments in the field of blood transfusion. A report from a surgeon, Samuel Lane, in The Lancet in 1840 described the control of post-operative bleeding with fresh blood in a boy with severe hemophilia. However, a lack of understanding of blood groups and basic transfusion methods hindered further development at the time.

The identification of factor VIII and the development of specific assays then permitted the subsequent development of therapeutic materials. Plasma concentrates In the early 1950s, plasma from animals was used for treatment. While often effective, allergic reactions to these porcine and bovine materials were frequent and often severe.

The work of Dr. Edwin Cohn in developing fractionation of plasma with variation of temperature and concentrations of saline and alcohol led to the development of fairly crude plasma concentrates of human factor VIII in a number of centres (“AHG” or “antihemophilic globulin”).

A truly major advance was the discovery by Dr. Judith Pool in 1965 that slow thawing of plasma to around 4 oC led to the appearance of a brown sediment which was rich in factor VIII, which she called cryoprecipitate. Within a decade, lyophilized coagulation factor concentrates made an appearance. These offered considerable advantages: they could be stored in a domestic refrigerator at 4 oC, and permitted the administration of a large and assayed quantity of coagulation factor rapidly and in a small volume.

The availability of such products facilitated home treatment, allowing patients for the first time to treat themselves at home, work, school, or even whilst on holiday abroad — freeing them from the physical and psychological shackles of hemophilia. However, we now recognise that this introduced the potential for the transmission of viruses.

Impact of HIV

The impact of HIV was particularly devastating, with large numbers of patients around the world being infected in the period 1979-1985. The hepatitis C virus (HCV) was first identified in 1989, and it soon became clear that an even higher proportion of PWH had been exposed to this virus, which results in chronic liver disease. Fortunately, the introduction of physical treatments of concentrates such as exposure to heat or the addition of a solvent-detergent mixture has effectively eliminated the risk of the transmission of these viruses.

Another landmark was the recognition by Prof. Pier Mannucci in 1977 that Desmopressin (DDAVP) could boost levels of both factor VIII and von Willebrand factor, and this remains a useful option in mild forms of these conditions. Recombinant products and gene therapy The structure of the factor VIII gene was characterised and cloned in 1984. This led to the availability of recombinant (genetically engineered) factor VIII a decade later. The availability of safe products has stimulated the growth of prophylactic treatment, although it must be emphasized that the concept is certainly not new and was developed by Prof. Inga Marie Nilsson in Sweden in the 1950s.The rate of progress continues apace, and gene therapy is a realistic goal.

Gene Therapy for Hemophilia

The often life-long reliance of patients with hemophilia or other bleeding disorders on replacement products will always be fraught with problems. Life-threatening bleeds and progressive joint destruction continue to be problems. Product availability and cost, as well as disruption of the lives of patients and their families due to a serious chronic, genetic disease, are additional concerns.

If seriously ill patients could, themselves, produce only one percent of normal factor levels, their illness could be transformed to a milder form of the disease. Thus, transfer of a corrected gene to a patient, so that the patient’s own body could produce the factor, potentially constitutes a cure. For a number of reasons, hemophilia is an ideal disease to target as the first to be cured by gene therapy.

Low levels of factor production would alleviate the most severe symptoms and almost entirely eliminate dependence on replacement products. Factor VIII and IX production following gene therapy need not be tightly regulated, because the precise amount produced is not as critical an issue as in other disorders. However, there is concern that a substantial overproduction of factor following gene therapy may introduce risk of venous thromboembolism due to increased clotting. Moreover, effectiveness of the corrected gene product is not dependent on other gene products as is the case, for example, with hemoglobinopathies.

International Workshop on Gene Therapy for Hemophilia

Current Research Recommendations from a March 1992 International Workshop on Gene Therapy for Hemophilia urged the NHLBI to proceed rapidly to develop gene therapy for hemophilia, not only because of the relative genetic simplicity of the disease but also because it could serve as a model system for other gene therapy efforts. The workshop led to a 1994 RFA on Gene Therapy for Hemophilia A and B that supported research on many viral and non-viral gene delivery systems and different target cells for gene expression.

Study findings have contributed significantly to our understanding of events that regulate hemophilia gene expression. Approaches — including use of lentiviruses, retroviruses, adenoviruses, adeno-associated viruses (AAV), and non-viral means of gene transfection — are being developed to repair endogenous factor VIII and IX genes or to introduce new ones into cells, and to stimulate expression of sufficient functional protein.

Hemophilic mouse and dog models, developed and maintained with NHLBI grant support, have shown that the vectors used to insert functional genes for factors VIII and IX often elicit an immune response themselves. Thus, not only do researchers need to develop an efficient system for transferring genes to patients, but they must also be certain that the patient does not produce antibodies to either the vector or the new gene product.

Related NHLBI activities have included co-sponsorship of the Hemophilia 1996

Research for a Cure Workshop organized by the National Hemophilia Foundation and the International Symposium on Gene Therapy for Hemophilia organized by the University of North Carolina at Chapel Hill. The Institute also sponsors an annual RFA grantees’ meeting to foster scientific collaboration. The NHGRI has an active intramural hemophilia research unit that focuses on development of gene therapy for hemophilia A and B.

Gene therapy initiatives include establishment of a CRADA (Cooperative Research and Development Agreement) to develop AAV vector-mediated gene transfer technology as a potential treatment for both factor VIII and factor IX deficiency. Plans are in place to investigate lentiviral vector systems as a new gene transfer system in preclinical studies. Lentiviral vectors offer significant advantages over existing retroviral vectors.

Oral delivery to the intestinal epithelium of vectors containing functional factor VIII and IX genes is also being explored. Several NHGRI laboratories are developing whole new classes of gene transfer vectors including human artificial chromosomes, modified adenoviral vectors, and viral-based gene transfer vectors, including chimeric viral vectors. Some of these new approaches may be applicable to hemophilia gene therapy.

In addition to research directed specifically to hemophilia, the NIH supports a number of related activities that have significant potential application for hemophilia gene therapy. For example, the NHLBI program on Gene Transfer Principles for Heart, Lung and Blood Diseases, established in 1997, is fostering research in gene transfer technology and somatic gene transfer. The NHLBI also provides support for the National Gene Vector Laboratories that help qualified investigators develop and produce clinical-grade gene vectors for human gene therapy trials.

Plans are under way to expand their scope to include preclinical toxicity testing as well. In addition, under the leadership of the NIH Office of Rare Diseases, several NIH institutes and the FDA are cooperating to identify special needs in the development of gene therapeutics for treatment of rare monogenic diseases. Future Plans The need for targeted support of preclinical and clinical studies of specific hemophilia gene therapy approaches is being evaluated to determine how best to move gene therapy to clinical use. Interest is high not only in providing a cure for hemophilia but also in applying the successful technology to other more complex diseases. Thus, hemophilia gene therapy will continue to be a high priority research area for the NIH. NHGRI scientists plan to enter into a CRADA to further develop and apply a new experimental strategy to correct mutations in genomic DNA in order to repair point mutations in hemophilia B.

In order to determine the efficacy of any gene therapy strategies prior to clinical testing, it will be important to evaluate them in animals that closely resemble humans. The NHLBI extramural program and NHGRI intramural scientists will continue to support substantial research to develop safe, effective gene therapy for hemophilia A and B. The variety of approaches under study increases the likelihood that some of them will be applicable to gene therapy in humans.

A second-generation version of the NHLBI RFA on gene therapy for hemophilia is being planned, that will focus on facilitating the transition from pre-clinical testing to testing in humans. National Gene Vector Laboratory support will continue to be used to produce clinical-grade gene vectors for human gene therapy trials.