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Hemophilia Gene
Therapy and the Liver
Welcome to Gene Therapy Science / Hemophilia Gene Therapy and the Liver
The liver plays a vital role in human metabolism and detoxification.1 In addition, it is the primary site of blood coagulation Factor VIII and Factor IX synthesis.2 The liver is, therefore, central to understanding and treating hemophilia, and is the main target tissue for adeno-associated virus (AAV)-mediated gene transfer.1
The liver exhibits various characteristics that support its role in gene therapy even beyond hemophilia. For example, the liver has a dual blood supply allowing for the rapid accumulation of vector particles following systemic administration of gene therapy.1
The liver also contains numerous cell types, including immune cells. The interaction of these different cell types with gene therapy vectors is key to understanding the potential of hemophilia gene therapy, as well as the potential barriers to be overcome for transduction.1,3
Refer to the figure below to learn more about the function and anatomy of the liver, including the various cell types that make up its composition and key properties of each.
AAV is the most commonly used vector for hemophilia gene therapy studies.11,12 There are a number of reasons for this, including:13
The immune system can impact gene therapy in several ways through both humoral and cellular immune responses.22–25
In a humoral immune response, the body generates antibodies to an antigen. In the case of gene therapy for hemophilia, this antigen could be components of the AAV-based vector or the transgene. If these antibodies are ‘neutralizing’, they may prevent the vectors from delivering the gene to the target cells.22,23 In a cellular immune response, the transduced cell presents antigens, capsid particles, to circulating T cells, which then eliminate the transduced cell and, as a consequence, reduce the number of cells containing the transgene.24,25 This can result in loss of, or reduced, gene expression, and in turn impacts the level of protein produced.24,25
Pre-existing immunity to naturally occurring AAV can cause both humoral and cellular immune responses, and this may be a barrier to the success of AAV gene transfer.26
However, the liver has numerous unique immunological properties.27 While the liver generally exhibits a strong innate immune response,27,28 this response has been shown to be low towards AAV-based vectors.29 It also demonstrates a poor adaptive immune response, resulting in a state of relative immune unresponsiveness and immune tolerance.29,30 This is demonstrated by the lack of immune response to the large number of antigens present in the blood that flow to the liver directly from the gut.29
This liver tolerance effect, known as being tolerogenic, can be exploited therapeutically by liver-directed gene therapy to induce immune tolerance to the transgene product; i.e. blood coagulation factor.31 Preclinical data from small and large animal models of hemophilia A with inhibitors suggest that liver-directed gene therapy may overcome pre-existing anti-FVIII antibodies, induce immune tolerance and provide sustained therapeutic FVIII expression to prevent bleeding.31
You can explore these topics in more detail, including the specific mechanisms that underly the immune tolerance effect in the liver by clicking here to access the section on Gene Therapy and the Immune System.
Liver-directed gene therapy has the potential for sustained therapeutic benefit for people with hemophilia, although it is not yet clear how long the effects of gene therapy may last.1,13 It is recognized that there is much to be understood about this therapeutic approach and a number of considerations to be taken into account.13
AAVs are naturally occurring and so people with hemophilia may have been naturally exposed to AAVs during their lifetime.13,32 This exposure can result in the development of AAV antibodies, which may limit the effectiveness of gene therapy by preventing the transduction of AAV vectors into target cells.22,23
Transgenes delivered to liver cells via AAV-derived vectors exist as episomes in the nucleus of transduced target cells.22,33 Unlike the adult liver, in which hepatocytes are post-mitotic and long-lived, cell division is rapid during childhood34 with liver weight doubling at 4 months, 16 months, 6 years, and 12 years.22 As a result of this growth from cell division, a dilutive effect of the transgenes may occur due to an unaccompanied concurrent replication of the episomes.35 However, as the rate of hepatocyte proliferation transitions from a high to low rate towards adulthood, current gene therapy strategies may be considered in the adolescent population in the future.35
Hemophilia gene therapy trials to date have excluded patients with active liver conditions, such as current hepatitis C infection.11,31 The safety of gene therapy in people with hemophilia who also have liver conditions is, therefore, currently unknown.36
There are a number of aspects of liver-directed gene therapy for hemophilia that remain unknown. These ‘known unknowns’ include:
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