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Haemophilia B gene therapy using adeno-associated virus
update
news
PSTT Vol. 2, No. 11 November 1999
Haemophilia B gene therapy using adeno-associated virus Anya Hillery, Julio Lopez 5, 2C, Madrid, E-28002, Spain, tel: 134 91 5196847, e-mail: [email protected]
Avigen Inc. (Alameda, CA, USA) has recently received exclusive global rights for the commercialization of Coagulin B™, a new form of haemophilia B gene therapy, using adenoassociated virus (AAV) as a vector. Haemophilia B gene therapy Haemophilia B is caused by a genetic abnormality or deficiency in the blood clotting protein, factor IX. Existing therapy relies on repeated infusions of factor IX, which are expensive, inconvenient for patients and fail to completely prevent bleeding. Fatal intracranial bleeding can occur between infusions, while other types of haemorrhaging can result in joint damage and chronic pain. The rationale behind this gene therapy approach is to use an AAV vector to deliver the missing genetic information to the body’s cells. The cells can subsequently produce the missing clotting factor, thereby treating not only the symptoms, but also ultimately the underlying cause of the disease itself. AAV vector Although many potential viral candidates for use in gene delivery are harmful and/or may trigger immune responses, the aforementioned AAV vector provides three levels of safety enhancement. • The vector is prepared from a non-pathogenic parent: AAV is described as ‘the benevolent virus’ because it has never been linked to illness or disease, even though the majority of the population has been exposed to it. • No viral genes in the vector: in developing a vector system, both viral genes are removed and replaced with the factor IX gene, thereby minimizing immune reactions and health risks. • No viral contaminants are present in the vector preparation: a proprietary process has been developed so that neither helper
428
adenovirus or wild-type AAV is present in the vector product. This vector possesses the capacity to efficiently deliver the therapeutic gene to both dividing and non-dividing cells, high and prolonged expression levels are attainable, and it is sufficiently stable to facilitate manufacture and storage in a similar manner to conventional pharmaceuticals. Genes can also be delivered to many tissue targets, including muscle, the CNS and skin. However, the AAV has not yet been widely pursued as a vector in gene therapy. As explained by Avigen’s President and CEO, John Monaghan, ‘this is partly because the adenovirus has never caused disease in humans, therefore until relatively recently, the virus was virtually unknown. Furthermore, AAV is a replication-defective virus that requires adenoviruses for its own replication. Large-scale production typically uses adenoviruses to initiate AAV replication, which can lead to pathogenic adenovirus contamination. However, a new manufacturing process has been developed which has replaced adenoviruses with a helper plasmid (comprising the five genes in adenovirus required for AAV replication), thereby eliminating adenoviral contamination and minimizing purification issues.’ Successful approach The success of this approach has been demonstrated in a large animal (canine) model of haemophilia. Long-term expression of factor IX at levels that would have a therapeutic effect in humans was reported following a single intramuscular administration of the AAV-mediated gene for factor IX (Ref. 1). Improvements in whole blood-clotting time and thromboplastin time were observed. Utilizing Coagulin-B™, therapeutic levels of factor IX have now been achieved in the animal model almost two years
after the initial treatment, whereas it has not been possible to achieve such sustained and long-term protein expression using other gene therapy systems. Even though factor IX is normally produced in the liver, the sustained protein expression was achieved by the minimally invasive procedure of percutaneous intramuscular injection at a single time point. No local or systemic toxicity was observed and the immune responses against factor IX were either absent or transient. Future prospects Following the success of the preclinical studies, Phase I human clinical trials have recently commenced. These trials are the first to examine the use of gene therapy, and also AAV, in the treatment of haemophilia, and may eventually lead to new therapies for this disease. Such AAV vector technology is also being applied to other genetically-based conditions, and animal studies have already demonstrated efficacy in the treatment of Parkinson’s disease and in erythropoietin gene therapy. Reference 1
Herzog, R.W. et al. (1999) Nat. Med. 5, 56–63
In brief… Peptide Therapeutics Group plc (Cambridge, UK) has extended and amended its collaboration with SmithKline Beecham to research and develop an allergy vaccine. The agreement builds upon the companies’ existing collaboration which has been successful in identifying several alternative epitopes (short peptide sequences) which could form the basis for allergy vaccine candidates. A one-year cofunded research plan is now in place to validate these findings and produce a potential clinical candidate.
1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00206-0
news
PSTT Vol. 2, No. 11 November 1999
Haemophilia B gene therapy using adeno-associated virus Anya Hillery, Julio Lopez 5, 2C, Madrid, E-28002, Spain, tel: 134 91 5196847, e-mail: [email protected]
Avigen Inc. (Alameda, CA, USA) has recently received exclusive global rights for the commercialization of Coagulin B™, a new form of haemophilia B gene therapy, using adenoassociated virus (AAV) as a vector. Haemophilia B gene therapy Haemophilia B is caused by a genetic abnormality or deficiency in the blood clotting protein, factor IX. Existing therapy relies on repeated infusions of factor IX, which are expensive, inconvenient for patients and fail to completely prevent bleeding. Fatal intracranial bleeding can occur between infusions, while other types of haemorrhaging can result in joint damage and chronic pain. The rationale behind this gene therapy approach is to use an AAV vector to deliver the missing genetic information to the body’s cells. The cells can subsequently produce the missing clotting factor, thereby treating not only the symptoms, but also ultimately the underlying cause of the disease itself. AAV vector Although many potential viral candidates for use in gene delivery are harmful and/or may trigger immune responses, the aforementioned AAV vector provides three levels of safety enhancement. • The vector is prepared from a non-pathogenic parent: AAV is described as ‘the benevolent virus’ because it has never been linked to illness or disease, even though the majority of the population has been exposed to it. • No viral genes in the vector: in developing a vector system, both viral genes are removed and replaced with the factor IX gene, thereby minimizing immune reactions and health risks. • No viral contaminants are present in the vector preparation: a proprietary process has been developed so that neither helper
428
adenovirus or wild-type AAV is present in the vector product. This vector possesses the capacity to efficiently deliver the therapeutic gene to both dividing and non-dividing cells, high and prolonged expression levels are attainable, and it is sufficiently stable to facilitate manufacture and storage in a similar manner to conventional pharmaceuticals. Genes can also be delivered to many tissue targets, including muscle, the CNS and skin. However, the AAV has not yet been widely pursued as a vector in gene therapy. As explained by Avigen’s President and CEO, John Monaghan, ‘this is partly because the adenovirus has never caused disease in humans, therefore until relatively recently, the virus was virtually unknown. Furthermore, AAV is a replication-defective virus that requires adenoviruses for its own replication. Large-scale production typically uses adenoviruses to initiate AAV replication, which can lead to pathogenic adenovirus contamination. However, a new manufacturing process has been developed which has replaced adenoviruses with a helper plasmid (comprising the five genes in adenovirus required for AAV replication), thereby eliminating adenoviral contamination and minimizing purification issues.’ Successful approach The success of this approach has been demonstrated in a large animal (canine) model of haemophilia. Long-term expression of factor IX at levels that would have a therapeutic effect in humans was reported following a single intramuscular administration of the AAV-mediated gene for factor IX (Ref. 1). Improvements in whole blood-clotting time and thromboplastin time were observed. Utilizing Coagulin-B™, therapeutic levels of factor IX have now been achieved in the animal model almost two years
after the initial treatment, whereas it has not been possible to achieve such sustained and long-term protein expression using other gene therapy systems. Even though factor IX is normally produced in the liver, the sustained protein expression was achieved by the minimally invasive procedure of percutaneous intramuscular injection at a single time point. No local or systemic toxicity was observed and the immune responses against factor IX were either absent or transient. Future prospects Following the success of the preclinical studies, Phase I human clinical trials have recently commenced. These trials are the first to examine the use of gene therapy, and also AAV, in the treatment of haemophilia, and may eventually lead to new therapies for this disease. Such AAV vector technology is also being applied to other genetically-based conditions, and animal studies have already demonstrated efficacy in the treatment of Parkinson’s disease and in erythropoietin gene therapy. Reference 1
Herzog, R.W. et al. (1999) Nat. Med. 5, 56–63
In brief… Peptide Therapeutics Group plc (Cambridge, UK) has extended and amended its collaboration with SmithKline Beecham to research and develop an allergy vaccine. The agreement builds upon the companies’ existing collaboration which has been successful in identifying several alternative epitopes (short peptide sequences) which could form the basis for allergy vaccine candidates. A one-year cofunded research plan is now in place to validate these findings and produce a potential clinical candidate.
1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00206-0