Adeno-associated virus (AAV) has become one of the most popular vectors for gene delivery in various in vivo gene therapy applications. Consequently, the gene therapy community is experiencing an exponential increase in the number of clinical trials, most of which are being conducted in the USA.
This is creating an increase in the number of companies specializing in the production of gene therapies for the treatment of genetic disorders. However, a lack of suitable and widespread reference material in gene therapy is just one of the many obstacles facing laboratories and regulatory authorities around the world attempting to find treatments for genetic diseases.
Finding the right dose
AAV-based gene therapies reach from small dose applications to high doses depending on the target organ or tissue. Yet, finding the right dose for a specific gene therapy represents a major question which needs to be answered during the clinical trials.
While the dose of the therapy is supposed to be high enough to allow the best possible treatment, it is important to evaluate the lowest dose possible to avoid severe side effects that might accompany the delivery of the transgene. AAV-based gene therapies are limited to a single application, so choosing the right dose is a critical step.
The dose of AAV gene therapies is usually defined by the copy number of viral genomes per kilogram (vg/kg). However, it is known that quantitative polymerase chain reaction methods (qPCR) show high inter-lab variabilities which makes it substantially difficult to compare the dose of different vectors used in different studies.
The comparability problem could be solved by the availability of suitable standard material for the analytical characterization of AAV gene therapy products. At the moment there is Reference Standard Material (RSM) for the AAV serotypes AAV2 and AAV8, but there is no comparable material for the remaining AAV serotypes. Though each lab has its own internal reference material, the comparability between different labs remains difficult due to the variability of available quantification methods and the lack of RSM.
Besides the contribution of pre-existing conditions, principal issues in transferability of data from animal experiments, as well as comparability of meaningful titers, can pose additional difficulties for the evaluation of the safety of a specific product.
For an deeper divev into the challenges of AAV-Based Gene Therapy read the following article as featured in the European Biopharmaceutical Review.
Hüseyin Besir, Director R&D and Dr. Dana Holzinger, Head of Product Management, discuss in depth the range of challenges faced with AAV-based Gene Therapy.