On this episode of Molecular Moments, Lynn Kamen, Ph.D., and Michelle Miller, Ph.D. DABT discuss their very different journeys to
A number of delivery systems can be used for gene therapy, in the form of either viral or non-viral vectors. Each approach presents unique advantages and challenges, and work is continually being done to improve the safety and efficacy of gene carrier formulations.
Oftentimes this results in modification of the gene therapy delivery vehicle or in the development of a novel approach to gene transfer, and the immunogenic profile of these new delivery systems must be carefully assessed.
Bringing together extensive immunogenicity testing expertise with real-world experience working with a vast range of gene therapy vectors, BioAgilytix has the skill and track record required to effectively evaluate innate, cell-mediated, and humoral adaptive immunity in the context of your unique gene delivery vehicle.
The success of a gene therapy depends largely on the efficiency of the vector – the method by which the genetic material is delivered into a patient’s cell – to transfect (in the case of a non-viral method) or transduce (when using a viral vector) the cell. Viral vectors such as adenovirus, adeno-associated virus (AAV), retrovirus, and lentivirus are typically more efficient at transferring DNA than non-viral vectors, but they are more immunogenic.
In the quest to create safer and more efficient vectors, scientists are attempting to combine the best features of different viruses into hybrid vectors, such as pairing AAV, which has demonstrated an excellent safety profile to date but can trigger the formation of neutralizing antibodies (NAbs) that can impair therapeutic efficiency, with the large cloning capacity of adenovirus.
Because of their non-toxic and non-infectious properties, non-viral vectors have also come more into focus to improve the safety of gene transfer. However, non-viral vectors have traditionally been limited by low gene transfer efficiency. That is why new non-viral vectors are also being developed to improve gene transferring efficiency while maintaining a strong safety profile. Such approaches include lipid nanoparticles (LNPs), dendrimers, and physical means like electroporation and microinjection.
All in cases, the immunogenicity impact of these modified or novel vehicles must be fully assessed to ensure new transfer benefits to do compromise the safety of the overall gene therapy.
In this case study, we discuss how the BioAgilytix team developed a cell-based assay to measure the presence of antibodies against the AAV9 serotype—a strain of AAV known to transduce most cell lines poorly—in patients for its gene therapy candidate in a clinical trial.
Multicomponent drug modalities like those used for gene therapies are complex, and each part of the compound can trigger a distinct immune response. The vector is one such component and BioAgilytix is experienced in evaluating innate and adaptive immunity in the context of many different gene transfer vehicles – even those that are modified or novel.
We are aware that a “one-size-fits-all” approach is not always applicable to these types of studies, and so we will tailor our approach specifically to the vector and immune response being evaluated. For example, when assessing cell-mediated immune responses, we may assess cytokine secretion or use immunophenotyping to detect differences in immune cell population ratios before and after administration of the compound. When assessing antibody-mediated immune responses, we typically employ a tier-based approach to include a screening assay, confirmatory assay, titration, and then characterization of neutralizing activity, isotyping, and epitope mapping – but may propose an alternative strategy depending on the prevalence of pre-existing antibodies against the gene therapeutic. In all cases, we will work on the basis of the specifics of your individual program to determine the best approach to meet your scientific and regulatory requirements. We also consider the nature of the vector alongside the nature of the therapeutic protein, the nature of the transgene, and the route of administration in order to gain a comprehensive understanding of the gene therapy’s overall immunogenic profile.
Learn more about the emerging class of cell therapies engineered via “ex vivo” gene therapy, how these cell-based gene therapies work, and how they lend themselves to a host of translatable techniques for future therapeutic candidates.
Gained from supporting more than 20 gene therapy development programs across a range of disease states, BioAgilytix’s team is deeply experienced in a range of delivery vehicles used for gene transfer, including viral vectors such as adenovirus, adeno-associated virus, retrovirus, gamma-retrovirus, lentivirus, alphavirus, and herpesvirus, and non-viral vectors including lipid nanoparticles (LNPs) and other nano-platforms.
We leverage this knowledge to assess your modified, hybrid, and novel vehicles with expert-level skill, evaluating their distinct unwanted immune responses and helping to develop strategies to circumvent those issues when possible. Whether working with our USA or European labs, you’ll have the support of seasoned scientists committed to helping you deliver safe and effective gene therapies to patients.