WATERTOWN, Mass. – Gene therapy was traditionally thought of as a one-time, therapeutic treatment option; however, research indicates that later doses may be required years after the initial treatment. Although adeno-associated viral vectors (AAV) are key components of this powerful therapeutic approach, they present two major challenges in gene therapy.
The first challenge is their immunogenicity. In gene therapy, the formation of neutralizing antibodies (Nabs) in response to vector administration of AAV prevents the withdrawal of patients due to the potentially dangerous immune response after the second or third administration of the medicine.
The second obstacle is related to their survival. The AAV vectors do not reproduce, so transgene sensitivity is expected to decline over time, especially in children who are expected to develop, and are likely to need to be reproduced. As many gene therapies in development are being studied for the treatment of rare, often fatal, pediatric disorders, the concerns of these therapies are of particular concern.
Researchers led by Takashi K. Kishimoto, Ph.D., demonstrated the benefits of an immune tolerance platform called ImmTORTM to overcome these challenges and ultimately unlock the potential of gene therapy. In a Science Advances paper titled “Enlargement of liver-induced transgene expression at initial and repeated doses of AAV vectors attached to ImmTOR nanoparticles,” researchers demonstrate the potential of ImmTOR nanoparticles to AAV vectors contribute to the efficacy, safety, and stability of gene therapies by mediating more efficient transgene expression at the first dose and by enabling vector replication by inhibiting the formation of specific capsid antibodies.
ImmTOR combines nanoparticle technology with an approved anti-inflammatory and immunomodulatory drug, rapamycin, or the tolerogenic adjuvant, to generate antigen-specific immune tolerance. In the study, researchers evaluated the effects of ImmTOR on re-administration of the same AAV vector expression secretory alkaline phosphatase (SEAP), a widely used reporter generator, in immune naïve mice. Co-administration of ImmTOR and AAV8-SEAP showed a beneficial effect on transgene sensitivity after the first dose and reached approximately two-to-three times higher levels than that observed in mice treated with the AAV vector by itself. The first benefit was an immediate dose, dose-dependent and not mouse weight or specific capsule.
The study also examined the extent to which implantation of ImmTOR nanoparticles to AAV vectors, known as admixing, is sensory and the potential mechanism. Admixing of ImmTOR and AAV showed even higher levels of vector genome replication in the liver and mRNA and protein expression of the SEAP transgene, compared with series administration of AAV-SEAP and ImmTOR or dosing with AAV-SEAP alone in mice . The cumulative benefit of increasing first-dose transgene expression and enabling repeated dosing can be up to a fourfold increase in transgene expression compared with gene therapy with vector AAV alone.
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