New technology shows potential to improve potency and durability benefits in gene therapy

WATERTOWN, Mass. - Gene therapy has traditionally been conceptualized as a one-time, curative treatment option; however, research shows that there may be a need for subsequent doses years after initial treatment. While adeno-associated viral (AAV) vectors are a core part of this powerful therapeutic approach, they present two key challenges in gene therapy.

The first challenge is their immunogenicity. In gene therapy, the formation of neutralizing antibodies (Nabs) in response to AAV vector administration precludes retreatment of a patient due to the potentially dangerous immune response that would occur after a second or third administration of the therapy.

The second obstacle relates to their durability. AAV vectors are non-replicating, so transgene expression is expected to wane over time, especially in children expected to grow, most likely necessitating redosing. As many gene therapies in development are being investigated for the treatment of rare, often lethal, pediatric disorders, the durability of these therapies is of particular concern.

Researchers led by Takashi K. Kishimoto, Ph.D., showed 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 "Enhancement of liver-directed transgene expression at initial and repeat doses of AAV vectors admixed with ImmTOR nanoparticles," researchers demonstrate that the addition of ImmTOR nanoparticles to AAV vectors has the potential enhance the efficacy, safety and durability of gene therapies by mediating more efficient transgene expression at the first dose and by enabling vector redosing by preventing the formation of capsid-specific 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 repeat administration of the same AAV vector expressing secreted embryonic alkaline phosphatase (SEAP), a widely used reporter gene transgene, in immunologically naïve mice. Co-administration of ImmTOR and AAV8-SEAP showed a beneficial effect on transgene expression after the first dose and reached levels approximately two-to-three-fold higher than that observed in mice treated with the AAV vector alone. The first dose benefit was immediate, dose dependent and not mouse strain or capsid specific.

The study also investigated the extent to which the addition of ImmTOR nanoparticles to AAV vectors, known as admixing, has on expression and its potential mechanism. Admixing of ImmTOR and AAV showed even higher levels of vector genome copies in the liver and mRNA and protein expression of the transgene SEAP, compared to sequential administration of AAV-SEAP and ImmTOR or dosing with AAV-SEAP alone in mice. The cumulative benefit of enhancing first dose transgene expression and enabling repeat dosing can provide up to a four-fold increase in transgene expression compared to gene therapy with AAV vector alone.

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