The new technology shows the potential for improving the efficacy and durability of gene therapy

Watertown, Massachusetts – Gene therapy has traditionally been envisioned as a one-time treatment option; However, research shows that up to two years may be required after the initial treatment. While adenoviral vectors (AAV) are an essential part of this robust therapeutic approach, they represent two major challenges in gene therapy.

The first challenge is deducing it. In gene therapy, the formation of neutralizing antibodies (Nabs) in response to the administration of the AAV vector precludes re-treatment of the patient due to the dangerous immune response that may occur after the second or third treatment is given.

The second obstacle is its durability. AAV vectors are not reproducible, so gene expression would be expected to diminish over time, particularly in expectant children, which would likely necessitate reduction. As many gene therapies are being investigated in development to treat rare and often fatal childhood disorders, the durability of these treatments is of particular concern.

Researchers led by Takashi Kishimoto, PhD, have demonstrated the benefits of an immune tolerance platform called ImmTORTM to overcome these challenges and ultimately unleash the potential of gene therapy. In the Science Advances paper titled “Enhancing liver-directed gene expression at initial and repeated doses of AAV vectors mixed with ImmTOR nanoparticles”, the researchers demonstrate that adding ImmTOR nanoparticles to AAV vectors has the potential to enhance the efficacy, safety, and robustness of gene therapies by mediating more gene expression Efficient at first dose and by enabling vector reduction by inhibiting capsid-specific antibody formation.

ImmTOR combines nanoparticle technology with an approved anti-inflammatory and immunomodulatory drug, rapamycin, or tolerable adjuvant, to generate immune tolerance to a specific antigen. In the study, researchers evaluated the effects of ImmTOR on repeated administration of the same AAV vector expressing secretion of fetal alkaline phosphatase (SEAP), a widely used transgenic reporter gene, in immunocompromised mice. Co-administration of ImmTOR and AAV8-SEAP showed a beneficial effect on transgenic expression after the first dose and reached levels approximately two to three times higher than those observed in mice treated with AAV vector alone. The first benefit of the dose was immediate, dose dependent and not straining the mice or the special capsid.

The study also investigated the extent to which the addition of ImmTOR nanoparticles to AAV vectors, known as mixing, affected expression and its potential mechanism. Mixing of ImmTOR and AAV showed higher levels of transcriptome of the liver transporter genome, mRNA, and protein expression of the SEAP transgenes, compared to the sequential administration of AAV-SEAP and ImmTOR or dosing with AAV-SEAP alone in mice. The cumulative benefit of enhancing gene expression for the first dose and enabling repeated doses could provide up to a fourfold increase in gene expression compared to gene therapy with the AAV vector alone.


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