NEWSROOM

Dr. Faust will present in the symposium entitled Evolution of AAVs for Widespread Gene Delivery to the Central Nervous System. The title of her presentation is The Immune Response to CNS-Directed AAV Gene Therapy

Millions of patients worldwide suffer from diseases and disorders that can be cured with gene therapy: using viruses to introduce new, healthy, genes into the cells of patients.

The challenge lies in the fact that the body views new genes introduced by viruses as potential threats, and the body’s immune system fights off the viruses with the healthy genes.

NxGEN Vector Solutions Transformative Technology solves this problem.

Find out more at our reception.

Open Bar, Hors d’oeuvres, and Catered Buffet
Signature cocktail: “End of the Interferon”

CEO & Founder, Dr. Susan Faust, meets with ASGCT attendees to discuss NxGEN Vector Solutions’ Transformative Technology at the NxGEN Vector Solutions’ Exhibit Booth in 2019.

“The best trade-off one can currently imagine is to engineer rAAV vectors with better transduction efficiency, carrying optimized therapeutic transgenes and with reduced immunogenic profiles (CpG depleted genome, [Faust et al.], inert capsids, contaminant-free batches, minimum amounts of empty capsids, etc.). Such vectors would provide a higher therapeutic index, as they would permit therapeutic efficiency at doses sufficient to bypass pre-existing humoral immunity, but not high enough to trigger deleterious cellular immunity.”
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“It is important to develop suitable strategies to overcome vector directed immune responses. In this regard, CpG-depleted AAV vectors have been shown to evade immune detection [Faust et al.]. In their pioneering studies, Faust et al. initially tested the immunogenicity of AAVrh32.33 in wild type as well as Tlr9 knockout mice. They found that in Tlr9-deficient mice, IFNγ T cell responses toward capsid and transgene antigen were suppressed resulting in minimal cellular infiltrate and stable transgene expression.”
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“Faust et al. hypothesized that a vector genome devoid of CpG motifs would be mostly invisible to TLR9. Sure enough, a vector containing such a stealthy genome packaged into the identical capsid failed to elicit CD8+ T-cell responses to a reporter gene, thus directing long-term expression even in wild-type mice with intact TLR9. The same concept applies to less immunogenic serotypes, where already weak responses can be further reduced. Future studies are likely to adapt this concept to therapeutic gene constructs.”
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“Strategies aimed at minimizing adaptive immunity to AAV vectors or reducing the need for repeat administration continue within the field. Removing CpG motifs from AAV vectors or designing hybrid AAV capsids has been shown to reduce innate and adaptive immune responses following intramuscular delivery [Faust et al.].”
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“In addition to an adaptive immunological reaction to the capsid of AAV, the transgene can elicit both an adaptive and an innate response…Finally, a transgene with a significant number of CpG dinucleotides can activate innate response through toll-like receptor (TLR) molecular pattern receptors [Faust et al., 2013].”
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INNATE IMMUNE RESPONSES TO AAV VECTORS:

“Although both PRRs are part of the same family, recognition of the viral capsid caused induction of a Nuclear Factor kB-dependent inflammatory response (14), while activation of TLR-9 induced secretion of type I interferon (IFN) that was found to be enhanced if vectors with self-complementary (sc) AAV vector genomes were used (15, 16). The nature of this enhanced immunogenicity remains to be clarified, but is maybe related to a negative impact of sc vector genomes on capsid stability (16) or to the additional inverted terminal repeat (ITR) sequence present in sc vector genomes (8). The later hypothesis would be in line with a recent study reporting significantly reduced adaptive immune responses toward the capsid and transgene product when using AAV vectors with a reduced number of CpG motifs, which are known TLR9 PAMP [Faust et al.].”
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