Dr. Paul Monahan has published a superb scientific article detailing the results of clinical trial NCT01687608 (Shire/Baxalta BAX335 aka Askbio009) for hemophilia B showing that long-term transgene expression was not achieved with AAV vectors having increased CpG content in the coding sequence for the transgene. Dr. Monahan concludes that BAX335 did not provide long-term expression of the FIX transgene in the clinical trial “due to the innate immune stimulatory effect of CpG motifs enriched within their vector cassette.” Through clinical data analysis, murine studies, and a retrospective on the field at the time of the launch of the BAX35 clinical trial, Dr. Monahan elegantly provides insights into the mechanism whereby CpG motifs result in transient transgene expression despite steroid administration in patients, with implications on the future design of AAV vectors.
A recent publication in Molecular Therapy detailed the data from eight gene therapy clinical trials, including variables such as the AAV serotype employed, the CpG dinucleotide content in the open reading frame of the therapeutic gene, the vector production method, the vector dosage and estimated total capsid dose, the immunosuppressive drugs administered, the correlation of AAV gene transfer with a cytotoxic T lymphocyte response (CTL) response, the outcome peak of the therapeutic transgene, and the durability of the transgene. The power of this clinical trial information is that it is the single largest AAV vector clinical data set for a single disease AAV gene therapy for hemophilia B—and allowed researchers to gain a clear insight into the key determinant for clinical success. Among the variables, CpG content was revealed to be the only factor that correlates well with clinical outcome and long-term transgene expression, with unmethylated CpG content in AAV vectors being the key attribute that triggers transgene expression-limiting immune responses in humans.
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NxGEN Vector Solutions merged last month with ImmunoCurex, a gene therapy company focused on generating programmed death ligand 1 (PD-L1) polypeptides for AAV gene transfer. NxGEN Vector Solutions will gain a second AAV gene therapy platform—an immunosuppressive therapy to treat immune or inflammatory diseases or conditions—and plans to continue to develop the technology. NxGEN Vector Solutions is collaborating with Robert Jarvik, MD, the inventor of the artificial heart and founder of Jarvik Heart, and Douglas McCarty, PhD, senior director of vector development at Pfizer, on this platform.
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The title of the abstract is CpG-Motifs within AAV Vectors Trigger Immune Activation upon Hepatic Gene Transfer. The results demonstrate that CpG depletion of AAV vector genomes provide an avenue to improve the clinical outcome of AAV-mediated gene transfer by preventing elimination of transgene product expressing hepatocytes by vector-induced T cell responses.
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.
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