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.
November 19th, 2020 - November 19, 2020 – You’ve probably seen the plethora of papers and presentations in 2020 demonstrating that stable transgene expression in human clinical trials is dependent on the AAV vector genome CpG motifs. This confirms the preclinical studies performed nearly 8 years ago by Dr. Susan Faust and Dr. Joseph Rabinowitz–both members of NxGEN Vector Solutions–and pioneers of CpG-depleted AAV vectors (NxGEN Technology). The desirability of CpG depletion of AAV vectors for the purpose of reducing the immune response to the vector and establishing long-term transgene expression is very hot in the manufacturing sector and of great interest to gene therapists.
